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Wang X, Wu YX, Hu WP, Zhang J. Incidence and risk factors of serious infections occurred in patients with lung cancer following immune checkpoint blockade therapy. BMC Cancer 2025; 25:307. [PMID: 39979857 PMCID: PMC11843754 DOI: 10.1186/s12885-025-13743-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/12/2024] [Accepted: 02/14/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) therapy has revolutionized anti-cancer therapy, with lung cancer exhibiting sustained clinical responses to it. However, there remains a lack of research into the risk factors of serious infections in patients with lung cancer following ICIs therapy. Therefore, we aimed to investigate the incidence and risk factors of serious infections in these patients. METHODS Medical records were retrospectively collected and reviewed from 710 patients with lung cancer receiving ICIs therapy at Zhongshan Hospital between January 2021 and February 2023. Serious infections were defined as infections requiring hospitalization or parenteral antimicrobials occurring at any time from the initiation of the ICIs therapy to 3 months after its discontinuation. RESULTS Among the study population, 191 patients had suffered from serious infections, with an overall infection rate of 26.90% during an average follow-up period of (432.62 ± 377.09) days. The predominant site of infection was the lung (75.61%), and the most prevalent pathogens were bacteria (85.07%), followed by Mycobacterium tuberculosis (6.47%), viruses (4.98%), and fungi (3.48%). In addition to chronic obstructive pulmonary disease (COPD), asthma, and systemic glucocorticoids use, low lymphocyte count and CD4/CD8 ratio were identified as independent risk factors (all p < 0.05). CONCLUSION Laboratory parameters may serve as strong predictors for serious infections in patients with lung cancer following ICIs therapy. Chronic airway diseases including COPD and asthma should be managed effectively. Systemic glucocorticoids should be used prudently to prevent serious infections in these patients.
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Affiliation(s)
- Xiao Wang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yu-Xiao Wu
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Department of Respiratory and Critical Care Medicine, Central Hospital affiliated to Shandong First Medical University, Jinan, 250014, China
| | - Wei-Ping Hu
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Jing Zhang
- Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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Cuttone G, La Via L, Pappalardo F, Sorbello M, Paternò DS, Piattoli M, Gregoretti C, Misseri G. An Updated Review on the Use of Noninvasive Respiratory Supports in the Management of Severe Asthma Exacerbations. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:328. [PMID: 40005443 DOI: 10.3390/medicina61020328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 12/29/2024] [Revised: 01/29/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025]
Abstract
Asthma is a reversible clinical condition characterized by airway obstruction due to bronchial smooth muscle contraction, inflammation and a hypersecretive state. Severe asthma exacerbations (SAE) may be a part of the natural history of this condition. Patients presenting with SAE are at higher risk of recurrent attacks, often nonresponsive to medical therapy and eventually requiring invasive mechanical ventilation (MV). The use of noninvasive respiratory supports (NRSs) may be beneficial in patients with SAE who are at risk of developing acute respiratory failure (ARF). However, their application is insufficiently supported by the evidence, as reports on their application in asthmatic patients are scarce and only a few retrospective studies with a limited number of participants have been published to date. This review discusses the potentialities of NRS in the treatment of SAE, with reference to the pathophysiological background and future perspectives on their use in asthma management.
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Affiliation(s)
- Giuseppe Cuttone
- Department of Anaesthesia and Trauma Center, Azienda Ospedaliera "Ospedali Riuniti Villa Sofia-Cervello", 90146 Palermo, Italy
| | - Luigi La Via
- Department of Anaesthesia and Intensive Care 1, University Hospital Policlinico "G. Rodolico-San Marco", 95123 Catania, Italy
| | - Federico Pappalardo
- Faculty of Medicine and Surgery, University of Enna "Kore", 94100 Enna, Italy
- Policlinico "G.B. Morgagni", 95125 Catania, Italy
| | - Massimiliano Sorbello
- Faculty of Medicine and Surgery, University of Enna "Kore", 94100 Enna, Italy
- Department of Anaesthesia and Intensive Care, Giovanni Paolo II Hospital, 97100 Ragusa, Italy
| | | | - Matteo Piattoli
- Faculty of Medicine and Dentistry, Università degli Studi di Roma "La Sapienza", 00185 Rome, Italy
- Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences "UniCamillus", 00131 Rome, Italy
| | - Cesare Gregoretti
- Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences "UniCamillus", 00131 Rome, Italy
- Department of Anaesthesia and Intensive Care, Fondazione Istituto "G. Giglio" Cefalù, 90015 Palermo, Italy
| | - Giovanni Misseri
- Department of Anaesthesia and Intensive Care, Fondazione Istituto "G. Giglio" Cefalù, 90015 Palermo, Italy
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Choi, JP, Kim, YE, Kim, MK, Kang, MH, Hwang, YK, Yoon, JE, Chang, YS, Kim, SH. Repeated and alternate stimulations with dsRNA and SEB alter responses in macrophages and epithelial cells. World Allergy Organ J 2025; 18:101026. [PMID: 39925983 PMCID: PMC11804812 DOI: 10.1016/j.waojou.2025.101026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2024] [Revised: 12/05/2024] [Accepted: 01/08/2025] [Indexed: 02/11/2025] Open
Abstract
Introduction The innate immune system is activated by foreign molecules via pattern recognition receptors and other surveillance systems, producing diverse cytokines that recruit and activate other immune cells. Recent studies have shown that once activated by foreign molecules, the innate immune system exhibits altered responses upon subsequent exposure to the same or different infectious agents, such as lipopolysaccharides (LPS) or bacteria. However, as these alterations in response to viral infection and staphylococcal enterotoxin B (SEB) in the airways have not been fully elucidated, we focused on the changes in immune responses induced by repeated stimulation of macrophages and epithelial cells with foreign molecules. Methods THP-1-derived macrophages and BEAS-2B epithelial cells were stimulated with dsRNA (double-stranded RNA) or SEB and cultured in fresh complete medium for 4 days. Subsequently, the cells were re-stimulated with different doses of dsRNA or SEB, and the cytokine and signal phosphorylation levels were evaluated. Results Repeated stimulation with high dose of dsRNA or SEB, induced an increase in IL-10, CCL2, CCL22, CCL24, CXCL10, and CXCL11 in macrophages, while only repeated stimulation with dsRNA stimulation resulted in an increase in IL-6, CCL2, CCL5, CCL24, CXCL11, and TGF-β in epithelial cells. Cross-stimulation with SEB-dsRNA induced an increase in CCL5, CCL20, CCL22, CCL24, CXCL10, and CXCL11 levels in macrophages. However, in epithelial cells, SEB-dsRNA stimulation increased the levels of CCL5, CXCL11, and TGF-β, while dsRNA-SEB stimulation elevated CCL1, CCL20, CXCL10, and CXCL11. These cytokine changes were driven by distinct phosphorylation patterns in macrophages and epithelial cells, depending on the type and intensity of stimuli. Conclusion Repeated stimulation with the same or cross-over stimuli induced alterations in the immune response of macrophages and epithelial cells. These observations indicated that persistent airway stimulation can lead to changes in airway inflammation, potentially leading to asthma.
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Affiliation(s)
- Jun-Pyo Choi,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yae-Eun Kim,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Min-Kyung Kim,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Mi-Hyun Kang,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yu-Kyoung Hwang,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jeong-Eun Yoon,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Yoon-Seok Chang,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sae-Hoon Kim,
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
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Yaeger MJ, Leuenberger L, Shaikh SR, Gowdy KM. Omega-3 Fatty Acids and Chronic Lung Diseases: A Narrative Review of Impacts from Womb to Tomb. J Nutr 2025; 155:453-464. [PMID: 39424068 DOI: 10.1016/j.tjnut.2024.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/19/2024] [Revised: 08/16/2024] [Accepted: 10/11/2024] [Indexed: 10/21/2024] Open
Abstract
The lungs are a mucosal organ constantly exposed to potentially harmful compounds and pathogens. Beyond their role in gas exchange, they must perform a well-orchestrated protective response against foreign invaders. The lungs identify these foreign compounds, respond to them by eliciting an inflammatory response, and restore tissue homeostasis after inflammation to ensure the lungs continue to function. In addition, lung function can be affected by genetics, environmental exposures, and age, leading to pulmonary diseases that infringe on quality of life. Recent studies indicate that diet can influence pulmonary health including the incidence and/or severity of lung diseases. Specifically, long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have gained attention because of their potential to reduce inflammation and promote resolution of inflammation. Docosahexaenoic acid and eicosapentaenoic acid are 2 potentially beneficial n-3 PUFAs primarily acquired through dietary intake. Here we review current literature examining the role of n-3 PUFAs and the biological mechanisms by which these fatty acids alter the incidence and pathologies of chronic lung diseases including asthma, chronic obstructive pulmonary disease, and interstitial lung disease. We also highlight the role of n-3 PUFAs in vulnerable populations such as pre/postnatal children, those with obesity, and the elderly. Lastly, we review the impact of n-3 PUFA intake and supplementation to evaluate if increasing consumption can mitigate mechanisms driving chronic lung diseases.
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Affiliation(s)
- Michael J Yaeger
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, United States.
| | - Laura Leuenberger
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, United States
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kymberly M Gowdy
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, United States.
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Sheng F, Li M, Yu JM, Yang SY, Zou L, Yang GJ, Zhang LL. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential. Front Immunol 2025; 16:1533335. [PMID: 39925809 PMCID: PMC11802536 DOI: 10.3389/fimmu.2025.1533335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/23/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.
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Affiliation(s)
- Feiya Sheng
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Mi Li
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Jia-Mei Yu
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Si-Yu Yang
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro−Products, Ningbo University, Ningbo, China
| | - Le-Le Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China
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Zhou J, Bränn E, Hysaj E, Seitz C, Hou Y, Song H, Bergstedt J, Chang Z, Fang F, Pedersen NL, Valdimarsdóttir UA, Lu D. Association between inflammatory biomarkers before pregnancy and risk of perinatal depression: A prospective cohort study of 4483 women in Sweden. J Affect Disord 2025; 368:477-486. [PMID: 39303887 DOI: 10.1016/j.jad.2024.09.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 06/18/2024] [Revised: 09/16/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
AIM Perinatal depression (PND) is a global health concern, affecting millions of childbearing women. Emerging data suggest that inflammation may play a role in the development of PND. Peripheral blood inflammatory biomarkers before pregnancy are widely tested in clinical practice at minimum cost, yet their potential role in PND risk remains unknown. METHODS We conducted a prospective cohort study of 4483 birthing women during 2009-2021 within the LifeGene study with linkage to Swedish registers. Peripheral blood inflammatory biomarkers were profiled at baseline. Cases of PND were identified using validated tools or clinical diagnosis from subsequent pregnancies and postpartum periods. Logistic regression models were employed to assess the associations of each inflammatory biomarker (z scored) with PND. RESULTS We identified 495 (11.0 %) PND cases with an average age of 29.2 years. Pre-pregnancy platelet-to-lymphocyte ratio (PLR) was positively associated [OR, 95 % CI:1.14(1.01,1.27)], while lymphocyte count was inversely associated [OR, 95 % CI: 0.89(0.80,0.98)] with PND. A dose-response relationship was indicated for both PLR and lymphocytes when analyzed in categories based on tertile distribution. These associations appeared more pronounced for postpartum depression than antepartum depression and were independent of psychiatric comorbidities. CONCLUSION With implications for future mechanistic research, these findings suggest that blood levels of lymphocytes and PLR before pregnancy are associated with subsequent risk of PND in a dose-response manner.
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Affiliation(s)
- Jing Zhou
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Emma Bränn
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Elgeta Hysaj
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Christina Seitz
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ying Hou
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Huan Song
- West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jacob Bergstedt
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Zheng Chang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Fang Fang
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Unnur A Valdimarsdóttir
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Donghao Lu
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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Mapindra MP, Castillo-Hernandez T, Clark H, Madsen J. Surfactant Protein-A and its immunomodulatory roles in infant respiratory syncytial virus infection: a potential for therapeutic intervention? Am J Physiol Lung Cell Mol Physiol 2025; 328:L179-L196. [PMID: 39662519 DOI: 10.1152/ajplung.00199.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/03/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 12/13/2024] Open
Abstract
The vast majority of early-life hospital admissions globally highlight respiratory syncytial virus (RSV), the leading cause of neonatal lower respiratory tract infections, as the major culprit behind the poor neonatal outcomes following respiratory infections. Unlike those of older children and adults, the immune system of neonates looks rather unique, therefore mostly counting on the innate immune system and antibodies of maternal origins. The collaborations between cells and immune compartments during infancy inclines bias toward a T-helper 2 (Th2) immune profile and thereby away from a T-helper 1 (Th1) immune response. What makes it more problematic is that RSV infection also tends to elicit a stronger Th2-biased immune response and drive an aberrant allergy-like inflammation. It is thus evident how RSV infections potentially pave the way for wheezing recurrences and childhood asthma later in life. Surfactant, the essential lung substance for normal breathing processes in mammals, has immunomodulatory properties including lung collectins such as Surfactant Protein-A (SP-A), which is the most abundant protein component of surfactant, and also Surfactant Protein-D (SP-D). Deficiency of SP-A and SP-D has been found to be associated with impaired pathogen clearance and exacerbated immune responses during infections. We therefore conducted a review of the literature to describe pathomechanisms of RSV infections during blunted neonatal immunity potentially facilitating allergy-like inflammatory events within the developing lungs and highlight the potential protective role of the humoral collectin SP-A to mitigate these in the "early in life" pulmonary immune system.
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Affiliation(s)
- Muhammad Pradhika Mapindra
- Targeted Lung Immunotherapy Group, Neonatology Department, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
| | - Tania Castillo-Hernandez
- Targeted Lung Immunotherapy Group, Neonatology Department, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
| | - Howard Clark
- Targeted Lung Immunotherapy Group, Neonatology Department, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
| | - Jens Madsen
- Targeted Lung Immunotherapy Group, Neonatology Department, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom
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Zhang Z, He Y, Liu H, Liu Y, Wu T, Li R, Wang Y, Ma W. NLRP3 regulates ferroptosis via the JAK2/STAT3 pathway in asthma inflammation: Insights from in vivo and in vitro studies. Int Immunopharmacol 2024; 143:113416. [PMID: 39426227 DOI: 10.1016/j.intimp.2024.113416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/09/2024] [Revised: 09/15/2024] [Accepted: 10/13/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND Ferroptosis, an iron-dependent form of cell death, plays a pivotal role in the pathologic progression of asthma. Electroacupuncture (EA) has demonstrated considerable efficacy in mitigating asthma airway inflammation, although its underlying mechanisms remain partially elucidated. METHODS We investigated the regulatory effect of NLRP3 on ferroptosis using a lipopolysaccharide (LPS)-induced inflammation model in BEAS-2B cells, where NLRP3 expression was modulated with si-RNA and overexpression plasmids. The levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 were quantified. We also assessed NLRP3 and JAK2/STAT3 pathway-related proteins, and evaluated lipid peroxidation, mitochondrial membrane potential (ΔΨm), and antioxidant system functionality. In vivo, we examined the impact of EA on ferroptosis and airway inflammation by modulating NLRP3 activation. Asthma inflammation severity was evaluated using H&E, Masson, and PAS staining, alongside ELISA. NLRP3 and JAK2/STAT3 pathway-related proteins, as well as ferroptosis indicators, were also analyzed. The mechanism by which NLRP3 activates ferroptosis was investigated through in vitro assays. RESULTS LPS exposure resulted in increased intracellular inflammatory cytokines, and activation of the NLRP3 and JAK2/STAT3 pathways, leading to enhanced lipid peroxidation, decreased ΔΨm, and disruption of antioxidant system balance, ultimately inducing ferroptosis. Si-NLRP3 countered the effects of LPS, whereas oe-NLRP3 exacerbated symptoms. In vivo studies revealed that EA reduced airway inflammation, inhibited NLRP3 activation, and decreased phosphorylation of JAK2/STAT3, effectively lowering ferroptosis-related indicators. Utilizing JAK2/STAT3 activators and inhibitors, we confirmed that NLRP3 mediates ferroptosis via the JAK2/STAT3 pathway. CONCLUSIONS EA alleviates HDM-induced asthma, primarily through the inhibition of NLRP3 activation, which modulates the JAK2/STAT3 pathway and mediates ferroptosis.
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Affiliation(s)
- Zhengze Zhang
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Yuewen He
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Hao Liu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Yurui Liu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Tong Wu
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Ruogen Li
- The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China
| | - Yong Wang
- Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China; State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
| | - Wuhua Ma
- Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, PR China.
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Quan J, Xie D, Li Z, Yu X, Liang Z, Chen Y, Wu L, Huang D, Lin L, Fan L. Luteolin alleviates airway remodeling in asthma by inhibiting the epithelial-mesenchymal transition via β-catenin regulation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156090. [PMID: 39393303 DOI: 10.1016/j.phymed.2024.156090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 04/19/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/13/2024]
Abstract
BACKGROUND Asthma is a prevalent long-term inflammatory condition that causes airway inflammation and remodeling. Increasing evidence indicates that epithelial-mesenchymal transition (EMT) holds a prominent implication in airway reconstruction in patients with asthma. Flavonoids obtained from Chinese Materia Medica (CMM), such as Luteolin (Lut), exhibit various beneficial effects in various asthma models. Lut has been shown to mitigate various asthma symptoms, including airway inflammation, hyperresponsiveness, bronchoconstriction, excessive mucus production, pulmonary autophagy, and neutrophilic asthma. However, whether flavonoids can suppress EMT-associated airway remodeling in asthma and the fundamental mechanisms involved remain unclear, with no studies specifically addressing Lut in this context. PURPOSE To evaluate the inhibition of airway remodeling in asthma by Lut and its potential mechanisms, while examining the significance of β-catenin in this process through cellular and animal studies. METHODS A BEAS-2B cell model stimulated by lipopolysaccharide (LPS) was established in vitro. Wound closure and Transwell assays were utilized to assess the cellular migratory ability. EMT- and fibrosis-related markers in LPS-stimulated cells were evaluated using RT-qPCR and western blotting. The status of the β-catenin/E-cadherin and β-catenin destruction complexes was evaluated using western blotting, immunofluorescence (IF) staining, and co-immunoprecipitation (Co-IP) analysis. The regulatory function of Lut in β-catenin-dependent EMT was further validated by β-catenin overexpression with adenovirus transduction and siRNA-mediated knockdown of β-catenin. Moreover, the counts of different types of bronchoalveolar lavage fluid (BALF) inflammatory cells from mice with asthma induced by ovalbumin (OVA) were evaluated in vivo using Congo red staining. Hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining were used to evaluate collagen deposition, mucus production, and inflammation in murine lung tissues. Western blotting and immunohistochemistry (IHC) assays were used to assess EMT- and fibrosis-related markers in the lung tissues in vivo. RESULT Six naturally derived flavonoids, including Lut, attenuated cell migration and prevented EMT in LPS-treated BEAS-2B cells. Moreover, Lut suppressed TGF-β1, MMP-9, fibronectin (FN), and α-smooth muscle actin (α-SMA) levels in LPS-stimulated BEAS-2B cells. Additionally, Lut downregulated the levels of β-catenin by modulating the β-catenin/E-cadherin and β-catenin destruction complexes, highlighting the pivotal role of β-catenin in EMT inhibition by Lut in LPS-stimulated BEAS-2B cells. Furthermore, Lut suppressed airway inflammation and attenuated EMT-associated airway remodeling through β-catenin blockade in OVA-induced asthmatic mice. The bronchial wall thickness notably reduced from 37.24 ± 4.00 μm in the asthmatic model group to 30.06 ± 4.40 μm in the Lut low-dose group and 24.69 ± 2.87 μm in the Lut high-dose group. CONCLUSION According to our current understanding, this research is the first to reveal that Lut diminishes airway remodeling in asthma by inhibiting EMT via β-catenin regulation, thereby filling a research gap concerning Lut and flavonoids. These results provide a theoretical basis for treating asthma with anti-asthmatic CMM, as well as a candidate and complementary therapeutic approach to treat asthma.
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Affiliation(s)
- Jingyu Quan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Zihong Li
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Xuhua Yu
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Ziyao Liang
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Yuanbin Chen
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Lei Wu
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China
| | - Donghui Huang
- Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, China.
| | - Lin Lin
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China.
| | - Long Fan
- State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Respiratory Disease, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou, China.
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10
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Fu J, Zou Y, Luo L, Zhang J, Wang X, Zhang D. Associations of advanced lung cancer inflammation index with all-cause and respiratory disease mortality in adults with asthma: NHANES, 1999-2018. Sci Rep 2024; 14:29693. [PMID: 39613823 DOI: 10.1038/s41598-024-80983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/28/2024] [Accepted: 11/22/2024] [Indexed: 12/01/2024] Open
Abstract
The Advanced Lung Cancer Inflammation Index (ALI) represents both the inflammatory and nutritional status of the host, but its link with mortality in asthma patients is uncertain. The purpose of this study was to look at the relationship between ALI levels and all-cause and respiratory disease mortality in asthmatic patients. We conducted our research using cohort data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The National Death Index was used to calculate mortality until December 31, 2019. The study employed multivariate logistic regression to look into the relationship between ALI levels and asthma prevalence. Weighted Kaplan-Meier and multivariate-adjusted Cox analyses were utilized for investigating the relationship between ALI levels and all-cause and respiratory disease mortality in individuals with asthma. A restricted cubic spline (RCS) analysis was used to assess their nonlinear relationship. Subgroup and sensitivity analyses were also performed to evaluate the robustness of the results that were obtained. We enrolled 40,497 people in our study, and 5,469 of them had asthma, representing a 14% prevalence. A median follow-up of 11.19 (9.38, 14.29) years revealed 109 fatalities from respiratory diseases and 724 deaths from all causes. After correcting for several covariates, there was no longer any link (P-trend = 0.2) between ALI levels and the prevalence of asthma. When compared to the lowest quartile, the highest quartile of ALI levels was substantially linked to a lower risk of mortality from respiratory diseases and all causes (all P-trend < 0.001). In the RCS regression model, the relationship between ALI level and both all-cause and respiratory disease mortality in asthmatic participants was nonlinear, with P for nonlinearity of 0.006 and 0.015, respectively. We also discovered that the probability of mortality from respiratory disease decreased progressively to a nadir at an ALI level of 109.13 and then increased as the ALI level increased. Multiple subgroup and sensitivity analyses revealed that ALI was consistently related to lower all-cause and respiratory disease mortality in asthma patients. Our findings suggest that ALI is associated with a reduced risk of all-cause and respiratory disease mortality in asthma patients.
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Affiliation(s)
- Jixin Fu
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Qingdao University, No. 3, Mishandong Road Xi, Wendeng District, Weihai, 264200, Shandong Province, China
| | - Yanan Zou
- Department of Anesthesiology, Weihai Central Hospital, Qingdao University, Weihai, Shandong, China
| | - Lei Luo
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University (Pingdu), Shandong, China
| | - Jian Zhang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University (Pingdu), Shandong, China
| | - Xinjian Wang
- Department of Gastrointestinal Surgery, Weihai Central Hospital, Qingdao University, No. 3, Mishandong Road Xi, Wendeng District, Weihai, 264200, Shandong Province, China.
| | - Dianliang Zhang
- Center of Colon and Rectum, Qingdao Municipal Hospital, Qingdao University, No. 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China.
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11
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Cui L, Song X, Peng Y, Shi M. Clinical Significance of Combined Detection of CCL22 and IL-1 as Potential New Bronchial Inflammatory Mediators in Children's Asthma. Immun Inflamm Dis 2024; 12:e70043. [PMID: 39508721 PMCID: PMC11542289 DOI: 10.1002/iid3.70043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/05/2024] [Revised: 09/19/2024] [Accepted: 10/01/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUNDS Severe asthma is a significant health burden because children with severe asthma are vulnerable to medication-related side effects, life-threatening deterioration, and impaired quality of life. However, there is a lack of data to elucidate the role of inflammatory variables in asthma. This study aimed to compare the levels of inflammatory factors in serum and sputum in children with acute and stable asthma to those in healthy children and the ability to predict clinical response to azithromycin therapy. METHODS This study recruited 95 individuals aged 1-3 years old and collected data from January 2018 to 2020. We examined serum and sputum inflammatory factors and constructed the least absolute shrinkage and selection operator (LASSO) model. Predictive models were constructed through multifactor logistic regression and presented in the form of column-line plots. The performance of the column-line diagrams was measured by subject work characteristics (ROC) curves, calibration plots, and decision curve analysis (DCA). Then, filter-paper samples were collected from 45 children with acute asthma who were randomly assigned to receive either azithromycin (10 mg/kg, n = 22) or placebo (n = 23). Pretreatment levels of immune mediators were then analyzed and compared with clinical response to azithromycin therapy. RESULTS Of the 95 eligible participants, 21 (22.11%) were healthy controls, 29 (30.53%) had stable asthma, and 45 (47.37%) had acute asthma. The levels of interferon-γ (IFN-γ), tumor necrosis factor-a (TNF-α), chemokine CCL22 (CCL22), interleukin 12 (IL-12), chemokine CCL4 (CCL4), chemokine CCL2 (CCL2), and chemokine CCL13 (CCL13)were significantly higher in the acute asthma group than in the stable asthma group. A logistic regression analysis was performed using CCL22 and IL-1 as independent variables. Additionally, IFN-γ, TNF-α, IL-1, IL-13, and CCL22 were identified in the LASSO model. Finally, we found that CCL22 and IL-1 were more responsive in predicting the response to azithromycin treatment. CONCLUSION Our results show that CCL22 and IL-1 are both representative markers during asthma symptom exacerbations and an immune mediator that can predict response to azithromycin therapy.
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Affiliation(s)
- Lei Cui
- Department of PediatricsPeople's Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, First Affliated Hospital of Jishou UniversityJishouChina
| | - Xiaozhen Song
- Department of PediatricsPeople's Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, First Affliated Hospital of Jishou UniversityJishouChina
| | - Yanping Peng
- Department of PediatricsPeople's Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, First Affliated Hospital of Jishou UniversityJishouChina
| | - Min Shi
- Department of PediatricsPeople's Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, First Affliated Hospital of Jishou UniversityJishouChina
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12
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Hansi RK, Ranjbar M, Whetstone CE, Gauvreau GM. Regulation of Airway Epithelial-Derived Alarmins in Asthma: Perspectives for Therapeutic Targets. Biomedicines 2024; 12:2312. [PMID: 39457624 PMCID: PMC11505104 DOI: 10.3390/biomedicines12102312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/23/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Asthma is a chronic respiratory condition predominantly driven by a type 2 immune response. Epithelial-derived alarmins such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 orchestrate the activation of downstream Th2 cells and group 2 innate lymphoid cells (ILC2s), along with other immune effector cells. While these alarmins are produced in response to inhaled triggers, such as allergens, respiratory pathogens or particulate matter, disproportionate alarmin production by airway epithelial cells can lead to asthma exacerbations. With alarmins produced upstream of the type 2 inflammatory cascade, understanding the pathways by which these alarmins are regulated and expressed is critical to further explore new therapeutics for the treatment of asthmatic patients. This review emphasizes the critical role of airway epithelium and epithelial-derived alarmins in asthma pathogenesis and highlights the potential of targeting alarmins as a promising therapeutic to improve outcomes for asthma patients.
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Affiliation(s)
| | | | | | - Gail M. Gauvreau
- Division of Respirology, Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; (R.K.H.); (M.R.); (C.E.W.)
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13
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Xie C, Yang J, Gul A, Li Y, Zhang R, Yalikun M, Lv X, Lin Y, Luo Q, Gao H. Immunologic aspects of asthma: from molecular mechanisms to disease pathophysiology and clinical translation. Front Immunol 2024; 15:1478624. [PMID: 39439788 PMCID: PMC11494396 DOI: 10.3389/fimmu.2024.1478624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/10/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024] Open
Abstract
In the present review, we focused on recent translational and clinical discoveries in asthma immunology, facilitating phenotyping and stratified or personalized interventions for patients with this condition. The immune processes behind chronic inflammation in asthma exhibit marked heterogeneity, with diverse phenotypes defining discernible features and endotypes illuminating the underlying molecular mechanisms. In particular, two primary endotypes of asthma have been identified: "type 2-high," characterized by increased eosinophil levels in the airways and sputum of patients, and "type 2-low," distinguished by increased neutrophils or a pauci-granulocytic profile. Our review encompasses significant advances in both innate and adaptive immunities, with emphasis on the key cellular and molecular mediators, and delves into innovative biological and targeted therapies for all the asthma endotypes. Recognizing that the immunopathology of asthma is dynamic and continuous, exhibiting spatial and temporal variabilities, is the central theme of this review. This complexity is underscored through the innumerable interactions involved, rather than being driven by a single predominant factor. Integrated efforts to improve our understanding of the pathophysiological characteristics of asthma indicate a trend toward an approach based on disease biology, encompassing the combined examination of the clinical, cellular, and molecular dimensions of the disease to more accurately correlate clinical traits with specific disease mechanisms.
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Affiliation(s)
- Cong Xie
- Department of Endocrinology and Clinical Immunology, Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Department of Integrative Medicine, Huashan Hospital Affiliated to Fudan University, Fudan Institutes of Integrative Medicine, Fudan University Shanghai Medical College, Shanghai, China
| | - Jingyan Yang
- The Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Aman Gul
- Department of Integrative Medicine, Huashan Hospital Affiliated to Fudan University, Fudan Institutes of Integrative Medicine, Fudan University Shanghai Medical College, Shanghai, China
- Department of Respiratory Medicine, Uyghur Medicines Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, China
- College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Yifan Li
- Department of Integrative Medicine, Huashan Hospital Affiliated to Fudan University, Fudan Institutes of Integrative Medicine, Fudan University Shanghai Medical College, Shanghai, China
| | - Rui Zhang
- Department of Pulmonary and Critical Care Medicine, Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, China
| | - Maimaititusun Yalikun
- Department of Integrative Medicine, Huashan Hospital Affiliated to Fudan University, Fudan Institutes of Integrative Medicine, Fudan University Shanghai Medical College, Shanghai, China
| | - Xiaotong Lv
- Department of Cardiology, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuhan Lin
- Department of Endocrinology and Clinical Immunology, Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Qingli Luo
- Department of Integrative Medicine, Huashan Hospital Affiliated to Fudan University, Fudan Institutes of Integrative Medicine, Fudan University Shanghai Medical College, Shanghai, China
| | - Huijuan Gao
- Department of Endocrinology and Clinical Immunology, Yuquan Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
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14
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Han S, Kim B, Hyeon DY, Jeong D, Ryu J, Nam JS, Choi YH, Kim BR, Park SC, Chung YW, Shin SJ, Lee JY, Kim JK, Park J, Lee SW, Kim TB, Cheon JH, Cho HJ, Kim CH, Yoon JH, Hwang D, Ryu JH. Distinctive CD39 +CD9 + lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis. Nat Commun 2024; 15:8628. [PMID: 39366998 PMCID: PMC11452667 DOI: 10.1038/s41467-024-53038-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2023] [Accepted: 09/30/2024] [Indexed: 10/06/2024] Open
Abstract
The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39+CD9+ IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39+CD9+ IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39+CD9+ IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma.
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Affiliation(s)
- Seunghan Han
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Bomin Kim
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Do Young Hyeon
- School of Biological Sciences, Seoul National University, Seoul, Korea
| | - Daeun Jeong
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jaechan Ryu
- Institut Pasteur, Microenvironment and Immunity Unit, Paris, France
| | - Jae-Sung Nam
- Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon Ha Choi
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Bo-Ram Kim
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Chul Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Youn Wook Chung
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Jae Shin
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - June-Yong Lee
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
- Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Kyoung Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Korea
| | - Jihye Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sei Won Lee
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Bum Kim
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung-Ju Cho
- Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Chang-Hoon Kim
- Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Joo-Heon Yoon
- Department of Otorhinolaryngology and Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Korea.
| | - Daehee Hwang
- School of Biological Sciences, Seoul National University, Seoul, Korea.
| | - Ji-Hwan Ryu
- Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Korea.
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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15
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Zou S, Meng F, Xu G, Yu R, Yang C, Wei Q, Xue Y. Identification of candidate genes and molecular mechanisms related to asthma progression using bioinformatics. Sleep Breath 2024; 28:2237-2246. [PMID: 39088141 PMCID: PMC11450000 DOI: 10.1007/s11325-024-03122-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/27/2024] [Revised: 07/18/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Asthma is a heterogeneous disorder. This study aimed to identify changes in gene expression and molecular mechanisms associated with moderate to severe asthma. METHODS Differentially expressed genes (DEGs) were analyzed in GSE69683 dataset among moderate asthma and its controls as well as between severe asthma and moderate asthma. Key module genes were identified via co-expression analysis, and the molecular mechanism of the module genes was explored through enrichment analysis and gene set enrichment analysis (GSEA). GSE89809 was used to verify the characteristic genes related to moderate and severe asthma. RESULTS Accordingly, 2540 DEGs were present between moderate asthma and the control group, while 6781 DEGs existed between severe asthma and moderate asthma. These genes were identified into 14 co-expression modules. Module 7 had the highest positive correlation with severe asthma and was recognized to be a key module by STEM. Enrichment analysis demonstrated that the module genes were mainly involved in oxidative stress-related signaling pathways. The expression of HSPA1A, PIK3CG and PIK3R6 was associated with moderate asthma, while MAPK13 and MMP9 were associated with severe asthma. The AUC values were verified by GSE89809. Additionally, 322 drugs were predicted to target five genes. CONCLUSION These results identified characteristic genes related to moderate and severe asthma and their corresponding molecular mechanisms, providing a basis for future research.
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Affiliation(s)
- Songbing Zou
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China
| | - Fangchan Meng
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China
| | - Guien Xu
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China
| | - Rongchang Yu
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China
| | - Chaomian Yang
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China
| | - Qiu Wei
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China.
| | - Yanlong Xue
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Nanning, Guangxi, China.
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16
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Christopoulou ME, Aletras AJ, Papakonstantinou E, Stolz D, Skandalis SS. WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD. Int J Mol Sci 2024; 25:10049. [PMID: 39337534 PMCID: PMC11432718 DOI: 10.3390/ijms251810049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/08/2024] [Revised: 09/12/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Recent advancements highlight the intricate interplay between the extracellular matrix (ECM) and immune responses, notably in respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). The ECM, a dynamic structural framework within tissues, orches-trates a plethora of cellular processes, including immune cell behavior and tissue repair mecha-nisms. WNT1-inducible-signaling pathway protein 1 (WISP1), a key ECM regulator, controls immune cell behavior, cytokine production, and tissue repair by modulating integrins, PI3K, Akt, β-catenin, and mTOR signaling pathways. WISP1 also induces macrophage migration inhibitory factor (MIF) expression via Src kinases and epidermal growth factor receptor (EGFR) activation. MIF, through its wide range of activities, enhances inflammation and tissue restructuring. Rec-ognized for its versatile roles in regulating the immune system, MIF interacts with multiple immune components, such as the NLRP3 inflammasome, thereby sustaining inflammatory pro-cesses. The WISP1-MIF axis potentially unveils complex molecular mechanisms governing im-mune responses and inflammation. Understanding the intricate roles of WISP1 and MIF in the pathogenesis of chronic respiratory diseases such as asthma and COPD could lead to the identi-fication of novel targets for therapeutic intervention to alleviate disease severity and enhance patient outcomes.
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Affiliation(s)
- Maria-Elpida Christopoulou
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Alexios J Aletras
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
| | - Eleni Papakonstantinou
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daiana Stolz
- Clinic of Pneumology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Spyros S Skandalis
- Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26504 Patras, Greece
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17
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Cheon J, Kim B, Lee J, Shin J, Kim TH. Functions and Clinical Applications of Extracellular Vesicles in T H2 Cell-Mediated Airway Inflammatory Diseases: A Review. Int J Mol Sci 2024; 25:9455. [PMID: 39273399 PMCID: PMC11394744 DOI: 10.3390/ijms25179455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/29/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Type 2 airway inflammation (T2AI), driven by type 2 innate lymphoid and CD4+ T helper 2 cells, leads to various diseases and conditions, such as chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma. Emerging evidence suggests the involvement of extracellular vesicles (EVs) in these diseases. In this review, we describe the immunological T2AI pathogenic mechanisms, outline EV characteristics, and highlight their applications in the diagnosis and treatment of T2AI. An extensive literature search was conducted using appropriate strategies to identify relevant articles from various online databases. EVs in various biological samples showed disease-specific characteristics for chronic rhinosinusitis with nasal polyps, allergic rhinitis, and asthma, with some demonstrating therapeutic effects against these conditions. However, most studies have been limited to in vitro and animal models, highlighting the need for further clinical research on the diagnostic and therapeutic applications of EVs.
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Affiliation(s)
- Jaehwan Cheon
- Department of Biomedical Science, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Byoungjae Kim
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Neuroscience Research Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Juhyun Lee
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Jaemin Shin
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Tae Hoon Kim
- Department of Otorhinolaryngology-Head & Neck Surgery, Korea University College of Medicine, Seoul 02841, Republic of Korea
- Mucosal Immunology Institute, Korea University College of Medicine, Seoul 02841, Republic of Korea
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Singh N, Nagar E, Roy D, Arora N. NLRP3/GSDMD mediated pyroptosis induces lung inflammation susceptibility in diesel exhaust exposed mouse strains. Gene 2024; 918:148459. [PMID: 38608794 DOI: 10.1016/j.gene.2024.148459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/14/2023] [Revised: 03/28/2024] [Accepted: 04/08/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND Genetic diversity among species influences the disease severity outcomes linked to air pollution. However, the mechanism responsible for this variability remain elusive and needs further investigation. OBJECTIVE To investigate the genetic factors and pathways linked with differential susceptibility in mouse strains associated with diesel exhaust exposure. METHODS C57BL/6 and Balb/c mice were exposed to diesel exhaust (DE) for 5 days/week for 30 min/day for 8 weeks. Body weight of mice was recorded every week and airway hyperresponsiveness towards DE exposure was recorded after 24 h of last exposure. Mice were euthanised to collect BALF, blood, lung tissues for immunobiochemical assays, structural integrity and genetic studies. RESULTS C57BL/6 mice showed significantly decreased body weight in comparison to Balb/c mice (p < 0.05). Both mouse strains showed lung resistance and damage to elastance upon DE exposure compared to respective controls (p < 0.05) with more pronounced effects in C57BL/6 mice. Lung histology showed increase in bronchiolar infiltration and damage to the wall in C57BL/6 mice (p < 0.05). DE exposure upregulated pro-inflammatory and Th2 cytokine levels in C57BL/6 in comparison to Balb/c mice. C57BL/6 mice showed increase in Caspase-1 and ASC expression confirming activation of downstream pathway. This showed significant activation of inflammasome pathway in C57BL/6 mice with ∼2-fold increase in NLRP3 and elevated IL-1β expression. Gasdermin-D levels were increased in C57BL/6 mice demonstrating induction of pyroptosis that corroborated with IL-1β secretion (p < 0.05). Genetic variability among both species was confirmed with sanger's sequencing suggesting presence of SNPs in 3'UTRs of IL-1β gene influencing expression between mouse strains. CONCLUSIONS C57BL/6 mice exhibited increased susceptibility to diesel exhaust in contrast to Balb/c mice via activation of NLRP3-related pyroptosis. Differential susceptibility between strains may be attributed via SNPs in the 3'UTRs of the IL-1β gene.
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Affiliation(s)
- Naresh Singh
- Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Ekta Nagar
- Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Deepti Roy
- Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India
| | - Naveen Arora
- Allergy and Immunology Section, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Zhang H, Wang L, Zhang A, Wang X, Liao Y, Chen X, Xu X, Yang L, Liu Y, Tang A, Yang P. Oligodeoxynucleotides containing CpG motifs (CpG-ODN) restores immune regulatory functions of airway macrophages of patients with asthma. Immunology 2024; 172:588-599. [PMID: 38634546 DOI: 10.1111/imm.13792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/02/2023] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL-10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL-10 in macrophages of BALF was associated with the levels of asthma-related parameters. The immune-suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL-10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL-10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG.
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Affiliation(s)
- Huanping Zhang
- Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Lihuan Wang
- Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Aizhi Zhang
- Department of Critical Care Medicine, Second Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Xiangyu Wang
- Marshall Laboratory of Biomedical Engineering, Shenzhen University, Shenzhen, China
- Department of Gastroenterology, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yun Liao
- Shenzhen Clinical College, Guangzhou Chinese Traditional Medial & Pharmaceutical University, Guangzhou, China
| | - Xiaoxue Chen
- Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xuejie Xu
- Institute of Allergy & Immunology, Shenzhen University, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University, Shenzhen, China
| | - Litao Yang
- Clinical Laboratory Department of The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Longgang District People's Hospital, Shenzhen, China
| | - Yu Liu
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Aifa Tang
- Department of General Practice Medicine, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Pingchang Yang
- Institute of Allergy & Immunology, Shenzhen University, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University, Shenzhen, China
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20
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Chen Z, Gao N, Wang X, Chen X, Zeng Y, Li C, Yang X, Cai Q, Wang X. Shared genetic aetiology of respiratory diseases: a genome-wide multitraits association analysis. BMJ Open Respir Res 2024; 11:e002148. [PMID: 38834332 PMCID: PMC11163672 DOI: 10.1136/bmjresp-2023-002148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/22/2023] [Accepted: 05/10/2024] [Indexed: 06/06/2024] Open
Abstract
OBJECTIVE This study aims to explore the common genetic basis between respiratory diseases and to identify shared molecular and biological mechanisms. METHODS This genome-wide pleiotropic association study uses multiple statistical methods to systematically analyse the shared genetic basis between five respiratory diseases (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung cancer and snoring) using the largest publicly available genome wide association studies summary statistics. The missions of this study are to evaluate global and local genetic correlations, to identify pleiotropic loci, to elucidate biological pathways at the multiomics level and to explore causal relationships between respiratory diseases. Data were collected from 27 November 2022 to 30 March 2023 and analysed from 14 April 2023 to 13 July 2023. MAIN OUTCOMES AND MEASURES The primary outcomes are shared genetic loci, pleiotropic genes, biological pathways and estimates of genetic correlations and causal effects. RESULTS Significant genetic correlations were found for 10 paired traits in 5 respiratory diseases. Cross-Phenotype Association identified 12 400 significant potential pleiotropic single-nucleotide polymorphism at 156 independent pleiotropic loci. In addition, multitrait colocalisation analysis identified 15 colocalised loci and a subset of colocalised traits. Gene-based analyses identified 432 potential pleiotropic genes and were further validated at the transcriptome and protein levels. Both pathway enrichment and single-cell enrichment analyses supported the role of the immune system in respiratory diseases. Additionally, five pairs of respiratory diseases have a causal relationship. CONCLUSIONS AND RELEVANCE This study reveals the common genetic basis and pleiotropic genes among respiratory diseases. It provides strong evidence for further therapeutic strategies and risk prediction for the phenomenon of respiratory disease comorbidity.
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Affiliation(s)
- Zhe Chen
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University Department of Thoracic Surgery, Changsha, Hunan, China
| | - Ning Gao
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xuanye Wang
- Department of Oncology, Xi'an Jiaotong University Second Affiliated Hospital Department of Oncology, Xi'an, Shaanxi, China
| | - Xiangming Chen
- Department of Orthopaedics, Xiangya Hospital Central South University, Changsha, Hunan, China
| | - YaQi Zeng
- Department of Psychiatry, Brain Hospital of Hunan Province, Changsha, Hunan, China
| | - Cong Li
- Department of Radiology, The Second Xiangya Hospital of Central South University Department of Radiology, Changsha, Hunan, China
| | - Xiahong Yang
- Department of Anesthesiology, The Second Xiangya Hospital of Central South University Department of Anesthesiology, Changsha, Hunan, China
| | - Qidong Cai
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University Department of Thoracic Surgery, Changsha, Hunan, China
| | - Xiang Wang
- Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University Department of Thoracic Surgery, Changsha, Hunan, China
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21
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Mamun AA, Shao C, Geng P, Wang S, Xiao J. Recent advances in molecular mechanisms of skin wound healing and its treatments. Front Immunol 2024; 15:1395479. [PMID: 38835782 PMCID: PMC11148235 DOI: 10.3389/fimmu.2024.1395479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/04/2024] [Accepted: 05/03/2024] [Indexed: 06/06/2024] Open
Abstract
The skin, being a multifaceted organ, performs a pivotal function in the complicated wound-healing procedure, which encompasses the triggering of several cellular entities and signaling cascades. Aberrations in the typical healing process of wounds may result in atypical scar development and the establishment of a persistent condition, rendering patients more vulnerable to infections. Chronic burns and wounds have a detrimental effect on the overall quality of life of patients, resulting in higher levels of physical discomfort and socio-economic complexities. The occurrence and frequency of prolonged wounds are on the rise as a result of aging people, hence contributing to escalated expenditures within the healthcare system. The clinical evaluation and treatment of chronic wounds continue to pose challenges despite the advancement of different therapeutic approaches. This is mainly owing to the prolonged treatment duration and intricate processes involved in wound healing. Many conventional methods, such as the administration of growth factors, the use of wound dressings, and the application of skin grafts, are used to ease the process of wound healing across diverse wound types. Nevertheless, these therapeutic approaches may only be practical for some wounds, highlighting the need to advance alternative treatment modalities. Novel wound care technologies, such as nanotherapeutics, stem cell treatment, and 3D bioprinting, aim to improve therapeutic efficacy, prioritize skin regeneration, and minimize adverse effects. This review provides an updated overview of recent advancements in chronic wound healing and therapeutic management using innovative approaches.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People’s Hospital, Lishui, Zhejiang, China
- Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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22
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Riyaz Tramboo S, Elkhalifa AM, Quibtiya S, Ali SI, Nazir Shah N, Taifa S, Rakhshan R, Hussain Shah I, Ahmad Mir M, Malik M, Ramzan Z, Bashir N, Ahad S, Khursheed I, Bazie EA, Mohamed Ahmed E, Elderdery AY, Alenazy FO, Alanazi A, Alzahrani B, Alruwaili M, Manni E, E. Hussein S, Abdalhabib EK, Nabi SU. The critical impacts of cytokine storms in respiratory disorders. Heliyon 2024; 10:e29769. [PMID: 38694122 PMCID: PMC11058722 DOI: 10.1016/j.heliyon.2024.e29769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/16/2024] [Revised: 04/15/2024] [Accepted: 04/15/2024] [Indexed: 05/03/2024] Open
Abstract
Cytokine storm (CS) refers to the spontaneous dysregulated and hyper-activated inflammatory reaction occurring in various clinical conditions, ranging from microbial infection to end-stage organ failure. Recently the novel coronavirus involved in COVID-19 (Coronavirus disease-19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) has been associated with the pathological phenomenon of CS in critically ill patients. Furthermore, critically ill patients suffering from CS are likely to have a grave prognosis and a higher case fatality rate. Pathologically CS is manifested as hyper-immune activation and is clinically manifested as multiple organ failure. An in-depth understanding of the etiology of CS will enable the discovery of not just disease risk factors of CS but also therapeutic approaches to modulate the immune response and improve outcomes in patients with respiratory diseases having CS in the pathogenic pathway. Owing to the grave consequences of CS in various diseases, this phenomenon has attracted the attention of researchers and clinicians throughout the globe. So in the present manuscript, we have attempted to discuss CS and its ramifications in COVID-19 and other respiratory diseases, as well as prospective treatment approaches and biomarkers of the cytokine storm. Furthermore, we have attempted to provide in-depth insight into CS from both a prophylactic and therapeutic point of view. In addition, we have included recent findings of CS in respiratory diseases reported from different parts of the world, which are based on expert opinion, clinical case-control research, experimental research, and a case-controlled cohort approach.
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Affiliation(s)
- Shahana Riyaz Tramboo
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ahmed M.E. Elkhalifa
- Department of Public Health, College of Health Sciences, Saudi Electronic University, Riyadh, 11673, Saudi Arabia
- Department of Haematology, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Syed Quibtiya
- Department of General Surgery, Sher-I-Kashmir Institute of Medical Sciences, Medical College, Srinagar, 190011, Jammu & Kashmir, India
| | - Sofi Imtiyaz Ali
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Naveed Nazir Shah
- Department of Chest Medicine, Govt. Medical College, Srinagar, 191202, Jammu & Kashmir, India
| | - Syed Taifa
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Rabia Rakhshan
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu & Kashmir, 190006, India
| | - Iqra Hussain Shah
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Muzafar Ahmad Mir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Masood Malik
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Zahid Ramzan
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Nusrat Bashir
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Shubeena Ahad
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
| | - Ibraq Khursheed
- Department of Zoology, Central University of Kashmir, 191201, Nunar, Ganderbal, Jammu & Kashmir, India
| | - Elsharif A. Bazie
- Pediatric Department, Faculty of Medicine, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Elsadig Mohamed Ahmed
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, 61922, Saudi Arabia
- Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti, 1158, Sudan
| | - Abozer Y. Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Fawaz O. Alenazy
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Awadh Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Muharib Alruwaili
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Emad Manni
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Sanaa E. Hussein
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Ezeldine K. Abdalhabib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Al-Qurayyat, Saudi Arabia
| | - Showkat Ul Nabi
- Preclinical Research Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Sher-e-Kashmir University of Agricultural Sciences and Technology (SKUAST-Kashmir), Srinagar, J&K, 190006, India
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23
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Au-Doung PLW, Chan JCH, Kui OYH, Ho MKY, Cheung YT, Lam JKW, Chan HK, Brannan J, Chan KCC, Li AM, Leung SSY. Objective monitoring tools for improved management of childhood asthma. Respir Res 2024; 25:194. [PMID: 38702779 PMCID: PMC11069259 DOI: 10.1186/s12931-024-02817-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/11/2024] [Accepted: 04/18/2024] [Indexed: 05/06/2024] Open
Abstract
Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.
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Affiliation(s)
- Phillip L W Au-Doung
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jason C H Chan
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Oliver Y H Kui
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Marco K Y Ho
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yin Ting Cheung
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jenny K W Lam
- Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, WC1N 1AX, UK
| | - Hak-Kim Chan
- Sydney Pharmacy School, University of Sydney, Sydney, NSW, Australia
| | - John Brannan
- Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, NSW, Australia
| | - Kate C C Chan
- Department of Paediatrics, Prince of Wales Hospital, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Albert M Li
- Department of Paediatrics, Prince of Wales Hospital, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Sharon S Y Leung
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong SAR, China.
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24
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Dai R, Xiang Y, Fang R, Zheng HH, Zhao QS, Wang Y. Lonicerin alleviates ovalbumin-induced asthma of mice via inhibiting enhancer of zeste homolog 2/nuclear factor-kappa B signaling pathway. Exp Anim 2024; 73:154-161. [PMID: 37952975 PMCID: PMC11091354 DOI: 10.1538/expanim.23-0068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/26/2023] [Accepted: 10/31/2023] [Indexed: 11/14/2023] Open
Abstract
Asthma is the most common chronic disease in the respiratory system of children caused by abnormal immunity that responses to common antigens. Lonicerin exerts anti-inflammatory activity in other inflammatory models through targeting enhancer of zeste homolog 2 (EZH2) that is related to asthma. We sought to explore the role and mechanism of lonicerin in regulating allergic airway inflammation. Mice were intraperitoneally injected 10 µg ovalbumin (OVA) on postnatal day 5 (P5) and P10, and then inhaled 3% aerosolized OVA for 10 min every day on P18-20, to establish asthmatic mice model. Lonicerin (10 or 30 mg/kg) was given to mice by intragastric administration on P16-P20. Notably, the administration of lonicerin amended infiltration of inflammatory cells and mucus hypersecretion. OVA-specific IgE level, inflammatory cell count and inflammatory cytokines in asthmatic mice were reduced after lonicerin treatment. Moreover, it suppressed the activity of EZH2 and activation of nuclear factor-kappa B (NF-κB) as evidenced by decreasing tri-methylation of histone H3 at lysine 27 and reducing nuclear translocation of NF-κB p65. In a word, Lonicerin may attenuate asthma by inhibiting EZH2/NF-κB signaling pathway.
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Affiliation(s)
- Rui Dai
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
| | - Yun Xiang
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
| | - Rui Fang
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
| | - Hai-Han Zheng
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
| | - Qing-Song Zhao
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
| | - Yan Wang
- Department of Pediatrics, The Second Affiliated Hospital of Anhui Medical University, No. 678, Furong Road, Hefei 230601, Anhui, P.R. China
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25
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Schenzel A, Geiger A, Nendel E, Yang Z, Krammer S, Leberle A, Brunst AK, Trump S, Mittler S, Rauh M, Geppert CI, Tausche P, Hohenberger K, Rieker RJ, Schieweck O, Zundler S, Finotto S. Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma. Front Nutr 2024; 11:1367864. [PMID: 38757128 PMCID: PMC11097976 DOI: 10.3389/fnut.2024.1367864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/09/2024] [Accepted: 04/15/2024] [Indexed: 05/18/2024] Open
Abstract
Background Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber's fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood. Objective In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated. Methods Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed. Results In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed. Conclusion Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV. Clinical implications Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations.
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Affiliation(s)
- Alicia Schenzel
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Adriana Geiger
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Elvedina Nendel
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Zuqin Yang
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Susanne Krammer
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Anna Leberle
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ann-Kathrin Brunst
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Sonja Trump
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Susanne Mittler
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Manfred Rauh
- Children’s Hospital, Department of Allergy and Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Carol I. Geppert
- Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Patrick Tausche
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katja Hohenberger
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Ralf J. Rieker
- Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
| | - Oliver Schieweck
- Laboratory of Clinic Medicine, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Department of Internal Medicine 1, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Susetta Finotto
- Department of Molecular Pneumology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany
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26
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Candeli N, Dayton T. Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models. Dis Model Mech 2024; 17:dmm050620. [PMID: 38813849 DOI: 10.1242/dmm.050620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 05/31/2024] Open
Abstract
Despite accounting for only ∼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease. Increased PNEC numbers have been reported in a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma. Moreover, PNECs are the primary cell of origin for lung neuroendocrine cancers, which account for 25% of aggressive lung cancers. Recent research has highlighted the crucial roles of PNECs in lung physiology, including in chemosensing, regeneration and immune regulation. Yet, little is known about the direct impact of PNECs on respiratory diseases. In this Review, we summarise the current associations of PNECs with lung pathologies, focusing on how new experimental disease models, such as organoids derived from human pluripotent stem cells or tissue stem cells, can help us to better understand the contribution of PNECs to respiratory diseases.
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Affiliation(s)
- Noah Candeli
- European Molecular Biology Laboratory (EMBL) Barcelona, Tissue Biology and Disease Modelling, 08003, Barcelona, Spain
| | - Talya Dayton
- European Molecular Biology Laboratory (EMBL) Barcelona, Tissue Biology and Disease Modelling, 08003, Barcelona, Spain
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27
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Cen Y, Li F, Li Y, Zhang K, Riaz F, Zhao K, Wei P, Pan F. Dimethyl fumarate alleviates allergic asthma by strengthening the Nrf2 signaling pathway in regulatory T cells. Front Immunol 2024; 15:1375340. [PMID: 38711519 PMCID: PMC11070462 DOI: 10.3389/fimmu.2024.1375340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/23/2024] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Allergic asthma is a widely prevalent inflammatory condition affecting people across the globe. T cells and their secretory cytokines are central to the pathogenesis of allergic asthma. Here, we have evaluated the anti-inflammatory impact of dimethyl fumarate (DMF) in allergic asthma with more focus on determining its effect on T cell responses in allergic asthma. By utilizing the ovalbumin (OVA)-induced allergic asthma model, we observed that DMF administration reduced the allergic asthma symptoms and IgE levels in the OVA-induced mice model. Histopathological analysis showed that DMF treatment in an OVA-induced animal model eased the inflammation in the nasal and bronchial tissues, with a particular decrease in the infiltration of immune cells. Additionally, RT-qPCR analysis exhibited that treatment of DMF in an OVA-induced model reduced the expression of inflammatory cytokine (IL4, IL13, and IL17) while augmenting anti-inflammatory IL10 and Foxp3 (forkhead box protein 3). Mechanistically, we found that DMF increased the expression of Foxp3 by exacerbating the expression of nuclear factor E2-related factor 2 (Nrf2), and the in-vitro activation of Foxp3+ Tregs leads to an escalated expression of Nrf2. Notably, CD4-specific Nrf2 deletion intensified the allergic asthma symptoms and reduced the in-vitro iTreg differentiation. Meanwhile, DMF failed to exert protective effects on OVA-induced allergic asthma in CD4-specific Nrf2 knock-out mice. Overall, our study illustrates that DMF enhances Nrf2 signaling in T cells to assist the differentiation of Tregs, which could improve the anti-inflammatory immune response in allergic asthma.
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Affiliation(s)
- Yanhong Cen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Otolaryngology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Fangfang Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yikui Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Kaimin Zhang
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Farooq Riaz
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Kuaile Zhao
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Research Center for Radiation Oncology, Shanghai, China
- Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Ping Wei
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Otolaryngology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
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Rong Y, Liu F, Zhou H, Yu T, Qin Z, Cao Q, Liu L, Ma X, Qu L, Xu P, Liao X, Jiang Q, Zhang N, Xu X. Reprogramming of arachidonic acid metabolism using α-terpineol to alleviate asthma: insights from metabolomics. Food Funct 2024; 15:4292-4309. [PMID: 38526853 DOI: 10.1039/d3fo04078j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 03/27/2024]
Abstract
Asthma is a chronic inflammatory disorder in airways with typical pathologic features of airway inflammation and mucus hypersecretion. α-Terpineol is a monocyclic terpene found in many natural plants and foods. It has been reported to possess a wide range of pharmacological activities including anti-inflammatory and expectorant effects. However, the role of α-terpineol in asthma and its potential protective mechanism have not been well elucidated. This study is designed to investigate the pharmacological effect and mechanism of α-terpineol on asthmatic mice using the metabolomics platform. A murine model of asthma was established using ovalbumin (OVA) sensitization and then challenged for one week. The leukocyte count and inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), lung histopathology, inflammatory infiltrate and mucus secretion were evaluated. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)-based metabolomics study was performed on lung tissues and serum to explore endogenous small molecule metabolites affected by α-terpineol in asthmatic mice. After α-terpineol treatment, leukocyte count, inflammatory cytokines in the BALF, and peribronchial inflammation infiltration were significantly downregulated. Goblet cell hyperplasia and mucus secretion were attenuated, with the level of Muc5ac in BALF decreased. These results proved the protective effect of α-terpineol against airway inflammation, mucus hypersecretion and Th1/Th2 immune imbalance. To further investigate the underlying mechanisms of α-terpineol in asthma treatment, UPLC-MS/MS-based metabolomics analysis was performed. 26 and 15 identified significant differential metabolites were found in the lung tissues and serum of the control, model and α-terpineol groups, respectively. Based on the above differential metabolites, enrichment analysis showed that arachidonic acid (AA) metabolism was reprogrammed in both mouse lung tissues and serum. 5-Lipoxygenase (5-LOX) and cysteinyl leukotrienes (CysLTs) are the key enzyme and the end product of AA metabolism, respectively. In-depth studies have shown that pretreatment with α-terpineol can alleviate asthma by decreasing the AA level, downregulating the expression of 5-LOX and reducing the accumulation of CysLTs in mouse lung tissues. In summary, this study demonstrates that α-terpineol is a potential agent that can prevent asthma via regulating disordered AA metabolism.
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Affiliation(s)
- Ying Rong
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Fanglin Liu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Hui Zhou
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Tong Yu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Zhaolong Qin
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Qianwen Cao
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Luyao Liu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xiaoge Ma
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Lingbo Qu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Peirong Xu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xinglin Liao
- Nanyang LANHAISENYUAN Medical Technology Ltd, CO. Nanyang, Henan, 473000, China
| | - Qiman Jiang
- Nanyang LANHAISENYUAN Medical Technology Ltd, CO. Nanyang, Henan, 473000, China
| | - Nan Zhang
- Department of Pharmaceutics, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
| | - Xia Xu
- Department of Medical Analysis, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
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Valdez RM, Rivera BN, Chang Y, Pennington JM, Fischer KA, Löhr CV, Tilton SC. Assessing susceptibility for polycyclic aromatic hydrocarbon toxicity in an in vitro 3D respiratory model for asthma. FRONTIERS IN TOXICOLOGY 2024; 6:1287863. [PMID: 38706568 PMCID: PMC11066177 DOI: 10.3389/ftox.2024.1287863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/12/2023] [Accepted: 04/04/2024] [Indexed: 05/07/2024] Open
Abstract
There is increased emphasis on understanding cumulative risk from the combined effects of chemical and non-chemical stressors as it relates to public health. Recent animal studies have identified pulmonary inflammation as a possible modifier and risk factor for chemical toxicity in the lung after exposure to inhaled pollutants; however, little is known about specific interactions and potential mechanisms of action. In this study, primary human bronchial epithelial cells (HBEC) cultured in 3D at the air-liquid interface (ALI) are utilized as a physiologically relevant model to evaluate the effects of inflammation on toxicity of polycyclic aromatic hydrocarbons (PAHs), a class of contaminants generated from incomplete combustion of fossil fuels. Normal HBEC were differentiated in the presence of IL-13 for 14 days to induce a profibrotic phenotype similar to asthma. Fully differentiated normal and IL-13 phenotype HBEC were treated with benzo[a]pyrene (BAP; 1-40 μg/mL) or 1% DMSO/PBS vehicle at the ALI for 48 h. Cells were evaluated for cytotoxicity, barrier integrity, and transcriptional biomarkers of chemical metabolism and inflammation by quantitative PCR. Cells with the IL-13 phenotype treated with BAP result in significantly (p < 0.05) decreased barrier integrity, less than 50% compared to normal cells. The effect of BAP in the IL-13 phenotype was more apparent when evaluating transcriptional biomarkers of barrier integrity in addition to markers of mucus production, goblet cell hyperplasia, type 2 asthmatic inflammation and chemical metabolism, which all resulted in dose-dependent changes (p < 0.05) in the presence of BAP. Additionally, RNA sequencing data showed that the HBEC with the IL-13 phenotype may have increased potential for uncontrolled proliferation and decreased capacity for immune response after BAP exposure compared to normal phenotype HBEC. These data are the first to evaluate the role of combined environmental factors associated with inflammation from pre-existing disease and PAH exposure on pulmonary toxicity in a physiologically relevant human in vitro model.
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Affiliation(s)
- Reese M. Valdez
- Environmental and Molecular Toxicology Department, Oregon State University, Corvallis, OR, United States
- Superfund Research Program, Oregon State University, Corvallis, OR, United States
| | - Brianna N. Rivera
- Environmental and Molecular Toxicology Department, Oregon State University, Corvallis, OR, United States
- Superfund Research Program, Oregon State University, Corvallis, OR, United States
| | - Yvonne Chang
- Environmental and Molecular Toxicology Department, Oregon State University, Corvallis, OR, United States
- Superfund Research Program, Oregon State University, Corvallis, OR, United States
| | - Jamie M. Pennington
- Environmental and Molecular Toxicology Department, Oregon State University, Corvallis, OR, United States
| | - Kay A. Fischer
- Oregon Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Oregon State University, Corvallis, OR, United States
| | - Christiane V. Löhr
- Oregon Veterinary Diagnostic Laboratory, College of Veterinary Medicine, Oregon State University, Corvallis, OR, United States
- Department of Biomedical Sciences, Oregon State University, Corvallis, OR, United States
| | - Susan C. Tilton
- Environmental and Molecular Toxicology Department, Oregon State University, Corvallis, OR, United States
- Superfund Research Program, Oregon State University, Corvallis, OR, United States
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Ochoa‐Avilés C, Ochoa‐Avilés A, Rivas‐Párraga R, Escandón S, Santos‐Jesus TD, Silva MDJ, Leão V, Salinas M, Vicuña Y, Baldeón L, Molina‐Cando MJ, Morillo D, Machuca M, Rodas C, Figueiredo C, Neira VA. Mother's smoking habits affects IL10 methylation but not asthma in Ecuadorian children. Mol Genet Genomic Med 2024; 12:e2438. [PMID: 38666495 PMCID: PMC11046467 DOI: 10.1002/mgg3.2438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/25/2023] [Revised: 03/22/2024] [Accepted: 03/28/2024] [Indexed: 04/29/2024] Open
Abstract
There is no evidence evaluating the IL10 epigenetic upregulation among mestizo children in a high-altitude Andean city in Latin America. OBJECTIVE To identify polymorphisms and methylation profiles in the IL10 gene associated with asthma in children aged 5 to 11. METHODS A case-control study was conducted with asthmatic and non-asthmatic children aged 5 to 11 years in Cuenca-Ecuador. Data on allergic diseases and risk factors were collected through a questionnaire for parents. Atopy was measured by skin prick test (SPT) to relevant aeroallergens. Three IL10 single nucleotide polymorphisms were evaluated in all participants, and methylation analysis was performed in 54 participants. Association between risk factors, allergic diseases and genetic factors were estimated using multivariate logistic regression. RESULTS The results of polymorphisms showed no differences between cases and controls when comparing the SNPs rs3024495, rs3024496, rs1800896 allelic and genotypic frequencies. In the methylation analysis, no differences in the IL10 methylation profile were found between cases and controls; however, the multivariate analysis showed an association between the mother's smoking habits and the IL10 methylation profile. CONCLUSION Smoking habit could be essential as an environmental exposure factor in regulating gene expression in children with asthma.
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Affiliation(s)
- Cristina Ochoa‐Avilés
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
- Departamento de Biorregulação, Instituto de Ciências da SaúdeUniversidade Federal da BahiaSalvadorBahiaBrazil
| | | | - Roque Rivas‐Párraga
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
- Biomass to Resources GroupUniversidad Regional Amazónica IkiamTenaNapoEcuador
| | - Samuel Escandón
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
| | - Talita Dos Santos‐Jesus
- Departamento de Biorregulação, Instituto de Ciências da SaúdeUniversidade Federal da BahiaSalvadorBahiaBrazil
| | - Milca de J. Silva
- Departamento de Biorregulação, Instituto de Ciências da SaúdeUniversidade Federal da BahiaSalvadorBahiaBrazil
| | - Valderiene Leão
- Departamento de Biorregulação, Instituto de Ciências da SaúdeUniversidade Federal da BahiaSalvadorBahiaBrazil
| | - Marco Salinas
- Biomass to Resources GroupUniversidad Regional Amazónica IkiamTenaNapoEcuador
| | - Yosselin Vicuña
- Instituto de Investigación en Biomedicina Facultad de Ciencias MédicasUniversidad Central del EcuadorQuitoPichinchaEcuador
| | - Lucy Baldeón
- Instituto de Investigación en Biomedicina Facultad de Ciencias MédicasUniversidad Central del EcuadorQuitoPichinchaEcuador
| | - María José Molina‐Cando
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
- Facultad de MedicinaUniversidad Internacional del EcuadorQuitoPichinchaEcuador
| | - Diana Morillo
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
- Facultad de MedicinaUniversidad Internacional del EcuadorQuitoPichinchaEcuador
| | - Marcos Machuca
- Facultad de MedicinaUniversidad del AzuayCuencaAzuayEcuador
| | - Claudia Rodas
- Facultad de MedicinaUniversidad del AzuayCuencaAzuayEcuador
| | - Camila Figueiredo
- Departamento de Biorregulação, Instituto de Ciências da SaúdeUniversidade Federal da BahiaSalvadorBahiaBrazil
| | - Vivian Alejandra Neira
- Departamento de BiocienciasUniversidad de CuencaCuencaAzuayEcuador
- Facultad de MedicinaUniversidad del AzuayCuencaAzuayEcuador
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31
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Guo SN, Jiang XQ, Chen N, Song SM, Fang Y, Xie QM, Fei GH, Wu HM. Melatonin regulates circadian clock proteins expression in allergic airway inflammation. Heliyon 2024; 10:e27471. [PMID: 38496876 PMCID: PMC10944242 DOI: 10.1016/j.heliyon.2024.e27471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/16/2023] [Revised: 02/20/2024] [Accepted: 02/29/2024] [Indexed: 03/19/2024] Open
Abstract
Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation.
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Affiliation(s)
- Si-Nuo Guo
- Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
| | - Xu-Qin Jiang
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China
| | - Ning Chen
- Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
| | - Si-Ming Song
- Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
| | - Yu Fang
- Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
| | - Qiu-Meng Xie
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Guang-He Fei
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Hui-Mei Wu
- Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
- Key Laboratory of Respiratory Disease research and Medical Transformation of Anhui Province, Hefei, 230022, China
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32
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Meng M, Wei R, Wu Y, Zeng R, Luo D, Ma Y, Zhang L, Huang W, Zeng H, Leung FW, Qiu X, Sha W, Chen H. Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study. EClinicalMedicine 2024; 69:102500. [PMID: 38389713 PMCID: PMC10882104 DOI: 10.1016/j.eclinm.2024.102500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 10/23/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 02/24/2024] Open
Abstract
Background In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Interpretation Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.
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Affiliation(s)
- Meijun Meng
- Department of Gastroenterology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Rui Wei
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Yanjun Wu
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Ruijie Zeng
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- Shantou University Medical College, Shantou, 515000, Guangdong, China
| | - Dongling Luo
- Department of Gastroenterology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yuying Ma
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Lijun Zhang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Wentao Huang
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Hanshi Zeng
- Department of Pediatrics, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Felix W Leung
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90024, CA, USA
- Sepulveda Ambulatory Care Center, Veterans Affairs Greater Los Angeles Healthcare System, North Hills, 91343, CA, USA
| | - Xinqi Qiu
- Cancer Prevention Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
- Shantou University Medical College, Shantou, 515000, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
- Shantou University Medical College, Shantou, 515000, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
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Dhupar R, Powers AA, Eisenberg SH, Gemmill RM, Bardawil CE, Udoh HM, Cubitt A, Nangle LA, Soloff AC. Orchestrating Resilience: How Neuropilin-2 and Macrophages Contribute to Cardiothoracic Disease. J Clin Med 2024; 13:1446. [PMID: 38592275 PMCID: PMC10934188 DOI: 10.3390/jcm13051446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/16/2024] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 04/10/2024] Open
Abstract
Immunity has evolved to balance the destructive nature of inflammation with wound healing to overcome trauma, infection, environmental insults, and rogue malignant cells. The inflammatory response is marked by overlapping phases of initiation, resolution, and post-resolution remodeling. However, the disruption of these events can lead to prolonged tissue damage and organ dysfunction, resulting long-term disease states. Macrophages are the archetypic phagocytes present within all tissues and are important contributors to these processes. Pleiotropic and highly plastic in their responses, macrophages support tissue homeostasis, repair, and regeneration, all while balancing immunologic self-tolerance with the clearance of noxious stimuli, pathogens, and malignant threats. Neuropilin-2 (Nrp2), a promiscuous co-receptor for growth factors, semaphorins, and integrins, has increasingly been recognized for its unique role in tissue homeostasis and immune regulation. Notably, recent studies have begun to elucidate the role of Nrp2 in both non-hematopoietic cells and macrophages with cardiothoracic disease. Herein, we describe the unique role of Nrp2 in diseases of the heart and lung, with an emphasis on Nrp2 in macrophages, and explore the potential to target Nrp2 as a therapeutic intervention.
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Affiliation(s)
- Rajeev Dhupar
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Surgical and Research Services, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
| | - Amy A. Powers
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Seth H. Eisenberg
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Robert M. Gemmill
- Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Charles E. Bardawil
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Hannah M. Udoh
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
| | - Andrea Cubitt
- aTyr Pharma, San Diego, CA 92121, USA; (A.C.); (L.A.N.)
| | | | - Adam C. Soloff
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; (R.D.); (H.M.U.)
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Surgical and Research Services, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA
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Yuan Y, Zhu H, Huang S, Zhang Y, Shen Y. Establishment of a diagnostic model based on immune-related genes in children with asthma. Heliyon 2024; 10:e25735. [PMID: 38375253 PMCID: PMC10875436 DOI: 10.1016/j.heliyon.2024.e25735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/15/2023] [Revised: 01/31/2024] [Accepted: 02/01/2024] [Indexed: 02/21/2024] Open
Abstract
Objective Allergic asthma is driven by an antigen-specific immune response. This study aimed to identify immune-related differentially expressed genes in childhood asthma and establish a classification diagnostic model based on these genes. Methods GSE65204 and GSE19187 were downloaded and served as training set and validation set. The immune cell composition was evaluated with ssGSEA algorithm based on the immune-related gene set. Modules that significantly related to the asthma were selected by WGCNA algorithm. The immune-related differentially expressed genes (DE-IRGs) were screened, the protein-protein interaction network and diagnostic model of DE-IRGs was constructed. The pathway and immune correlation analysis of hub DE-IRGs was analyzed. Results Eight immune cell types exhibited varying levels of abundance between the asthma and control groups. A total of 112 differentially expressed immune-related genes (DE-IRGs) was identified. Through the application of four ranking methods (MCC, MNC, DEGREE, and EPC), 17 hub DE-IRGs with overlapping significance were further selected. Subsequently, 8 optimized were identified using univariate logistic regression analysis and the LASSO regression algorithm, based on which a robust diagnostic model was constructed. Notably, TNF and CD40LG emerged as direct participants in asthma-related signaling pathways, displaying a positive correlation with the immune cell types of immature B cells, activated B cells, activated CD8 T cells, activated CD4 T cells, and myeloid-derived suppressor cells. Conclusion The diagnostic model constructed using the DE-IRGs (CCL5, CCR5, CD40LG, CD8A, IL2RB, PDCD1, TNF, and ZAP70) exhibited high and specific diagnostic value for childhood asthma. The diagnostic model may contribute to the diagnosis of childhood asthma.
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Affiliation(s)
- Yuyun Yuan
- Department of Pediatrics, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 201999, China
| | - Honghua Zhu
- Department of Medical Imaging, Shanghai Seventh People's Hospital, Shanghai, 200137, China
| | - Sihong Huang
- Department of Pediatrics, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 201999, China
| | - Yantao Zhang
- Department of Pediatrics, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 201999, China
| | - Yiyun Shen
- Department of Pediatrics, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 201999, China
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35
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Qin Z, Chen Y, Wang Y, Xu Y, Liu T, Mu Q, Huang C. Immunometabolism in the pathogenesis of asthma. Immunology 2024; 171:1-17. [PMID: 37652466 DOI: 10.1111/imm.13688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/06/2023] [Accepted: 08/14/2023] [Indexed: 09/02/2023] Open
Abstract
Bronchial asthma is a heterogeneous disease characterised by chronic airway inflammation. A variety of immune cells such as eosinophils, mast cells, T lymphocytes, neutrophils and airway epithelial cells are involved in the airway inflammation and airway hyperresponsiveness in asthma pathogenesis, resulting in extensive and variable reversible expiratory airflow limitation. However, the precise molecular mechanisms underlying the allergic immune responses, particularly immunometabolism, remains unclear. Studies have detected enhanced oxidative stress, and abnormal metabolic progresses of glycolysis, fatty acid and amino acid in various immune cells, inducing dysregulation of innate and adaptive immune responses in asthma pathogenesis. Immunometabolism mechanisms contain multiple signalling pathways, providing novel therapy targets for asthma. This review summarises the current knowledge on immunometabolism reprogramming in asthma pathogenesis, as well as potential therapy strategies.
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Affiliation(s)
- Ziwen Qin
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yujuan Chen
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yue Wang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Yeyang Xu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Tingting Liu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Qian Mu
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Chuanjun Huang
- Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Wu Z, Luo Z, Sun W, Shi Y, Ding Q. Integrating Network Pharmacology and Experimental Validation to Elucidate the Mechanism of Jiegeng Decoction in Improving Allergic Asthma. ACS OMEGA 2023; 8:48081-48090. [PMID: 38144091 PMCID: PMC10733997 DOI: 10.1021/acsomega.3c06914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Academic Contribution Register] [Received: 09/11/2023] [Revised: 11/21/2023] [Accepted: 11/24/2023] [Indexed: 12/26/2023]
Abstract
Allergic asthma is a prevalent form of asthma that is characterized primarily by airway inflammation. Jiegeng decoction (JGT) is a traditional Chinese herbal formula known for its anti-inflammatory properties and has been used to treat respiratory diseases for centuries. This study aimed to investigate the biological effects and mechanisms of action of JGT in improving allergic asthma. An experimental allergic asthma mouse model was established using ovalbumin. The results showed that JGT significantly improved inflammation cell infiltration in the lung tissue of allergic asthmatic mice and the inflammatory environment of Th2 cells in the bronchoalveolar lavage fluid while also reducing serum IgE levels. Subsequently, 38 components of JGT were identified through liquid chromatography-mass spectrometry. Network pharmacology revealed that regulating inflammation and immune responses is the primary biological process by which JGT improves allergic asthma, with Th2 cell differentiation and the JAK-STAT signaling pathway being the key mechanisms of action. Finally, qPCR, flow cytometry, and Western blotting were used to validate that JGT inhibited Th2 cell differentiation by blocking the JAK1-STAT6 signaling pathway in CD4+ T cells, ultimately improving allergic asthma. This study provides a novel perspective on the therapeutic potential of JGT in the treatment of allergic asthma.
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Affiliation(s)
- Zhihai Wu
- School
of Life Sciences, Beijing University of
Chinese Medicine, Beijing 100029, China
| | - Zhiqiang Luo
- National
Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di
Herbs, Beijing 100700, China
- State
Key Laboratory of Dao-di Herbs, National Resource Center for Chinese
Materia Medica, China Academy of Chinese
Medical Sciences, Beijing 100700, China
| | - Wen Sun
- School
of Life Sciences, Beijing University of
Chinese Medicine, Beijing 100029, China
| | - Yuanyuan Shi
- School
of Life Sciences, Beijing University of
Chinese Medicine, Beijing 100029, China
- Shenzhen
Research Institute, Beijing University of
Chinese Medicine, Shenzhen 518118, China
| | - Qi Ding
- Shenzhen
Research Institute, Beijing University of
Chinese Medicine, Shenzhen 518118, China
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Gao P, Tang K, Lu Y, Wang M, Wang W, Wang T, Sun Y, Zhao J, Mao Y. Increased expression of ficolin-1 is associated with airway obstruction in asthma. BMC Pulm Med 2023; 23:470. [PMID: 37996869 PMCID: PMC10668451 DOI: 10.1186/s12890-023-02772-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/09/2022] [Accepted: 11/17/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND The activated complement cascade is involved in asthmatic airway inflammation. Ficolins are essential for innate immunity and can activate the complement lectin pathway. Despite this, the significance of ficolins in asthma has yet to be determined. This study aimed to explore the presence of ficolins in individuals with asthma and to determine the relationship between ficolins and clinical characteristics. METHODS For the study, 68 asthmatic patients and 30 healthy control subjects were recruited. Enzyme-linked immunosorbent assay was used to determine plasma ficolin-1, ficolin-2, and ficolin-3 concentrations both before and after inhaled corticosteroid (ICS) therapy. Further, the associations of plasma ficolin-1 level with pulmonary function and asthma control questionnaire (ACQ) score were examined in the asthma patients. RESULTS Patients with asthma exhibited significantly elevated plasma ficolin-1 levels (median, 493.9 ng/mL; IQR, 330.2-717.8 ng/mL) in comparison to healthy controls (median, 330.6 ng/mL; IQR, 233.8-371.1 ng/mL). After ICS treatment, plasma ficolin-1 (median, 518.1 ng/mL; IQR, 330.2-727.0 ng/mL) in asthmatic patients was significantly reduced (median, 374.7 ng/mL; IQR, 254.8-562.5 ng/mL). Additionally, ficolin-1 expressions in plasma were significantly correlated with pulmonary function parameters and ACQ score in asthmatic patients. Asthma patients with higher plasma ficolin-1 levels demonstrated poorer lung function than those with lower plasma ficolin-1 levels. CONCLUSIONS The results revealed that asthmatic patients had higher plasma ficolin-1 concentrations, which decreased after ICS treatment and were linked to their lung function, implying a potential involvement of ficolin-1 in asthma pathogenesis.
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Affiliation(s)
- Pengfei Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China.
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Kun Tang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yanjiao Lu
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Meijia Wang
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China
| | - Tongsheng Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China
| | - Yuxia Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China
| | - Jianping Zhao
- Department of Respiratory and Critical Care Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Yimin Mao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China.
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Groiss S, Somvilla I, Daxböck C, Stückler M, Pritz E, Brislinger D. Bei Mu Gua Lou San facilitates mucus expectoration by increasing surface area and hydration levels of airway mucus in an air-liquid-interface cell culture model of the respiratory epithelium. BMC Complement Med Ther 2023; 23:414. [PMID: 37978392 PMCID: PMC10655387 DOI: 10.1186/s12906-023-04251-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/23/2023] [Accepted: 11/09/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Bei Mu Gua Lou San (BMGLS) is an ancient formulation known for its moisturizing and expectorant properties, but the underlying mechanisms remain unknown. We investigated concentration-dependent effects of BMGLS on its rehydrating and mucus-modulating properties using an air-liquid-interface (ALI) cell culture model of the Calu-3 human bronchial epithelial cell line and primary normal human bronchial epithelial cells (NHBE), and specifically focused on quantity and composition of the two major mucosal proteins MUC5AC and MUC5B. METHODS ALI cultures were treated with BMGLS at different concentrations over three weeks and evaluated by means of histology, immunostaining and electron microscopy. MUC5AC and MUC5B mRNA levels were assessed and quantified on protein level using an automated image-based approach. Additionally, expression levels of the major mucus-stimulating enzyme 15-lipoxygenase (ALOX15) were evaluated. RESULTS BMGLS induced concentration-dependent morphological changes in NHBE but not Calu-3 ALI cultures that resulted in increased surface area via the formation of herein termed intra-epithelial structures (IES). While cellular rates of proliferation, apoptosis or degeneration remained unaffected, BMGLS caused swelling of mucosal granules, increased the area of secreted mucus, decreased muco-glycoprotein density, and dispensed MUC5AC. Additionally, BMGLS reduced expression levels of MUC5AC, MUC5B and the mucus-stimulating enzyme 15-lipoxygenase (ALOX15). CONCLUSIONS Our studies suggest that BMGLS rehydrates airway mucus while stimulating mucus secretion by increasing surface areas and regulating goblet cell differentiation through modulating major mucus-stimulating pathways.
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Affiliation(s)
- Silvia Groiss
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria
| | - Ina Somvilla
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria
| | - Christine Daxböck
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria
| | - Manuela Stückler
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria
| | - Elisabeth Pritz
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria
| | - Dagmar Brislinger
- Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre, Medical University of Graz, Neue Stiftingtalstraße 6/II, Graz, 8010, Austria.
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Tee JH, Vijayakumar U, Shanmugasundaram M, Lam TYW, Liao W, Yang Y, Wong WSF, Ge R. Isthmin-1 attenuates allergic Asthma by stimulating adiponectin expression and alveolar macrophage efferocytosis in mice. Respir Res 2023; 24:269. [PMID: 37932719 PMCID: PMC10626717 DOI: 10.1186/s12931-023-02569-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023] Open
Abstract
BACKGROUND Allergic asthma is a common respiratory disease that significantly impacts human health. Through in silico analysis of human lung RNASeq, we found that asthmatic lungs display lower levels of Isthmin-1 (ISM1) expression than healthy lungs. ISM1 is an endogenous anti-inflammatory protein that is highly expressed in mouse lungs and bronchial epithelial cells, playing a crucial role in maintaining lung homeostasis. However, how ISM1 influences asthma remains unclear. This study aims to investigate the potential involvement of ISM1 in allergic airway inflammation and uncover the underlying mechanisms. METHODS We investigated the pivotal role of ISM1 in airway inflammation using an ISM1 knockout mouse line (ISM1-/-) and challenged them with house dust mite (HDM) extract to induce allergic-like airway/lung inflammation. To examine the impact of ISM1 deficiency, we analyzed the infiltration of immune cells into the lungs and cytokine levels in bronchoalveolar lavage fluid (BALF) using flow cytometry and multiplex ELISA, respectively. Furthermore, we examined the therapeutic potential of ISM1 by administering recombinant ISM1 (rISM1) via the intratracheal route to rescue the effects of ISM1 reduction in HDM-challenged mice. RNA-Seq, western blot, and fluorescence microscopy techniques were subsequently used to elucidate the underlying mechanisms. RESULTS ISM1-/- mice showed a pronounced worsening of allergic airway inflammation and hyperresponsiveness upon HDM challenge. The heightened inflammation in ISM1-/- mice correlated with enhanced lung cell necroptosis, as indicated by higher pMLKL expression. Intratracheal delivery of rISM1 significantly reduced the number of eosinophils in BALF and goblet cell hyperplasia. Mechanistically, ISM1 stimulates adiponectin secretion by type 2 alveolar epithelial cells partially through the GRP78 receptor and enhances adiponectin-facilitated apoptotic cell clearance via alveolar macrophage efferocytosis. Reduced adiponectin expression under ISM1 deficiency also contributed to intensified necroptosis, prolonged inflammation, and heightened severity of airway hyperresponsiveness. CONCLUSIONS This study revealed for the first time that ISM1 functions to restrain airway hyperresponsiveness to HDM-triggered allergic-like airway/lung inflammation in mice, consistent with its persistent downregulation in human asthma. Direct administration of rISM1 into the airway alleviates airway inflammation and promotes immune cell clearance, likely by stimulating airway adiponectin production. These findings suggest that ISM1 has therapeutic potential for allergic asthma.
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Affiliation(s)
- Jong Huat Tee
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Udhaya Vijayakumar
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Mahalakshmi Shanmugasundaram
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Terence Y W Lam
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore
| | - Wupeng Liao
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Yuansheng Yang
- Bioprocessing Technology Institute, A*STAR, Singapore, 138668, Singapore
| | - W S Fred Wong
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- Singapore-HUJ Alliance for Research and Enterprise (SHARE), National University of Singapore, Singapore, 138602, Singapore.
- Drug Discovery and Optimization Platform, Yong Loo Lin School of Medicine, National University Health System, Singapore, 117600, Singapore.
| | - Ruowen Ge
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore.
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40
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Kim J, Lee SH, Zhang S, Bong SK, Kim AT, Lee H, Liu X, Kim SM, Kim SN. Anti-Allergic Inflammatory Effect of Agarum cribrosum and Its Phlorotannin Component, Trifuhalol A, against the Ovalbumin-Induced Allergic Asthma Model. Curr Issues Mol Biol 2023; 45:8882-8893. [PMID: 37998734 PMCID: PMC10669934 DOI: 10.3390/cimb45110557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/18/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 11/25/2023] Open
Abstract
Asthma is a chronic inflammatory disease involving structural changes to the respiratory system and severe immune responses mediated by allergic cytokines and pro-inflammatory mediators. Agarum cribrosum (AC) is a kind of seaweed which contains a phlorotannin, trifuhalol A. To evaluate its anti-allergic inflammatory effect against asthma, an ovalbumin inhalation-induced mouse asthma model was used. Histologic observations proved that trifuhalol A is minimizing the lung and tracheal structure changes as well as the infiltration of eosinophils and mast cells against ovalbumin inhalation challenge. From the serum and bronchoalveolar lavage fluid, ovalbumin-specific IgE and Th2-specific cytokines, IL-4, -5, and -13, were reduced with trifuhalol A treatment. In addition, IL-1β, IL-6, and TNF-α concentrations in lung homogenate were also significantly reduced via trifuhalol A treatment. Taken together, trifuhalol A, isolated from AC, was able to protect lung and airways from Th2-specific cytokine release, and IgE mediated allergic inflammation as well as the attenuation of IL-1β, IL-6, and TNF-α in lung, which results in the suppression of eosinophils and the mast cells involved asthmatic pathology.
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Affiliation(s)
- Joonki Kim
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Sang Heon Lee
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
| | - Siqi Zhang
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Sim-Kyu Bong
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
| | - Aaron Taehwan Kim
- Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA;
| | - Hara Lee
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
- Department of Dentistry, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea
| | - Xiaoyong Liu
- Haizhibao Deutschland GmbH, Heiliggeistgasse, 85354 Freising, Germany;
| | - Sang Moo Kim
- Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangneung 25457, Republic of Korea;
| | - Su-Nam Kim
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; (J.K.); (S.H.L.); (S.Z.); (S.-K.B.); (H.L.)
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
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41
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Vanharen M, Girard D. Impact of gold nanoparticles (AuNPs) on eosinophils isolated from male and female individuals. Immunobiology 2023; 228:152762. [PMID: 38006680 DOI: 10.1016/j.imbio.2023.152762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/04/2023] [Revised: 11/06/2023] [Accepted: 11/19/2023] [Indexed: 11/27/2023]
Abstract
It is well established that some differences exist between the male and female immune systems. Despites this, a sex-based analysis is not frequently performed in most scientific published reports. Knowing that inflammation is a common undesired effect observed resulting from nanoparticle (NP) exposure, we investigate here how in vitro treatment of gold NPs with a primary size of 20 and 70 nm (AuNP20 and AuNP70, respectively) will alter the biology of human eosinophils isolated from men and women blood. We found that treatment of AuNP70, but not AuNP20, significantly delay apoptosis only in eosinophils isolated from women. AuNPs were found to decrease eosinophil phagocytosis, however, significance was only observed in AuNP20-induced eosinophils isolated from women. The production of IL-8 was significantly increased in response to both AuNPs but only in eosinophils isolated from men and the production of IL-1β was increased in AuNPs-induced eosinophils, although significance was observed only in AuNP70-induced eosinophils isolated from women. We conclude that future studies investigating the toxicity of AuNPs (or other NPs) should include a sex-based analysis, especially if the tested NPs have potential medical applications knowing the increased interest in the development of personalized precision medicine.
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Affiliation(s)
- Marion Vanharen
- Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, Québec, Canada
| | - Denis Girard
- Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, INRS-Centre Armand-Frappier Santé Biotechnologie, Laval, Québec, Canada.
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Yuan F, Yang Y, Liu L, Zhou P, Zhu Y, Chai Y, Chen K, Tang W, Huang Q, Zhang C. Research progress on the mechanism of astragaloside IV in the treatment of asthma. Heliyon 2023; 9:e22149. [PMID: 38045181 PMCID: PMC10692808 DOI: 10.1016/j.heliyon.2023.e22149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/03/2023] [Revised: 11/03/2023] [Accepted: 11/05/2023] [Indexed: 12/05/2023] Open
Abstract
Asthma is a common chronic respiratory disease, and its treatment is a core problem and challenge in clinical practice. Glucocorticoids (GCs) are the first-line therapy for the treatment of asthma. Local and systemic adverse reactions caused by GCs create obstacles to the treatment of asthma. Therefore, the research target is to find a new, safe, and effective therapeutic medicine at present. Natural products are an important source for treating asthma with low cost and low toxicity. Astragaloside IV (AS-IV) is an active ingredient of traditional Chinese medicine Astragalus mongholicus Bunge. Previous studies have indicated that AS-IV plays a therapeutic role in the treatment of asthma by inhibiting airway inflammation and remodeling the airway, and by regulating immunity and neuroendocrine function (Fig. 1) . It has a variety of biological characteristics such as multi-target intervention, high safety, and good curative effect. This article reviews the specific mechanism of AS-IV for the treatment of asthma to provide references for subsequent research.
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Affiliation(s)
- Fanyi Yuan
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yang Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Liu
- Department of Pharmacy, Hospital of Chengdu university of Traditional Chinese Medicine, Chengdu, China
| | - Pengcheng Zhou
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yi Zhu
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yilu Chai
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Keling Chen
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenjun Tang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qingsong Huang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuantao Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Ma F, Feng X, Wang E, Ma C, Wu J, He S, Tian Y, Qiu P, Tan L, Liu J, Li J, Hu S, Yang P, Ning Y. The regulation of tolerogenic dendritic cells by a Chinese herb formula improves abortion prone in mice. Am J Reprod Immunol 2023; 90:e13714. [PMID: 37881127 DOI: 10.1111/aji.13714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/11/2022] [Revised: 04/07/2023] [Accepted: 05/05/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Abortion prone (AP) is a common clinical event. The underlying mechanism remains unclear. Traditional Chinese formulas are known to be efficient in the management of abortion. The purpose of this study is to observe the effects of Anzitiaochongtang (AZT), a traditional formulation of Chinese medicine, on improving AP in mice by regulating immune tolerance. METHODS An established abortion model (CBA/J×DBA/2) was employed. AZT was prepared and administered to mice in a manner consistent with clinical practice. Tolerogenic dendritic cells (tDC) and type 1 regulatory T cells (Tr1 cell) in mice were analyzed by immunological approaches to be used as representative immune tolerant parameters. RESULTS An AP model was established with CBA/J × DBA/2 mice. The expression of IL-10 in tDC and Tr1 cell frequency in the mouse decidua tissues were lower in the AP group than that in the normal pregnancy (NP) group. Administration of AZT up regulated the expression of IL-10 in tDCs and Tr1 cell generation in the decidua tissues, and improved the pregnancy and tissue structure in AP mice. The main mechanism by which AZT improves pregnancy in AP mice is that AZT enhanced the expression of galectin-9 in the epithelial cells of decidua tissues. Galectin 9 activates TIM3 on DCs to promote the IL-10 expression. The DCs induced more Tr1 cells in the decidua tissues. CONCLUSIONS Dysfunctional tDCs were detected in the AP decidua tissues. Administration of AZT improved pregnancy in AP mice by regulating tDC function and generation of Tr1 cells in the maternal-fetal interface.
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Affiliation(s)
- Fei Ma
- Department of Traditional Chinese Medicine, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Xiaoyang Feng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
| | - Erfeng Wang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chang Ma
- Department of Respirology, Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jiaman Wu
- Department of Traditional Chinese Medicine, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Shan He
- Department of Pharmacy, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Ying Tian
- Department of Traditional Chinese Medicine, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Pingping Qiu
- Department of Traditional Chinese Medicine, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
| | - Liya Tan
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jin Liu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia Li
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Suqin Hu
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen, China
| | - Pingchang Yang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- Institute of Allergy & Immunology of Shenzhen University, State Key Laboratory of Respiratory Disease Allergy Division at Shenzhen University, Shenzhen, China
| | - Yan Ning
- Department of Traditional Chinese Medicine, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, China
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Qian G, Jiang W, Sun D, Sun Z, Chen A, Fang H, Wang J, Liu Y, Yin Z, Wei H, Fang H, Zhang X. B-cell-derived IL-10 promotes allergic sensitization in asthma regulated by Bcl-3. Cell Mol Immunol 2023; 20:1313-1327. [PMID: 37653127 PMCID: PMC10616210 DOI: 10.1038/s41423-023-01079-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/19/2023] [Accepted: 08/15/2023] [Indexed: 09/02/2023] Open
Abstract
Aeroallergen sensitization, mainly mediated by lung epithelium and dendritic cells (DCs), is integral to allergic asthma pathogenesis and progression. IL-10 has a dual role in immune responses, as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation. Here, we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma. Specifically, Bcl-3-/- mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites (HDMs). IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells. Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development. IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3-Blimp-1-Bcl-6 regulation. Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization, thereby demonstrating resistance to HDM-induced asthma. Moreover, responses to HDM stimulation in Bcl-3-/- mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3+/+ mice. The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production. Thus, targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma. IL-10 is released rapidly from lung plasma cells under Bcl-3-Blimp-1-Bcl-6 regulation upon house dust mite exposure and amplifies lung epithelial cell (EC)-derived CCL-20 production and subsequent dendritic cell (DC) recruitment to promote allergic sensitization in asthma.
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Affiliation(s)
- Guojun Qian
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China.
- Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, 200001, Shanghai, China.
| | - Wenxia Jiang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Donglin Sun
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China
| | - Zhun Sun
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China
| | - Anning Chen
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China
| | - Hongwei Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Jingyao Wang
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China
| | - Yongzhong Liu
- Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Zhinan Yin
- Zhuhai People's Hospital, Biomedical Translational Research Institute, Jinan University, 510632, Guangzhou, China
| | - Haiming Wei
- Institute of Immunology, University of Science and Technology of China, 230000, Hefei, China
| | - Hao Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
- Department of Anesthesiology, Minhang Hospital, Fudan University, 201100, Shanghai, China.
| | - Xiaoren Zhang
- Affiliated Cancer Hospital/Institute and GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, State Key Laboratory of Respiratory Disease, 511436, Guangzhou, China.
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 200031, Shanghai, China.
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Accordini S, Lando V, Calciano L, Bombieri C, Malerba G, Margagliotti A, Minelli C, Potts J, van der Plaat DA, Olivieri M. SNPs in FAM13Aand IL2RBgenes are associated with FeNO in adult subjects with asthma. J Breath Res 2023; 18:016001. [PMID: 37733009 DOI: 10.1088/1752-7163/acfbf1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/05/2023] [Accepted: 09/21/2023] [Indexed: 09/22/2023]
Abstract
Nitric oxide has different roles in asthma as both an endogenous modulator of airway function and a pro-inflammatory mediator. Fractional exhaled nitric oxide (FeNO) is a reliable, quantitative, non-invasive, simple, and safe biomarker for assessing airways inflammation in asthma. Previous genome-wide and genetic association studies have shown that different genes and single nucleotide polymorphisms (SNPs) are linked to FeNO. We aimed at identifying SNPs in candidate genes or gene regions that are associated with FeNO in asthma. We evaluated 264 asthma cases (median age 42.8 years, female 47.7%) who had been identified in the general adult population within the Gene Environment Interactions in Respiratory Diseases survey in Verona (Italy; 2008-2010). Two hundred and twenty-one tag-SNPs, which are representative of 50 candidate genes, were genotyped by a custom GoldenGate Genotyping Assay. A two-step association analysis was performed without assuming ana priorigenetic model: step (1) a machine learning technique [gradient boosting machine (GBM)] was used to select the 15 SNPs with the highest variable importance measure; step (2) the GBM-selected SNPs were jointly tested in a linear regression model with natural log-transformed FeNO as the normally distributed outcome and with age, sex, and the SNPs as covariates. We replicated our results within an independent sample of 296 patients from the European Community Respiratory Health Survey III. We found that SNP rs987314 in family with sequence similarity 13 member A (FAM13A) and SNP rs3218258 in interleukin 2 receptor subunit beta (IL2RB) gene regions are significantly associated with FeNO in adult subjects with asthma. These genes are involved in different mechanisms that affect smooth muscle constriction and endothelial barrier function responses (FAM13A), or in immune response processes (IL2RB). Our findings contribute to the current knowledge on FeNO in asthma by identifying two novel SNPs associated with this biomarker of airways inflammation.
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Affiliation(s)
- Simone Accordini
- Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy
| | - Valentina Lando
- Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy
| | - Lucia Calciano
- Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy
| | - Cristina Bombieri
- Biology and Genetics Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy
| | - Giovanni Malerba
- Biology and Genetics Section, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy
| | - Antonino Margagliotti
- Unit of Epidemiology and Medical Statistics, Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy
| | - Cosetta Minelli
- National Heart and Lung Institute, Imperial College London, London SW3 6LR, United Kingdom
| | - James Potts
- National Heart and Lung Institute, Imperial College London, London SW3 6LR, United Kingdom
| | - Diana A van der Plaat
- National Heart and Lung Institute, Imperial College London, London SW3 6LR, United Kingdom
| | - Mario Olivieri
- Retired Professor of Occupational Medicine, University of Verona, Verona, Italy
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Schneble D, El-Gazzar A, Kargarpour Z, Kramer M, Metekol S, Stoshikj S, Idzko M. Cell-type-specific role of P2Y2 receptor in HDM-driven model of allergic airway inflammation. Front Immunol 2023; 14:1209097. [PMID: 37790940 PMCID: PMC10543084 DOI: 10.3389/fimmu.2023.1209097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/20/2023] [Accepted: 08/28/2023] [Indexed: 10/05/2023] Open
Abstract
Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute aggravation. It is characterized by IgE-dependent activation of mast cells, infiltration of eosinophils, and activated T-helper cell type 2 (Th2) lymphocytes into airway mucosa. Purinergic receptor signaling is known to play a crucial role in inducing and maintaining allergic airway inflammation. Previous studies in an ovalbumin (OVA)-alum mouse model demonstrated a contribution of the P2Y2 purinergic receptor subtype (P2RY2) in allergic airway inflammation. However, conflicting data concerning the mechanism by which P2RY2 triggers AAI has been reported. Thus, we aimed at elucidating the cell-type-specific role of P2RY2 signaling in house dust mite (HDM)-driven model of allergic airway inflammation. Thereupon, HDM-driven AAI was induced in conditional knockout mice, deficient or intact for P2ry2 in either alveolar epithelial cells, hematopoietic cells, myeloid cells, helper T cells, or dendritic cells. To analyze the functional role of P2RY2 in these mice models, flow cytometry of bronchoalveolar lavage fluid (BALF), cytokine measurement of BALF, invasive lung function measurement, HDM re-stimulation of mediastinal lymph node (MLN) cells, and lung histology were performed. Mice that were subjected to an HDM-based model of allergic airway inflammation resulted in reduced signs of acute airway inflammation including eosinophilia in BALF, peribronchial inflammation, Th2 cytokine production, and bronchial hyperresponsiveness in mice deficient for P2ry2 in alveolar epithelial cells, hematopoietic cells, myeloid cells, or dendritic cells. Furthermore, the migration of bone-marrow-derived dendritic cells and bone-marrow-derived monocytes, both deficient in P2ry2, towards ATP was impaired. Additionally, we found reduced levels of MCP-1/CCL2 and IL-8 homologues in the BALF of mice deficient in P2ry2 in myeloid cells and lower concentrations of IL-33 in the lung tissue of mice deficient in P2ry2 in alveolar epithelial cells. In summary, our results show that P2RY2 contributes to HDM-induced airway inflammation by mediating proinflammatory cytokine production in airway epithelial cells, monocytes, and dendritic cells and drives the recruitment of lung dendritic cells and monocytes.
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Affiliation(s)
- Dominik Schneble
- Department of Pneumology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Ahmed El-Gazzar
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
| | - Zahra Kargarpour
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
| | - Markus Kramer
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
| | - Seda Metekol
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
| | - Slagjana Stoshikj
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
| | - Marco Idzko
- Department of Pneumology, Medical Center – University of Freiburg, Freiburg, Germany
- Department of Pulmonology, Medical University of Vienna, Vienna, Austria
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47
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Chatziparasidis G, Bush A, Chatziparasidi MR, Kantar A. Airway epithelial development and function: A key player in asthma pathogenesis? Paediatr Respir Rev 2023; 47:51-61. [PMID: 37330410 DOI: 10.1016/j.prrv.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/05/2023] [Revised: 04/07/2023] [Accepted: 04/25/2023] [Indexed: 06/19/2023]
Abstract
Though asthma is a common and relatively easy to diagnose disease, attempts at primary or secondary prevention, and cure, have been disappointing. The widespread use of inhaled steroids has dramatically improved asthma control but has offered nothing in terms of altering long-term outcomes or reversing airway remodeling and impairment in lung function. The inability to cure asthma is unsurprising given our limited understanding of the factors that contribute to disease initiation and persistence. New data have focused on the airway epithelium as a potentially key factor orchestrating the different stages of asthma. In this review we summarize for the clinician the current evidence on the central role of the airway epithelium in asthma pathogenesis and the factors that may alter epithelial integrity and functionality.
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Affiliation(s)
- Grigorios Chatziparasidis
- Paediatric Respiratory Unit, IASO Hospital, Larissa, Thessaly, Greece; Faculty of Nursing, Thessaly University, Greece.
| | - Andrew Bush
- National Heart and Lung Institute, Royal Brompton & Harefield NHS Foundation Trust, London, UK
| | | | - Ahmad Kantar
- Pediatric Asthma and Cough Centre, Instituti Ospedalieri Bergamaschi, University and Research Hospitals, Bergamo, Italy
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48
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Vasileva D, Greenwood CMT, Daley D. A Review of the Epigenetic Clock: Emerging Biomarkers for Asthma and Allergic Disease. Genes (Basel) 2023; 14:1724. [PMID: 37761864 PMCID: PMC10531327 DOI: 10.3390/genes14091724] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/01/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/29/2023] Open
Abstract
DNA methylation (DNAm) is a dynamic, age-dependent epigenetic modification that can be used to study interactions between genetic and environmental factors. Environmental exposures during critical periods of growth and development may alter DNAm patterns, leading to increased susceptibility to diseases such as asthma and allergies. One method to study the role of DNAm is the epigenetic clock-an algorithm that uses DNAm levels at select age-informative Cytosine-phosphate-Guanine (CpG) dinucleotides to predict epigenetic age (EA). The difference between EA and calendar age (CA) is termed epigenetic age acceleration (EAA) and reveals information about the biological capacity of an individual. Associations between EAA and disease susceptibility have been demonstrated for a variety of age-related conditions and, more recently, phenotypes such as asthma and allergic diseases, which often begin in childhood and progress throughout the lifespan. In this review, we explore different epigenetic clocks and how they have been applied, particularly as related to childhood asthma. We delve into how in utero and early life exposures (e.g., smoking, air pollution, maternal BMI) result in methylation changes. Furthermore, we explore the potential for EAA to be used as a biomarker for asthma and allergic diseases and identify areas for further study.
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Affiliation(s)
- Denitsa Vasileva
- Centre for Heart Lung Innovation, University of British Columbia and Saint Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada;
| | - Celia M. T. Greenwood
- Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada;
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A 0G4, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada
| | - Denise Daley
- Centre for Heart Lung Innovation, University of British Columbia and Saint Paul’s Hospital, Vancouver, BC V6Z 1Y6, Canada;
- Department of Medicine, Respiratory Division, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Li L, Xu X, Wang X, Zhang S, Yao W, Liu J, Liu Z, Yang P. Galectin-9 in synergy with NF-κB inhibition restores immune regulatory capability in dendritic cells of subjects with food allergy. Clin Exp Immunol 2023; 213:155-163. [PMID: 37279535 PMCID: PMC10361740 DOI: 10.1093/cei/uxad062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/03/2022] [Revised: 03/08/2023] [Accepted: 06/02/2023] [Indexed: 06/08/2023] Open
Abstract
The pathogenesis of immune tolerance disruption is not fully understood. Galectin-9 (Gal9) has immune regulatory functions. The objective of the present study is to assess the role of Gal9 in maintaining immune tolerance. Blood and intestinal biopsies were taken from patients with food allergy (FA). The status of tolerogenic dendritic cells (tDC) and type 1 regulatory T cells (Tr1 cells) in the samples was evaluated and used as representative parameters of immune tolerance. An FA mouse model was established to assess the role of Gal9 in maintaining immune tolerance. We found that peripheral CD11c+ CD5+ CD1d+ tDC frequency was significantly lower in FA patients as compared to health control (HC) subjects. There was no significant change in CD11c+ DC frequency between the FA group and the HC group. The expression of IL-10 in peripheral tDCs was lower in the FA group than that in the HC group. A positive correlation was detected between the serum levels of IL-10 and Gal9. The expression of Gal9 was observed in intestinal biopsies, which was positively correlated with the serum levels of Gal9 as well as serum IL-10 levels. Peripheral Tr1 cells had lower frequencies in the FA group than in the non-FA (Con) group. tDCs demonstrated the ability to generate Tr1 cells, which was weaker in the FA group as compared with the Con group. Exposure of FA tDCs to Gal9 in culture restored the ability to generate Tr1 cells. In summary, the lower frequency of tDC and Tr1 cell of FA patients was associated with the levels of Gal9. The presence of Gal9 restored the capacity of tDC to generate Tr1 cells.
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Affiliation(s)
- Linjing Li
- Department of Gastroenterology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuejie Xu
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Institute of Allergy & Immunology of Shenzhen University, Shenzhen, China
| | - Xinxin Wang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Institute of Allergy & Immunology of Shenzhen University, Shenzhen, China
| | - Shuang Zhang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Institute of Allergy & Immunology of Shenzhen University, Shenzhen, China
| | - Wenkai Yao
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Institute of Allergy & Immunology of Shenzhen University, Shenzhen, China
| | - Jiangqi Liu
- Department of Allergy, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Zhiqiang Liu
- Department of Allergy, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Pingchang Yang
- Guangdong Provincial Regional Disease Key Laboratory, Shenzhen, China
- State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University, Institute of Allergy & Immunology of Shenzhen University, Shenzhen, China
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Xing Y, Feng L, Dong Y, Li Y, Zhang L, Wu Q, Huo R, Dong Y, Tian X, Tian X. Exploration and Validation of Potential Biomarkers and Therapeutic Targets in Ferroptosis of Asthma. J Asthma Allergy 2023; 16:689-710. [PMID: 37465372 PMCID: PMC10350417 DOI: 10.2147/jaa.s416276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/07/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023] Open
Abstract
Purpose Asthma is a chronic inflammatory airway disease involving multiple mechanisms, of which ferroptosis is a form of programmed cell death. Recent studies have shown that ferroptosis may play a crucial role in the pathogenesis of asthma, but no specific ferroptosis gene has been found in asthma, and the exact mechanism is still unclear. The present study aimed to screen ferroptosis genes associated with asthma and find therapeutic targets, in order to contribute a new clue for the diagnosis and therapy of asthma. Methods Ferroptosis-related differentially expressed genes (FR-DEGs) in asthma were selected by the GSE41861, GSE43696 and ferroptosis datasets. Next, the FR-DEGs were subjected by GO and KEGG enrichment, and the mRNA-miRNA network was constructed. Then, GSEA and GSVA enrichment analysis and Immune infiltration analysis were performed, followed by targeted drug prediction. Finally, the expression of FR-DEGs was confirmed using GSE63142 dataset and RT-PCR assay. Results We found 13 FR-DEGs by the GSE41861, GSE43696 and ferroptosis database. Functional enrichment analysis revealed that the 13 FR-DEGs were enriched in oxidative stress, immune response, ferroptosis, lysosome, necrosis, apoptosis etc. Moreover, our results revealed the mRNA-miRNA network of the FR-DEGs and identified candidate drugs. Also, immune infiltration revealed that ELAVL1, CREB5, CBR1 and NR1D2 are associated with the immune cells and may be potential targets in asthma. Finally, 10 FR-DEGs were validated by the GSE63142 database. It was verified that 7 FR-DEGs were differentially expressed by collecting asthma patients and healthy controls. Conclusion This study ultimately identified 7 FR-DEGs for the diagnosis and therapy of asthma. These 7 FR-DEGs contribute to oxidative stress and immune responses. This study provides potential therapeutic targets and biomarkers for asthma patients, shedding further light on the pathogenesis of asthma as well as providing new insights into the treatment of asthma.
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Affiliation(s)
- Yanqing Xing
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Liting Feng
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Yangdou Dong
- College of Basic Medicine, Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Yupeng Li
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Lulu Zhang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Qiannan Wu
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Rujie Huo
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Yanting Dong
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Xinrui Tian
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Xinli Tian
- Department of Cardiology, Chinese PLA General Hospital, Beijing, People’s Republic of China
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