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Liu Z, Zheng Q, Li Z, Huang M, Zhong C, Yu R, Jiang R, Dai H, Zhang J, Gu X, Xu Y, Li C, Shan S, Xu F, Hong Y, Ren T. Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosis. EBioMedicine 2025; 112:105538. [PMID: 39753035 PMCID: PMC11754162 DOI: 10.1016/j.ebiom.2024.105538] [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: 08/27/2024] [Revised: 11/21/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways. METHODS Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation. FINDINGS An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function. INTERPRETATION Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways. FUNDING National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).
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Affiliation(s)
- Zeyu Liu
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Qi Zheng
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zhoubin Li
- Department of Lung Transplantation and Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR China
| | - Moli Huang
- Department of Bioinformatics, School of Biological and Basic Medical Sciences, Soochow University, Suzhou, 215123, China
| | - Cheng Zhong
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Ruize Yu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China
| | - Rong Jiang
- Department of Bioinformatics, School of Biological and Basic Medical Sciences, Soochow University, Suzhou, 215123, China
| | - Haotian Dai
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jingyuan Zhang
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xiaohua Gu
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yongle Xu
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Chunwei Li
- Department of Otolaryngology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Shan Shan
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Feng Xu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China.
| | - Yue Hong
- School of Life and Health Sciences, Hainan University, Haikou, Hainan 570228, China; Hainan Province Key Laboratory of One Health, Collaborative Innovation Center of One Health, Hainan University, Haikou, Hainan 570228, China.
| | - Tao Ren
- Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Smith-Davidson P, Altartoor K, Kabongo MM, Claussen H, Arthur RA, Johnston HR, DelGaudio JM, Wise SK, Solares CA, Barrow EM, Magliocca KR, Koval M, Levy JM. Prostaglandin E Receptor 2 (EP2) Dysregulation in Allergic Fungal Rhinosinusitis Nasal Polyp Epithelium. Laryngoscope 2024. [PMID: 39487665 DOI: 10.1002/lary.31868] [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: 05/09/2024] [Revised: 08/14/2024] [Accepted: 10/10/2024] [Indexed: 11/04/2024]
Abstract
OBJECTIVES Allergic fungal rhinosinusitis (AFRS) is an eosinophilic subtype of chronic rhinosinusitis with nasal polyposis (CRSwNP). This study aimed to investigate the transcriptome of AFRS nasal polyp epithelium. METHODS Sinonasal epithelial cells were harvested from healthy nasal mucosa and polyp tissue collected from participants undergoing elective sinonasal surgery. Primary epithelial cells were subsequently grown in air/liquid interface and subjected to RNA-seq analysis, RT-qPCR, immunoblotting, and immunostaining. RESULTS A total of 19 genes were differentially expressed between healthy and AFRS sample epithelium. The second top candidate gene, ranked by adjusted p-value, was prostaglandin E receptor 2 (PTGER2). The upregulation of PTGER2 was confirmed by RT-qPCR and immunoblot. The presence of the EP2 receptor, encoded by the PTGER2 gene, was confirmed by immunocytochemistry. CONCLUSION PTGER2 is a potential novel therapeutic target for AFRS. EP2 dysregulation is associated with aspirin-exacerbated respiratory disease, potentially giving insight into common mechanisms of disease in severe CRSwNP. LEVEL OF EVIDENCE NA Laryngoscope, 2024.
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Affiliation(s)
- Prestina Smith-Davidson
- Sinonasal and Olfaction Program, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland, U.S.A
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Khaled Altartoor
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - M M Kabongo
- Sinonasal and Olfaction Program, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland, U.S.A
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Henry Claussen
- Emory Integrated Computational Core, Emory University, Atlanta, Georgia, U.S.A
| | - Robert A Arthur
- Emory Integrated Computational Core, Emory University, Atlanta, Georgia, U.S.A
| | - H R Johnston
- Emory Integrated Computational Core, Emory University, Atlanta, Georgia, U.S.A
| | - John M DelGaudio
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Sarah K Wise
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - C A Solares
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Emily M Barrow
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
| | - Kelly R Magliocca
- Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University, Atlanta, Georgia, U.S.A
| | - Michael Koval
- Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, Georgia, U.S.A
| | - Joshua M Levy
- Sinonasal and Olfaction Program, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland, U.S.A
- Department of Otolaryngology - Head and Neck Surgery, Emory University School of Medicine, Emory University, Atlanta, Georgia, U.S.A
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Hanusrichterova J, Kolomaznik M, Barosova R, Adamcakova J, Mokra D, Mokry J, Skovierova H, Kelly MM, de Heuvel E, Wiehler S, Proud D, Shen H, Mukherjee PG, Amrein MW, Calkovska A. Pulmonary surfactant and prostaglandin E 2 in airway smooth muscle relaxation of human and male guinea pigs. Physiol Rep 2024; 12:e70026. [PMID: 39245804 PMCID: PMC11381196 DOI: 10.14814/phy2.70026] [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: 05/18/2024] [Revised: 08/12/2024] [Accepted: 08/22/2024] [Indexed: 09/10/2024] Open
Abstract
Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to β2-agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2-related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways.
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Grants
- APVV-17-0250 Agentúra na Podporu Výskumu a Vývoja (APVV)
- VEGA 1/0055/19 Vedecká Grantová Agentúra MŠVVaŠ SR a SAV (VEGA)
- 26246 Ministerstvo školstva, vedy, výskumu a športu SR | Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR (Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU)
- 34237 Ministerstvo školstva, vedy, výskumu a športu SR | Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR (Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU)
- University of Calgary (U of C)
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Affiliation(s)
- J Hanusrichterova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - M Kolomaznik
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - R Barosova
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - J Adamcakova
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - D Mokra
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - J Mokry
- Department of Pharmacology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - H Skovierova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - M M Kelly
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - E de Heuvel
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - S Wiehler
- Department of Physiology and Pharmacology and Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - D Proud
- Department of Physiology and Pharmacology and Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - H Shen
- Department of Mathematics and Statistics, Faculty of Science, University of Calgary, Calgary, Alberta, Canada
| | - P G Mukherjee
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - M W Amrein
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - A Calkovska
- Department of Physiology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
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Zhou Q, Chen Y, Liang Y, Sun Y. The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Metabolites 2024; 14:317. [PMID: 38921452 PMCID: PMC11205356 DOI: 10.3390/metabo14060317] [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: 04/19/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment.
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Affiliation(s)
- Qiqiang Zhou
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
| | - Yahong Chen
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Ying Liang
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
| | - Yongchang Sun
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China; (Q.Z.); (Y.C.); (Y.S.)
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing 100191, China
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5
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Xu D, Wang X, Shi W, Bao Y. Lonicera flos and Curcuma longa L. extracts improve growth performance, antioxidant capacity and immune response in broiler chickens. Front Vet Sci 2024; 11:1388632. [PMID: 38681856 PMCID: PMC11045969 DOI: 10.3389/fvets.2024.1388632] [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: 02/20/2024] [Accepted: 03/28/2024] [Indexed: 05/01/2024] Open
Abstract
Alternatives to antibiotics are urgently needed to maintain broiler growth and health. The present study was conducted to evaluate the effects of Lonicera flos and Curcuma longa L. extracts (LCE) as antibiotic substitutes on growth performance, antioxidant capacity and immune response in broilers. A total of 480 one-day-old female broilers (WOD168) were allocated to 3 treatments with 5 replicates of 32 birds for 35 days. The 3 treatments were: an antibiotic-free basal diet (control, CON), CON +50 mg/kg spectinomycin hydrochloride and 25 mg/kg lincomycin hydrochloride (ANT), CON +500 mg/kg LCE (LCE). During the entire experimental period, supplementation of ANT and LCE increased (p < 0.01) average daily gain (ADG) and decreased (p < 0.05) feed conversion ratio (FCR), thereby resulting in greater final body weight (BW) compared with CON. Dietary LCE supplementation increased (p < 0.05) serum (glutathione peroxidase) GSH-Px, (superoxide dismutase) SOD and total antioxidant capacity (T-AOC) activities, and decreased (p < 0.05) serum malonaldehyde (MDA) concentration at day 35 compared with CON. There was no significant difference in serum catalase (CAT) activity among treatments. Birds in LCE group had lower (p < 0.05) MDA concentration and higher SOD activity in liver than those in CON and ANT groups at day 35. Birds in LCE group had higher (p < 0.05) phagocytic index and serum antibody titers to Newcastle disease virus (NDV) than those in CON group. Lower (p < 0.05) concentrations of pro-inflammatory cytokines and higher (p < 0.05) concentrations of anti-inflammatory cytokines in serum and liver were observed in birds fed LCE diet than those fed CON diet. In conclusion, dietary supplementation of LCE improved growth performance by enhancing antioxidant capacity, strengthening immune system and alleviating inflammation, which has potential as antibiotic alternatives.
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Affiliation(s)
- Dahai Xu
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Xiao Wang
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Wanyu Shi
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Hebei Provincial Veterinary Biotechnology Innovation Center, Baoding, China
- Hebei Provincial Traditional Chinese Veterinary Medicine Technology Innovation Center, Baoding, China
| | - Yongzhan Bao
- College of Traditional Chinese Veterinary Medicine, Hebei Agricultural University, Baoding, China
- Hebei Provincial Veterinary Biotechnology Innovation Center, Baoding, China
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Zheng M, Zhu W, Gao F, Zhuo Y, Zheng M, Wu G, Feng C. Novel inhalation therapy in pulmonary fibrosis: principles, applications and prospects. J Nanobiotechnology 2024; 22:136. [PMID: 38553716 PMCID: PMC10981316 DOI: 10.1186/s12951-024-02407-6] [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: 09/24/2023] [Accepted: 03/18/2024] [Indexed: 04/01/2024] Open
Abstract
Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.
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Affiliation(s)
- Meiling Zheng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100010, China
- Peking University People's Hospital, Beijing, 100032, China
| | - Wei Zhu
- Department of Ophthalmology, Changshu No. 2 People's Hospital, Changshu, 215500, China
| | - Fei Gao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
| | - Yu Zhuo
- Department of Medical Oncology Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 100010, China
| | - Mo Zheng
- Department of Medical Oncology Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 100010, China
| | - Guanghao Wu
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China.
| | - Cuiling Feng
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100010, China.
- Peking University People's Hospital, Beijing, 100032, China.
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Cui Y, Lv Z, Yang Z, Lei J. Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection. Lung 2023; 201:591-601. [PMID: 37934242 DOI: 10.1007/s00408-023-00651-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/02/2023] [Accepted: 10/13/2023] [Indexed: 11/08/2023]
Abstract
PURPOSE Acute rejection is a frequent complication among lung transplant recipients and poses substantial therapeutic challenges. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme responsible for the inactivation of prostaglandin E2 (PGE2), has recently been implicated in inflammatory lung diseases. However, the role of 15-PGDH in lung transplantation rejection remains elusive. The present study was undertaken to examine the expression of 15-PGDH in rejected lung allografts and whether inhibition of 15-PGDH ameliorates acute lung allograft rejection. METHODS Orthotopic mouse lung transplantations were performed between donor and recipient mice of the same strain or allogeneic mismatched pairs. The expression of 15-PGDH in mouse lung grafts was measured. The efficacy of a selective 15-PGDH inhibitor (SW033291) in ameliorating acute rejection was assessed through histopathological examination, micro-CT imaging, and pulmonary function tests. Additionally, the mechanism underlying the effects of SW033291 treatment was explored using CD8+ T cells isolated from mouse lung allografts. RESULTS Increased 15-PGDH expression was observed in rejected allografts and allogeneic CD8+ T cells. Treatment with SW033291 led to an accumulation of PGE2, modulation of CD8+ T-cell responses and mitochondrial activity, and improved allograft function and survival. CONCLUSION Our study provides new insights into the role of 15-PGDH in acute lung rejection and highlights the therapeutic potential of inhibiting 15-PGDH for enhancing graft survival. The accumulation of PGE2 and modulation of CD8+ T-cell responses represent potential mechanisms underlying the benefits of 15-PGDH inhibition in this model. Our findings provide impetus for further exploring 15-PGDH as a target for improving lung transplantation outcomes.
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Affiliation(s)
- Ye Cui
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xi Tou Tiao, You An Men Wai, Fengtai, Beijing, 100069, People's Republic of China.
| | - Zhe Lv
- Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xi Tou Tiao, You An Men Wai, Fengtai, Beijing, 100069, People's Republic of China
| | - Zeran Yang
- Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People's Republic of China
| | - Jianfeng Lei
- Research Core Facilities, Capital Medical University, Beijing, 100069, People's Republic of China
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Yudhawati R, Shimizu K. PGE2 Produced by Exogenous MSCs Promotes Immunoregulation in ARDS Induced by Highly Pathogenic Influenza A through Activation of the Wnt-β-Catenin Signaling Pathway. Int J Mol Sci 2023; 24:ijms24087299. [PMID: 37108459 PMCID: PMC10138595 DOI: 10.3390/ijms24087299] [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: 02/06/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation.
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Affiliation(s)
- Resti Yudhawati
- Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga-Dr. Soetomo General Academic Hospital, Surabaya 60286, Indonesia
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
| | - Kazufumi Shimizu
- Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Institute of Tropical Disease, Airlangga University, Surabaya 60286, Indonesia
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Wang Z, He Y, Li Q, Zhao Y, Zhang G, Luo Z. Network analyses of upper and lower airway transcriptomes identify shared mechanisms among children with recurrent wheezing and school-age asthma. Front Immunol 2023; 14:1087551. [PMID: 36776870 PMCID: PMC9911682 DOI: 10.3389/fimmu.2023.1087551] [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: 11/09/2022] [Accepted: 01/16/2023] [Indexed: 01/30/2023] Open
Abstract
Background Predicting which preschool children with recurrent wheezing (RW) will develop school-age asthma (SA) is difficult, highlighting the critical need to clarify the pathogenesis of RW and the mechanistic relationship between RW and SA. Despite shared environmental exposures and genetic determinants, RW and SA are usually studied in isolation. Based on network analysis of nasal and tracheal transcriptomes, we aimed to identify convergent transcriptomic mechanisms in RW and SA. Methods RNA-sequencing data from nasal and tracheal brushing samples were acquired from the Gene Expression Omnibus. Combined with single-cell transcriptome data, cell deconvolution was used to infer the composition of 18 cellular components within the airway. Consensus weighted gene co-expression network analysis was performed to identify consensus modules closely related to both RW and SA. Shared pathways underlying consensus modules between RW and SA were explored by enrichment analysis. Hub genes between RW and SA were identified using machine learning strategies and validated using external datasets and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential value of hub genes in defining RW subsets was determined using nasal and tracheal transcriptome data. Results Co-expression network analysis revealed similarities in the transcriptional networks of RW and SA in the upper and lower airways. Cell deconvolution analysis revealed an increase in mast cell fraction but decrease in club cell fraction in both RW and SA airways compared to controls. Consensus network analysis identified two consensus modules highly associated with both RW and SA. Enrichment analysis of the two consensus modules indicated that fatty acid metabolism-related pathways were shared key signals between RW and SA. Furthermore, machine learning strategies identified five hub genes, i.e., CST1, CST2, CST4, POSTN, and NRTK2, with the up-regulated hub genes in RW and SA validated using three independent external datasets and qRT-PCR. The gene signatures of the five hub genes could potentially be used to determine type 2 (T2)-high and T2-low subsets in preschoolers with RW. Conclusions These findings improve our understanding of the molecular pathogenesis of RW and provide a rationale for future exploration of the mechanistic relationship between RW and SA.
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Affiliation(s)
- Zhili Wang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yu He
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Qinyuan Li
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Yan Zhao
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Ministry of Education, Chongqing, China.,Chongqing Key Laboratory of Pediatrics, Chongqing, China
| | - Guangli Zhang
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengxiu Luo
- Department of Respiratory Medicine, Children's Hospital of Chongqing Medical University, Chongqing, China
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10
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The role of PGE2 and EP receptors on lung's immune and structural cells; possibilities for future asthma therapy. Pharmacol Ther 2023; 241:108313. [PMID: 36427569 DOI: 10.1016/j.pharmthera.2022.108313] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/08/2022] [Revised: 10/06/2022] [Accepted: 11/17/2022] [Indexed: 11/27/2022]
Abstract
Asthma is the most common airway chronic disease with treatments aimed mainly to control the symptoms. Adrenergic receptor agonists, corticosteroids and anti-leukotrienes have been used for decades, and the development of more targeted asthma treatments, known as biological therapies, were only recently established. However, due to the complexity of asthma and the limited efficacy as well as the side effects of available treatments, there is an urgent need for a new generation of asthma therapies. The anti-inflammatory and bronchodilatory effects of prostaglandin E2 in asthma are promising, yet complicated by undesirable side effects, such as cough and airway irritation. In this review, we summarize the most important literature on the role of all four E prostanoid (EP) receptors on the lung's immune and structural cells to further dissect the relevance of EP2/EP4 receptors as potential targets for future asthma therapy.
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11
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Bae GH, Kim YS, Park JY, Lee M, Lee SK, Kim JC, Kim JG, Shin YJ, Lee H, Kim SY, Bae YS, Zabel BA, Kim HS, Bae YS. Unique characteristics of lung-resident neutrophils are maintained by PGE2/PKA/Tgm2-mediated signaling. Blood 2022; 140:889-899. [PMID: 35679477 PMCID: PMC9412003 DOI: 10.1182/blood.2021014283] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/30/2021] [Accepted: 06/05/2022] [Indexed: 11/20/2022] Open
Abstract
Lung-resident neutrophils need to be tightly regulated to avoid degranulation- and cytokine-associated damage to fragile alveolar structures that can lead to fatal outcomes. Here we show that lung neutrophils (LNs) express distinct surface proteins and genes that distinguish LNs from bone marrow and blood neutrophils. Functionally, LNs show impaired migratory activity toward chemoattractants and produce high levels of interleukin-6 (IL-6) at steady state and low levels of tumor necrosis factor-α in response to lipopolysaccharide (LPS) challenge. Treating bone marrow neutrophils with bronchoalveolar lavage fluid or prostaglandin E2 induces LN-associated characteristics, including the expression of transglutaminase 2 (Tgm2) and reduced production of inflammatory cytokines upon LPS challenge. Neutrophils from Tgm2-/- mice release high levels of inflammatory cytokines in response to LPS. Lung damage is significantly exacerbated in Tgm2-/- mice in an LPS-induced acute respiratory distress syndrome model. Collectively, we demonstrate that prostaglandin E2 is a key factor for the generation of LNs with unique immune suppressive characteristics, acting through protein kinase A and Tgm2, and LNs play essential roles in protection of the lungs against pathogenic inflammation.
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Affiliation(s)
- Geon Ho Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ye Seon Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ji Ye Park
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Mingyu Lee
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
| | - Sung Kyun Lee
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
| | - Ji Cheol Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jang Gyu Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ye Ji Shin
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ho Lee
- Graduate School of Cancer Science and Policy and
| | - Soo-Youl Kim
- Research Institute, Division of Cancer Biology, National Cancer Center, Goyang, Republic of Korea; and
| | - Yong-Soo Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Brian A Zabel
- Palo Alto Veterans Institute for Research, Veterans Affairs Hospital, Palo Alto, CA
| | - Hong Sook Kim
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
| | - Yoe-Sik Bae
- Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea
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12
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Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers. Metabolites 2022; 12:metabo12070619. [PMID: 35888743 PMCID: PMC9319897 DOI: 10.3390/metabo12070619] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/07/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 12/13/2022] Open
Abstract
COVID-19 is characterised by a dysregulated immune response, that involves signalling lipids acting as mediators of the inflammatory process along the innate and adaptive phases. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The second publication in a series reports the results of quantitative LC-MS/MS profiling of 63 small lipids including oxylipins, free fatty acids, and endocannabinoids. Compared to samples taken from ward patients, intensive care unit (ICU) patients had 2−4-fold lower levels of arachidonic acid (AA) and its cyclooxygenase-derived prostanoids, as well as lipoxygenase derivatives, exhibiting negative correlations with inflammation markers. The same derivatives showed 2−5-fold increases in recovering ward patients, in paired comparison to early hospitalisation. In contrast, ICU patients showed elevated levels of oxylipins derived from poly-unsaturated fatty acids (PUFA) by non-enzymatic peroxidation or activity of soluble epoxide hydrolase (sEH), and these oxylipins positively correlated with markers of macrophage activation. The deficiency in AA enzymatic products and the lack of elevated intermediates of pro-resolving mediating lipids may result from the preference of alternative metabolic conversions rather than diminished stores of PUFA precursors. Supporting this, ICU patients showed 2-to-11-fold higher levels of linoleic acid (LA) and the corresponding fatty acyl glycerols of AA and LA, all strongly correlated with multiple markers of excessive immune response. Our results suggest that the altered oxylipin metabolism disrupts the expected shift from innate immune response to resolution of inflammation.
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13
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Plasma and bronchoalveolar lavage fluid oxylipin levels in experimental porcine lung injury. Prostaglandins Other Lipid Mediat 2022; 160:106636. [PMID: 35307566 DOI: 10.1016/j.prostaglandins.2022.106636] [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: 10/06/2021] [Revised: 03/13/2022] [Accepted: 03/15/2022] [Indexed: 11/20/2022]
Abstract
Inflammatory signaling pathways involving eicosanoids and other regulatory lipid mediators are a subject of intensive study, and a role for these in acute lung injury is not yet well understood. We hypothesized that oxylipin release from lung injury could be detected in bronchoalveolar lavage fluid and in plasma. In a porcine model of surfactant depletion, ventilation with hyperinflation was assessed. Bronchoalveolar lavage and plasma samples were analyzed for 37 different fatty acid metabolites (oxylipins). Over time, hyperinflation altered concentrations of 4 oxylipins in plasma (TXB2, PGE2, 15-HETE and 11-HETE), and 9 oxylipins in bronchoalveolar lavage fluid (PGF2α, PGE2, PGD2, 12,13-DiHOME, 11,12-DiHETrE, 13-HODE, 9-HODE, 15-HETE, 11-HETE). Acute lung injury caused by high tidal volume ventilation in this porcine model was associated with rapid changes in some elements of the oxylipin profile, detectable in lavage fluid, and plasma. These oxylipins may be relevant in the pathogenesis of acute lung injury by hyperinflation.
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14
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Jin Y, Liu Q, Chen P, Zhao S, Jiang W, Wang F, Li P, Zhang Y, Lu W, Zhong TP, Ma X, Wang X, Gartland A, Wang N, Shah KM, Zhang H, Cao X, Yang L, Liu M, Luo J. A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration. Cell Discov 2022; 8:24. [PMID: 35256606 PMCID: PMC8901748 DOI: 10.1038/s41421-022-00382-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/28/2021] [Accepted: 01/28/2022] [Indexed: 01/15/2023] Open
Abstract
Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration.
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Affiliation(s)
- Yunyun Jin
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Qianqian Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Peng Chen
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Siyuan Zhao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Wenhao Jiang
- Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China
| | - Fanhua Wang
- Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China
| | - Peng Li
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, China
| | - Yuanjin Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Tao P Zhong
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xinran Ma
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xin Wang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Alison Gartland
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Ning Wang
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Karan Mehul Shah
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK
| | - Hankun Zhang
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Xu Cao
- Departments of Orthopaedic Surgery and Biomedical Engineering and Institute of Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lei Yang
- Orthopedic Institute, Soochow University, Suzhou, Jiangsu, China.,Center for Health Science and Engineering, School of Materials Science and Engineering, Hebei University of Technology, Tianjin, China
| | - Mingyao Liu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
| | - Jian Luo
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China. .,Yangzhi Rehabilitation Hospital (Sunshine Rehabilitation Centre), Tongji University School of Medicine, Shanghai, China.
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15
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Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling. Cells 2022; 11:cells11040707. [PMID: 35203356 PMCID: PMC8870046 DOI: 10.3390/cells11040707] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/22/2021] [Revised: 02/01/2022] [Accepted: 02/14/2022] [Indexed: 02/08/2023] Open
Abstract
Apart from its role in the metabolism of carcinogens, the aryl hydrocarbon receptor (AhR) has been suggested to be involved in the control of inflammatory responses within the respiratory tract. However, the mechanisms responsible for this are only partially known. In this study, we used A549 cell line, as a human model of lung alveolar type II (ATII)-like cells, to study the functional role of the AhR in control of inflammatory responses. Using IL-1β as an inflammation inducer, we found that the induction of cyclooxygenase-2 and secretion of prostaglandins, as well as expression and release of pro-inflammatory cytokines, were significantly higher in the AhR-deficient A549 cells. This was linked with an increased nuclear factor-κB (NF-κB) activity, and significantly enhanced phosphorylation of its regulators, IKKα/β, and their target IκBα, in the AhR-deficient A549 cells. In line with this, when we mimicked the exposure to a complex mixture of airborne pollutants, using an organic extract of reference diesel exhaust particle mixture, an exacerbated inflammatory response was observed in the AhR-deficient cells, as compared with wild-type A549 cells. Together, the present results indicate that the AhR may act as a negative regulator of the inflammatory response in the A549 model, via a direct modulation of NF-κB signaling. Its role(s) in the control of inflammation within the lung alveoli exposed to airborne pollutants, especially those which simultaneously activate the AhR, thus deserve further attention.
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16
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Ulu A, Velazquez JV, Burr A, Sveiven SN, Yang J, Bravo C, Hammock BD, Nordgren TM. Sex-Specific Differences in Resolution of Airway Inflammation in Fat-1 Transgenic Mice Following Repetitive Agricultural Dust Exposure. Front Pharmacol 2022; 12:785193. [PMID: 35095496 PMCID: PMC8793679 DOI: 10.3389/fphar.2021.785193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/28/2021] [Accepted: 12/23/2021] [Indexed: 11/13/2022] Open
Abstract
In agriculture industries, workers are at increased risk for developing pulmonary diseases due to inhalation of agricultural dusts, particularly when working in enclosed confinement facilities. Agricultural dusts inhalation leads to unresolved airway inflammation that precedes the development and progression of lung disease. We have previously shown beneficial effects of the omega-3 polyunsaturated fatty acid (ω-3 PUFA) DHA in protecting against the negative inflammatory effects of repetitive dust exposure in the lung. Dietary manipulation of pulmonary disease risk is an attractive and timely approach given the contribution of an increased ω-6 to ω-3 PUFA ratio to low grade inflammation and chronic disease in the Western diet. To prevent any confounding factors that comes with dietary supplementation of ω-3 PUFA (different sources, purity, dose, and duration), we employed a Fat-1 transgenic mouse model that convert ω-6 PUFA to ω-3 PUFA, leading to a tissue ω-6 to ω-3 PUFA ratio of approximately 1:1. Building on our initial findings, we hypothesized that attaining elevated tissue levels of ω-3 PUFA would attenuate agricultural dust-induced lung inflammation and its resolution. To test this hypothesis, we compared wild-type (WT) and Fat-1 transgenic mice in their response to aqueous extracts of agricultural dust (DE). We also used a soluble epoxide hydrolase inhibitor (sEH) to potentiate the effects of ω-3 PUFA, since sEH inhibitors have been shown to stabilize the anti-inflammatory P450 metabolites derived from both ω-3 and ω-6 PUFA and promote generation of specialized pro-resolving lipid mediators from ω-3 PUFA. Over a three-week period, mice were exposed to a total of 15 intranasal instillations of DE obtained from swine confinement buildings in the Midwest. We observed genotype and sex-specific differences between the WT vs. Fat-1 transgenic mice in response to repetitive dust exposure, where three-way ANOVA revealed significant main effects of treatment, genotype, and sex. Also, Fat-1 transgenic mice displayed reduced lymphoid aggregates in the lung following DE exposure as compared to WT animals exposed to DE, suggesting improved resilience to the DE-induced inflammatory effects. Overall, our data implicate a protective role of ω-3 FA in the lung following repetitive dust exposure.
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Affiliation(s)
- Arzu Ulu
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Jalene V Velazquez
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Abigail Burr
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Stefanie N Sveiven
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Jun Yang
- Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States
| | - Carissa Bravo
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Bruce D Hammock
- Department of Entomology and Nematology, University of California Davis Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States
| | - Tara M Nordgren
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States.,Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, United States
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17
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Santin JR, Benvenutti L, Broering MF, Nunes R, Goldoni FC, Patel YBK, de Souza JA, Kopp MAT, de Souza P, da Silva RDCV, Pastor MVD, de Souza AB, Testoni LD, Couto AG, Bresolin TMB, Quintão NLM. Sambucus nigra: A traditional medicine effective in reducing inflammation in mice. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114736. [PMID: 34648899 DOI: 10.1016/j.jep.2021.114736] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/14/2021] [Revised: 10/06/2021] [Accepted: 10/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Sambucus nigra L. is a plant of European origin and popularly known as elder, elderberry, black elder, European elder, European elderberry, and European black elderberry, being described in pharmacopoeia of several countries. Its flowers and berries have been used in folk medicine to treat feverish conditions, coughing, nasal congestion, and influenza besides its popular use as anti-inflammatory, analgesic, and diuretic agent. AIM OF THE STUDY The aim of this investigation was to elucidate the anti-inflammatory and the relaxant effect of the lyophilized aqueous extract obtained from S. nigra's flowers on in vivo and in vitro inflammation assays and on the isolated rat vascular and airway smooth muscle tissue. MATERIAL AND METHODS The anti-inflammatory activity of the extract was investigated using carrageenan-induced inflammation model in the subcutaneous tissue of male Swiss mice orally treated with S. nigra extract (30, 100, 300 or 600 mg/kg). Leukocyte influx and the secretion of chemical mediators were quantified in the inflamed exudate. Additionally, histological analysis of the pouches was performed. N-Formyl-methionine-leucine-phenylalanine-induced chemotaxis, lipopolysaccharide-induced TNF, IL-6, IL-1β, IL-10 and NO production, and adhesion molecule expression (CD62L, CD49d and CD18, flow cytometry) were analyzed in vitro using oyster glycogen-recruited peritoneal neutrophils or macrophages (RAW 264.7) stimulated with LPS and treated with the extract (1, 10 or 100 μg/mL). The resolution of inflammation was accessed by efferocytosis assay, and the antinociceptive activity was investigated using carrageenan-induced mechanical hypersensitivity. Finally, the effect of the extract was evaluated in isolated rat aorta and trachea rings. RESULTS The oral treatment with S. nigra promoted reduction in the neutrophil migration as well as the decrease of TNF, IL-1β and IL-6 levels in the inflamed exudate. In vitro treatment with S. nigra decreased NO2-, TNF, IL-1β and IL-6 and promoted increase of IL-10 in LPS-stimulated neutrophils. Similarly, the extract reduced the NO2-, TNF and IL-6 in LPS-stimulated macrophages. Rutin, the major constituent of S. nigra extract reduced NO2-, TNF, IL-1β, and IL-6 and promoted the increase of IL-10 in LPS-stimulated neutrophils supernatant. The extract also shed CD62L and CD18 expressions. The extract was able to increase the efferocytosis of apoptotic neutrophils by increasing the IL-10 and decreasing the TNF levels. Additionally, the extract reduced the hypersensitivity induced by carrageenan and promoted a relaxant effect in isolated vascular and non-vascular rat tissue. CONCLUSIONS S. nigra flowers extract presents anti-inflammatory effect by modulating macrophage and neutrophil functions including the production of inflammatory mediators and cell migration, by promoting efferocytosis and consequently the resolution of acute inflammation, besides exerting antinociceptive effects, scientifically proving its popular use as medicinal plant. Allied to the relaxant effect in both vascular and non-vascular smooth muscle tissue, S. nigra extract represents an important tool for the management of acute inflammation.
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Affiliation(s)
- José Roberto Santin
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Larissa Benvenutti
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Milena Fronza Broering
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Roberta Nunes
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Fernanda Capitanio Goldoni
- Biomedicine Course, School of Health Sciences, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Jade André de Souza
- Biomedicine Course, School of Health Sciences, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Mainara Adriane Tesser Kopp
- Biomedicine Course, School of Health Sciences, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Priscila de Souza
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | | | - Angelita Boldieri de Souza
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Letícia Debatin Testoni
- Pharmacy Course, School of Health Sciences, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Angélica Garcia Couto
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Tania Mari Belle Bresolin
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Nara Lins Meira Quintão
- Postgraduate Program in Pharmaceutical Science, Universidade Do Vale Do Itajaí, Itajaí, Santa Catarina, Brazil.
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18
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Kotlyarov S. Involvement of the Innate Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2022; 23:985. [PMID: 35055174 PMCID: PMC8778852 DOI: 10.3390/ijms23020985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/27/2021] [Revised: 01/14/2022] [Accepted: 01/15/2022] [Indexed: 01/27/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a common, socially significant disease characterized by progressive airflow limitation due to chronic inflammation in the bronchi. Although the causes of COPD are considered to be known, the pathogenesis of the disease continues to be a relevant topic of study. Mechanisms of the innate immune system are involved in various links in the pathogenesis of COPD, leading to persistence of chronic inflammation in the bronchi, their bacterial colonization and disruption of lung structure and function. Bronchial epithelial cells, neutrophils, macrophages and other cells are involved in the development and progression of the disease, demonstrating multiple compromised immune mechanisms.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia
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19
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Olave CJ, Ivester KM, Couëtil LL, Franco-Marmolejo J, Mukhopadhyay A, Robinson JP, Park JH. Effects of forages, dust exposure and proresolving lipids on airway inflammation in horses. Am J Vet Res 2021; 83:153-161. [PMID: 34843444 DOI: 10.2460/ajvr.21.08.0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To investigate the role of omega-3 polyunsaturated fatty acids (Ω-3)-derived proresolving lipid mediators (PRLM) in the resolution of mild airway inflammation in horses. ANIMALS 20 horses with mild airway inflammation. PROCEDURES Horses previously eating hay were fed hay pellets (low Ω-3 content; n = 10) or haylage (high Ω-3 content; 9) for 6 weeks. Dust exposure was measured in the breathing zone with a real-time particulate monitor. Bronchoalveolar lavage (BAL) was performed at baseline, week 3, and week 6. The effect of PRLM on neutrophil apoptosis and efferocytosis was examined in vitro. BAL fluid inflammatory cell proportions, apoptosis of circulating neutrophils, efferocytosis displayed by alveolar macrophages, and plasma lipid concentrations were compared between groups fed low and high amounts of Ω-3 by use of repeated measures of generalized linear models. RESULTS Dust exposure was significantly higher with hay feeding, compared to haylage and pellets, and equivalent between haylage and pellets. BAL fluid neutrophil proportions decreased significantly in horses fed haylage (baseline, 11.8 ± 2.4%; week 6, 2.5 ± 1.1%) but not pellets (baseline, 12.1 ± 2.3%; week 6, 8.5% ± 1.7%). At week 6, horses eating haylage had significantly lower BAL neutrophil proportions than those eating pellets, and a significantly lower concentration of stearic acid than at baseline. PRLM treatments did not affect neutrophil apoptosis or efferocytosis. CLINICAL RELEVANCE Despite similar reduction in dust exposure, horses fed haylage displayed greater resolution of airway inflammation than those fed pellets. This improvement was not associated with increased plasma Ω-3 concentrations. Feeding haylage improves airway inflammation beyond that due to reduced dust exposure, though the mechanism remains unclear.
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Affiliation(s)
- Carla J Olave
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN
| | - Kathleen M Ivester
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN
| | - Laurent L Couëtil
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN
| | | | - Abhijit Mukhopadhyay
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN
| | - J Paul Robinson
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN.,Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN
| | - Jae H Park
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN
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20
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Olguín-Martínez E, Ruiz-Medina BE, Licona-Limón P. Tissue-Specific Molecular Markers and Heterogeneity in Type 2 Innate Lymphoid Cells. Front Immunol 2021; 12:757967. [PMID: 34759931 PMCID: PMC8573327 DOI: 10.3389/fimmu.2021.757967] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/13/2021] [Accepted: 09/21/2021] [Indexed: 12/25/2022] Open
Abstract
Innate lymphoid cells (ILCs) are the most recently described group of lymphoid subpopulations. These tissue-resident cells display a heterogeneity resembling that observed on different groups of T cells, hence their categorization as cytotoxic NK cells and helper ILCs type 1, 2 and 3. Each one of these groups is highly diverse and expresses different markers in a context-dependent manner. Type 2 innate lymphoid cells (ILC2s) are activated in response to helminth parasites and regulate the immune response. They are involved in the etiology of diseases associated with allergic responses as well as in the maintenance of tissue homeostasis. Markers associated with their identification differ depending on the tissue and model used, making the study and understanding of these cells a cumbersome task. This review compiles evidence for the heterogeneity of ILC2s as well as discussion and analyses of molecular markers associated with their identity, function, tissue-dependent expression, and how these markers contribute to the interaction of ILC2s with specific microenvironments to maintain homeostasis or respond to pathogenic challenges.
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Affiliation(s)
- Enrique Olguín-Martínez
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
| | - Blanca E Ruiz-Medina
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
| | - Paula Licona-Limón
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
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21
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Rossner P, Cervena T, Vojtisek-Lom M, Neca J, Ciganek M, Vrbova K, Ambroz A, Novakova Z, Elzeinova F, Sima M, Simova Z, Holan V, Beranek V, Pechout M, Macoun D, Rossnerova A, Topinka J. Markers of lipid oxidation and inflammation in bronchial cells exposed to complete gasoline emissions and their organic extracts. CHEMOSPHERE 2021; 281:130833. [PMID: 34015653 DOI: 10.1016/j.chemosphere.2021.130833] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 01/15/2021] [Revised: 04/29/2021] [Accepted: 05/04/2021] [Indexed: 06/12/2023]
Abstract
Road traffic emissions consist of gaseous components, particles of various sizes, and chemical compounds that are bound to them. Exposure to vehicle emissions is implicated in the etiology of inflammatory respiratory disorders. We investigated the inflammation-related markers in human bronchial epithelial cells (BEAS-2B) and a 3D model of the human airways (MucilAir™), after exposure to complete emissions and extractable organic matter (EOM) from particles generated by ordinary gasoline (E5), and a gasoline-ethanol blend (E20; ethanol content 20% v/v). The production of 22 lipid oxidation products (derivatives of linoleic and arachidonic acid, AA) and 45 inflammatory molecules (cytokines, chemokines, growth factors) was assessed after days 1 and 5 of exposure, using LC-MS/MS and a multiplex immunoassay, respectively. The response observed in MucilAir™ exposed to E5 gasoline emissions, characterized by elevated levels of pro-inflammatory AA metabolites (prostaglandins) and inflammatory markers, was the most pronounced. E20 EOM exposure was associated with increased levels of AA metabolites with anti-inflammatory effects in this cell model. The exposure of BEAS-2B cells to complete emissions reduced lipid oxidation, while E20 EOM tended to increase concentrations of AA metabolite and chemokine production; the impacts on other inflammatory markers were limited. In summary, complete E5 emission exposure of MucilAir™ induces the processes associated with the pro-inflammatory response. This observation highlights the potential negative health impacts of ordinary gasoline, while the effects of alternative fuel are relatively weak.
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Affiliation(s)
- Pavel Rossner
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Tereza Cervena
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University, Vinicna 7, 128 44, Prague, Czech Republic.
| | - Michal Vojtisek-Lom
- Centre of Vehicles for Sustainable Mobility, Faculty of Mechanical Engineering, Czech Technical University in Prague, Technicka 4, 160 00, Prague, Czech Republic.
| | - Jiri Neca
- Department of Chemistry and Toxicology, Veterinary Research Institute, 621 00, Brno, Czech Republic.
| | - Miroslav Ciganek
- Department of Chemistry and Toxicology, Veterinary Research Institute, 621 00, Brno, Czech Republic.
| | - Kristyna Vrbova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Antonin Ambroz
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Zuzana Novakova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Fatima Elzeinova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Michal Sima
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Zuzana Simova
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Vladimir Holan
- Department of Nanotoxicology and Molecular Epidemiology, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Vit Beranek
- Centre of Vehicles for Sustainable Mobility, Faculty of Mechanical Engineering, Czech Technical University in Prague, Technicka 4, 160 00, Prague, Czech Republic.
| | - Martin Pechout
- Department of Vehicles and Ground Transport, Czech University of Life Sciences in Prague, Kamycka 129, 165 21, Prague, Czech Republic.
| | - David Macoun
- Department of Vehicles and Ground Transport, Czech University of Life Sciences in Prague, Kamycka 129, 165 21, Prague, Czech Republic.
| | - Andrea Rossnerova
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
| | - Jan Topinka
- Department of Genetic Toxicology and Epigenetics, Institute of Experimental Medicine of the CAS, Videnska 1083, 142 20, Prague, Czech Republic.
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22
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Gad El-Hak HN, Mohamed OE, Nabil ZI. Evaluating the protective role of Deglycyrrhizinated licorice root supplement on bleomycin induced pulmonary oxidative damage. Toxicol Mech Methods 2021; 32:180-193. [PMID: 34488542 DOI: 10.1080/15376516.2021.1977881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/06/2023]
Abstract
The goal of this study was to investigate the protective effect of licorice supplements in a rat model of Bleomycin-induced lung oxidative damage over a duration of one month. The rats were randomly divided into six groups (n = 10 per group). Control group; Bleomycin group (B): rats were IP injected with bleomycin 5 mg/kg twice weekly. Licorice group (L): rats received orally 300 mg/kg licorice extract. Bleomycin and a low dose of Licorice group (BLLG): rats received orally 75 mg/kg licorice daily and injected as the B group. Bleomycin and a middle dose of Licorice group (BMLG): rats received orally 150 mg/kg licorice daily and injected as the Bleomycin group. Bleomycin and a high dose of Licorice group (BHLG): rats received orally 300 mg/kg licorice daily and injected as the Bleomycin group. Treatment with Bleomycin induced inflammation and oxidative damage to the lungs expressed in the disturbance of the measured parameters in the blood serum, the lung tissue, and the broncholavage fluid. In addition to the decreased expression of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT) in the lung tissues. Bleomycin caused deformative changes in the histopathological and cellular examination of the lungs especially in the alveolar cells and the interstitial space. On the other hand, treated the bleomycin group with different doses of licorice supplement activates the antioxidant defense mechanism and attenuates the oxidative damage and damage induced to the lung. In conclusion, Deglycyrrhizinated licorice root supplement provided strong antioxidant and protective effects on Bleomycin-induced lung damage.
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Affiliation(s)
- Heba N Gad El-Hak
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Osman E Mohamed
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
| | - Zohour I Nabil
- Zoology Department, Faculty of Science, Suez Canal University, Ismailia, Egypt
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23
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Kountz TS, Jairaman A, Kountz CD, Stauderman KA, Schleimer RP, Prakriya M. Differential Regulation of ATP- and UTP-Evoked Prostaglandin E 2 and IL-6 Production from Human Airway Epithelial Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:1275-1287. [PMID: 34389624 PMCID: PMC8816324 DOI: 10.4049/jimmunol.2100127] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 02/09/2021] [Accepted: 07/07/2021] [Indexed: 11/19/2022]
Abstract
The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE2 limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE2 and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca2+ release-activated Ca2+ (CRAC) channels. ATP-mediated synthesis of PGE2 required activation of metabotropic P2Y2 receptors and CRAC channel-mediated cytosolic phospholipase A2 signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE2 and IL-6, the uridine nucleotide, UTP, stimulated PGE2 but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y2 receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.
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Affiliation(s)
- Timothy S Kountz
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Amit Jairaman
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Candace D Kountz
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - Robert P Schleimer
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Murali Prakriya
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL;
- Division of Allergy and Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
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24
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Eicosanoid receptors as therapeutic targets for asthma. Clin Sci (Lond) 2021; 135:1945-1980. [PMID: 34401905 DOI: 10.1042/cs20190657] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/18/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 12/16/2022]
Abstract
Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.
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25
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Bottemanne P, Paquot A, Ameraoui H, Guillemot-Legris O, Alhouayek M, Muccioli GG. 25-Hydroxycholesterol metabolism is altered by lung inflammation, and its local administration modulates lung inflammation in mice. FASEB J 2021; 35:e21514. [PMID: 33734509 DOI: 10.1096/fj.202002555r] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/23/2020] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 12/12/2022]
Abstract
Inflammation is a critical component of many lung diseases including asthma and acute lung injury (ALI). Using high-performance liquid chromatography-mass spectrometry, we quantified the levels of oxysterols in two different murine models of lung diseases. These are lipid mediators derived from cholesterol and known to modulate immunity and inflammation. Interestingly, 25-hydroxycholesterol (25-OHC) was the only oxysterol with altered levels during lung inflammation, and its levels were differently affected according to the model. Therefore, we sought to assess how this oxysterol would affect lung inflammatory responses. In a model of lipopolysaccharide (LPS)-induced acute lung inflammation, 25-OHC levels were increased, and most of the hallmarks of the model (eg, leukocyte recruitment, mRNA expression, and secretion of inflammatory cytokines) were decreased following its intratracheal administration. We also found that, when administered in the lung, 25-OHC is metabolized locally into 25-hydroxycholesterol-3-sulfate and 7α,25-dihydroxycholesterol. Their administration in the lungs did not recapitulate all the effects of 25-OHC. Conversely, in a model of allergic asthma induced by intranasal administration of house dust mites (HDM), 25-OHC levels were decreased, and when intranasally administered, this oxysterol worsened the hallmarks of the model (eg, leukocyte recruitment, tissue remodeling [epithelium thickening and peribranchial fibrosis], and cytokine expression) and induced changes in leukotriene levels. Ex vivo, we found that 25-OHC decreases LPS-induced primary alveolar macrophage activation while having no effect on neutrophil activation. Its sulfated metabolite, 25-hydroxycholesterol-3-sulfate, decreased neutrophil, but not macrophage activation. Taken together, our data support a differential role of 25-OHC in ALI and allergic inflammation models.
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Affiliation(s)
- Pauline Bottemanne
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Adrien Paquot
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Hafsa Ameraoui
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Owein Guillemot-Legris
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
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26
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van Geffen C, Deißler A, Beer-Hammer S, Nürnberg B, Handgretinger R, Renz H, Hartl D, Kolahian S. Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4. Front Immunol 2021; 12:695933. [PMID: 34322123 PMCID: PMC8311661 DOI: 10.3389/fimmu.2021.695933] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/15/2021] [Accepted: 06/24/2021] [Indexed: 01/22/2023] Open
Abstract
Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice. Collectively, our results provide evidence that MDSCs dampen airway inflammation in murine asthma through a mechanism involving EP4.
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MESH Headings
- Adoptive Transfer
- Animals
- Antigens, Dermatophagoides/immunology
- Arginase/metabolism
- Arginase/pharmacology
- Arthropod Proteins/immunology
- Asthma/immunology
- Asthma/metabolism
- Asthma/therapy
- Cells, Cultured
- Cytokines/metabolism
- Dinoprostone/pharmacology
- Disease Models, Animal
- Female
- Lung/drug effects
- Lung/immunology
- Lung/metabolism
- Mice, Inbred BALB C
- Myeloid-Derived Suppressor Cells/drug effects
- Myeloid-Derived Suppressor Cells/immunology
- Myeloid-Derived Suppressor Cells/metabolism
- Myeloid-Derived Suppressor Cells/transplantation
- Nitric Oxide Synthase Type II/metabolism
- Pneumonia/immunology
- Pneumonia/metabolism
- Pneumonia/therapy
- Pyroglyphidae/immunology
- Pyrrolidinones/pharmacology
- Receptors, Prostaglandin E, EP2 Subtype/agonists
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP4 Subtype/agonists
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Signal Transduction
- Tetrazoles/pharmacology
- Mice
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Affiliation(s)
- Chiel van Geffen
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Astrid Deißler
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
| | - Sandra Beer-Hammer
- Department of Pharmacology, Experimental Therapy & Toxicology and Interfaculty Center of Pharmacogenomics & Drug Research (IZePhA), University Hospitals and Clinics, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Bernd Nürnberg
- Department of Pharmacology, Experimental Therapy & Toxicology and Interfaculty Center of Pharmacogenomics & Drug Research (IZePhA), University Hospitals and Clinics, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Rupert Handgretinger
- Children’s University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Dominik Hartl
- Department of Pediatrics I, Eberhard Karls University of Tübingen, Tübingen, Germany
- Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Saeed Kolahian
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
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27
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Hult EM, Gurczynski SJ, Moore BB. M2 macrophages have unique transcriptomes but conditioned media does not promote profibrotic responses in lung fibroblasts or alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 2021; 321:L518-L532. [PMID: 34231378 DOI: 10.1152/ajplung.00107.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022] Open
Abstract
Macrophages are critical regulators of pulmonary fibrosis. Their plasticity, proximity, and ability to cross talk with structural cells of the lung make them a key cell type of interest in the regulation of lung fibrosis. Macrophages can express a variety of phenotypes, which have been historically represented through an "M1-like" to "M2-like" delineation. In this classification, M1-like macrophages are proinflammatory and have increased phagocytic capacity compared with alternatively activated M2-like macrophages that are profibrotic and are associated with wound healing. Extensive evidence in the field in both patients and animal models aligns pulmonary fibrosis with M2 macrophages. In this study, we performed RNA sequencing (RNAseq) to fully characterize M1- vs. M2-skewed bone marrow-derived macrophages (BMDMs) and investigated the profibrotic abilities of M2 BMDM conditioned media (CM) to promote fibroblast migration and proliferation, alveolar epithelial cell (AEC) apoptosis, and mRNA expression of key fibrotic genes in both fibroblasts and AECs. Although M2 CM-treated fibroblasts had increased migration and M2 CM-treated fibroblasts and AECs had increased expression of profibrotic proteins over M1 CM-treated cells, all differences can be attributed to M2 polarization reagents IL-4 and IL-13 also present in the CM. Collectively, these data suggest that the profibrotic effects associated with M2 macrophage CM in vitro are attributable to effects of polarization cytokines rather than additional factors secreted in response to those polarizing cytokines.
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Affiliation(s)
- Elissa M Hult
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Stephen J Gurczynski
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan
| | - Bethany B Moore
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan.,Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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28
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Ripon MAR, Bhowmik DR, Amin MT, Hossain MS. Role of arachidonic cascade in COVID-19 infection: A review. Prostaglandins Other Lipid Mediat 2021; 154:106539. [PMID: 33592322 PMCID: PMC7882227 DOI: 10.1016/j.prostaglandins.2021.106539] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/30/2020] [Revised: 02/01/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023]
Abstract
The World Health Organization has described the 2019 Coronavirus disease caused by an influenza-like virus called SARS-CoV-2 as a pandemic. Millions of people worldwide are already infected by this virus, and severe infection causes hyper inflammation, thus disrupting lung function, exacerbating breath difficulties, and death. Various inflammatory mediators bio-synthesized through the arachidonic acid pathway play roles in developing cytokine storms, injuring virus-infected cells. Since pro-inflammatory eicosanoids, including prostaglandins, and leukotrienes, are key brokers for physiological processes such as inflammation, fever, allergy, and pain but, their function in COVID-19 is not well defined. This study addresses eicosanoid's crucial role through the arachidonic pathway in inflammatory cascading and recommends using bioactive lipids, NSAIDs, steroids, cell phospholipase A2 (cPLA2) inhibitors, and specialized pro-resolving mediators (SPMs) to treat COVID-19 disease. The role of soluble epoxide hydrolase inhibitors (SEHIs) in promoting the activity of epoxyeicosatrienoic acids (EETs) and 17-hydroxide-docosahexaenoic acid (17-HDHA) is also discussed. Additional research that assesses the eicosanoid profile in COVID-19 patients or preclinical models generates novel insights into coronavirus-host interaction and inflammation regulation.
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Affiliation(s)
- Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Dipty Rani Bhowmik
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Mohammad Tohidul Amin
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh.
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Bormann T, Maus R, Stolper J, Jonigk D, Welte T, Gauldie J, Kolb M, Maus UA. Role of the COX2-PGE 2 axis in S. pneumoniae-induced exacerbation of experimental fibrosis. Am J Physiol Lung Cell Mol Physiol 2020; 320:L377-L392. [PMID: 33296268 DOI: 10.1152/ajplung.00024.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/26/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) associated with high morbidity and mortality. Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and/or bacterial infections. Prostaglandin E2 (PGE2) is an eicosanoid released in a cyclooxygenase-2 (COX2)-dependent manner and is considered to contribute to regulation of lung fibrosis. However, its role in infection-induced exacerbation of lung fibrosis is poorly defined. We found significantly increased levels of PGE2 in lung tissue of patients with ILD. Increased levels of PGE2 were also found in lung tissue of mice with AdTGF-β1-induced lung fibrosis and even more so in Streptococcus pneumoniae exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE2 release during exacerbating fibrosis. Application of parecoxib to inhibit PGE2 synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE2 worsened lung fibrosis in mice. Both interventions had no effect on S. pneumoniae-exacerbated lung fibrosis. Together, we found that the COX2-PGE2 axis has dual roles in fibrosis that may offset each other: PGE2 helps resolve infection/attenuate inflammation in fibrosis exacerbation but accentuates TGF-β/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE2 interventions in the setting of non-exacerbating lung fibrosis.
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Affiliation(s)
- Tina Bormann
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | - Regina Maus
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | - Jennifer Stolper
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany
| | - Danny Jonigk
- Department of Pathology, Hannover Medical School, Hannover, Germany.,German Center for Lung Research, partner site BREATH, Hannover, Germany
| | - Tobias Welte
- German Center for Lung Research, partner site BREATH, Hannover, Germany.,Clinic for Pneumology, Hannover Medical School, Hannover, Germany
| | - Jack Gauldie
- Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Martin Kolb
- Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Ulrich A Maus
- Division of Experimental Pneumology, Hannover Medical School, Hannover, Germany.,German Center for Lung Research, partner site BREATH, Hannover, Germany
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30
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Robb CT, Goepp M, Rossi AG, Yao C. Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19. Br J Pharmacol 2020; 177:4899-4920. [PMID: 32700336 PMCID: PMC7405053 DOI: 10.1111/bph.15206] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/17/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
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Affiliation(s)
- Calum T. Robb
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Marie Goepp
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Adriano G. Rossi
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
| | - Chengcan Yao
- Centre for Inflammation Research, Queen's Medical Research InstituteThe University of EdinburghEdinburghUK
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31
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Yang M, Wang Y, Zhang Y, Li Y, Li Q, Tan J. Role of Interleukin-33 in Staphylococcus epidermidis-Induced Septicemia. Front Immunol 2020; 11:534099. [PMID: 33178181 PMCID: PMC7593707 DOI: 10.3389/fimmu.2020.534099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/04/2020] [Accepted: 09/10/2020] [Indexed: 11/13/2022] Open
Abstract
Interleukin (IL)-33 is a member of the IL-1 family, which plays an important role in inflammatory response. In this study, we evaluated the effect of IL-33 on septicemia and the underlying mechanisms by establishing a Staphylococcus epidermidis (S. epidermidis)-induced septicemic mouse model. The expression of IL-33, IL-1α, IL-1β, IL-6, IL-17A, IL-22, and PGE2 were measured by double antibody sandwich enzyme-linked immunosorbent assay, and bacterial colony formation in peripheral blood and kidneys were counted postinfection. The percentages of neutrophils, eosinophils, and inflammatory monocytes were evaluated by flow cytometry, and tissue damage was assessed by hematoxylin and eosin (H&E) staining. The survival of septicemic mice was monitored daily. IL-33 expression was significantly augmented following S. epidermidis infection. High IL-33 expression significantly decreased the survival of model mice, and aggravated the damage of lung, liver, and kidney tissues. However, administration of ST2 (receptor for IL-33) to the S. epidermidis-infected mice blocked the IL-33 signaling pathway, which elevated PGE2, IL-17A, and IL-22, and promoted healing of organ damage. In addition, ST2 suppressed the mobilization of inflammatory monocytes, but promoted the accumulation of neutrophils and eosinophils in S. epidermidis-infected mice. Inhibition of PGE2, IL-17A, and IL-22 facilitated the development of septicemia and organ damage in S. epidermidis-infected mice, as well as reducing their survival. Our findings reveal that IL-33 aggravates organ damage in septicemic mice by inhibiting PGE2, IL-17A, and IL-22 production.
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Affiliation(s)
- Min Yang
- Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiwen Wang
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yonghong Zhang
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanjun Li
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qifeng Li
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jintong Tan
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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32
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Norel X, Sugimoto Y, Ozen G, Abdelazeem H, Amgoud Y, Bouhadoun A, Bassiouni W, Goepp M, Mani S, Manikpurage HD, Senbel A, Longrois D, Heinemann A, Yao C, Clapp LH. International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E 2 Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions. Pharmacol Rev 2020; 72:910-968. [PMID: 32962984 PMCID: PMC7509579 DOI: 10.1124/pr.120.019331] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/02/2023] Open
Abstract
Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.
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Affiliation(s)
- Xavier Norel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yukihiko Sugimoto
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Gulsev Ozen
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Heba Abdelazeem
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yasmine Amgoud
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amel Bouhadoun
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Wesam Bassiouni
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Marie Goepp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Salma Mani
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Hasanga D Manikpurage
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amira Senbel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Dan Longrois
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Akos Heinemann
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Chengcan Yao
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Lucie H Clapp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
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Abstract
Prostaglandin induced signalling is involved in different cancers. As previously described, the EP3 receptor expression decreases with increasing stage of cervical intraepithelial lesions (CIN). In addition, in cervical cancer EP3 is an independent prognosticator for overall survival and correlates with FIGO stages. Currently the role of Prostaglandin 2 receptor 2 (EP2) in CIN is unknown. The aim of this study was to analyse the expression of EP2 for potential prognostic value for patients with cervical dysplasia. EP2 expression was analysed by immunohistochemistry in 33 patient samples (CIN1–3) using the immune-reactivity scoring system (IRS). Expression levels were correlated with clinical outcome to analyse prognostic relevance in patients with CIN2. Data analysis was performed using non parametric Kruskal–Wallis and Spearman rank sum test. Cytoplasmic expression levels of EP2 correlated significantly (p < 0.001) with different grades of cervical dysplasia. Median EP2-IRS in CIN1 was 2 (n = 8), 3 in CIN2 (n = 9) and 6 in CIN3 (n = 16). Comparing regressive (n = 3, median IRS = 2) to progressive (n = 6, median IRS = 4) CIN2 cases the median IRS differed significantly (p = 0.017). Staining intensity (p = 0.009) and IRS (p = 0.005) of EP2 and EP3 correlate inversely. EP2 expression level significantly increases with higher grade of CIN and could qualify as a potential prognostic marker for the regressive or progressive course in CIN2 lesions. These findings emphasize the significant role of PGE2 signalling in CIN and could help to identify targets for future therapies.
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Nakanishi T, Sakiyama S, Takashima H, Honda R, Shumba MN, Nakamura Y, Kasahara K, Tamai I. Toxicological implication of prostaglandin transporter SLCO2A1 inhibition by cigarette smoke in exacerbation of lung inflammation. Toxicol Appl Pharmacol 2020; 405:115201. [PMID: 32828905 DOI: 10.1016/j.taap.2020.115201] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/24/2020] [Revised: 08/11/2020] [Accepted: 08/14/2020] [Indexed: 12/21/2022]
Abstract
We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(-/-)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in the lungs of BLM-instilled mice. Bronchoalveolar lavage (BAL) fluid cell analysis indicated more severe inflammation in Slco2a1(-/-) on day 5 after BLM intratracheal instillation, and Slco2a1 deletion increased mRNA expression of pro-inflammatory cytokines (Tnf-α and Il-1β) and chemokine (Ccl5) in BAL cells. Male Slco2a1(-/-) exhibited significantly higher amounts of released Il-1β in BAL fluid, compared with female Slco2a1(-/-), male or female Slco2a1(+/+) group. The amount of PGE2 collected in BAL fluid tended to increase in Slco2a1(-/-) compared with Slco2a1(+/+) group, whereas the PGE2 concentrations in lung tissues were comparable between both groups. Besides, PGE2 accumulated more in BAL fluid of male than that of female mice. Therefore, Slco2a1-deficient male mice were found to be more susceptible to BLM-treatment. Moreover, CS extracts (CSE) significantly reduced initial PGE2 uptake by rat type1 alveolar epithelial cell-like (AT1-L) cells and human SLCO2A1-transfected cells. Exposure of AT1-L cells to CSE resulted in decreased mRNA expression of Slco2a1, suggesting that CS modulates SLCO2A1 function. These results indicate that exacerbated lung inflammation is attributed to an increase in Il-1β peptide and PGE2 accumulation in the alveolar space, which exhibits a male predominance. SLCO2A1 inhibition by CSE is considered to be a new rationale for the lung toxicity of CS.
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Affiliation(s)
- Takeo Nakanishi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Japan.
| | - Shiori Sakiyama
- School of Pharmaceutical Sciences, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Hiroki Takashima
- School of Pharmaceutical Sciences, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Ryokichi Honda
- School of Pharmaceutical Sciences, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Melody N Shumba
- Depatiment of Nutrition, Faculty of Health and Welfare, Takasaki University of Health and Welfare, Takasaki, Japan
| | - Yoshinobu Nakamura
- Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki, Japan
| | - Kazuo Kasahara
- School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan
| | - Ikumi Tamai
- School of Pharmaceutical Sciences, Kakuma-machi, Kanazawa 920-1192, Japan
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35
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In Vivo Anti-inflammatory Potential of Viscozyme ®-Treated Jujube Fruit. Foods 2020; 9:foods9081033. [PMID: 32752184 PMCID: PMC7466189 DOI: 10.3390/foods9081033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/08/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/11/2022] Open
Abstract
The fruit of Ziziphus jujuba, commonly called jujube, has long been consumed for its health benefits. The aim of this study was to examine the protective effect of dietary supplementation of enzymatically hydrolyzed jujube against lung inflammation in mice. The macerated flesh of jujube was extracted with aqueous ethanol before and after Viscozyme treatment. The extract of enzyme-treated jujube, called herein hydrolyzed jujube extract (HJE), contained higher levels of quercetin, total phenolics, and flavonoids, and exhibited more effective radical-scavenging abilities in comparison to non-hydrolyzed jujube extract (NHJE). HJE treatment decreased production of inflammation-associated molecules, including nitric oxide and pro-inflammatory cytokines from activated Raw 264.7 or differentiated THP-1 cells. HJE treatment also reduced expression of nuclear factor-κB and its downstream proteins in A549 human lung epithelial cells. Moreover, oral supplementation of 1.5 g of HJE per kg of body weight (BW) attenuated histological lung damage, decreased plasma cytokines, and inhibited expression of inflammatory proteins and oxidative stress mediators in the lungs of mice exposed to benzo(a)pyrene at 50 mg/kg BW. Expression levels of antioxidant and cytoprotective factors, such as nuclear factor erythroid-derived 2-related factor 2 and heme oxygenase-1, were increased in lung and liver tissues from mice treated with HJE, compared to mice fed NHJE. These findings indicate that dietary HJE can reduce benzo(a)pyrene-induced lung inflammation by inhibiting cytokine release from macrophages and promoting antioxidant defenses in vivo.
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Kazeminasab S, Emamalizadeh B, Jouyban A, Shoja MM, Khoubnasabjafari M. Macromolecular biomarkers of chronic obstructive pulmonary disease in exhaled breath condensate. Biomark Med 2020; 14:1047-1063. [PMID: 32940079 DOI: 10.2217/bmm-2020-0121] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023] Open
Abstract
Biomarkers provide important diagnostic and prognostic information on heterogeneous diseases such as chronic obstructive pulmonary disease (COPD). However, finding a suitable specimen for clinical analysis of biomarkers for COPD is challenging. Exhaled breath condensate (EBC) sampling is noninvasive, rapid, cost-effective and easily repeatable. EBC sampling has also provided recent progress in the identification of biological macromolecules, such as lipids, proteins and DNA in EBC samples, which has increased its utility for clinical scientists. In this article, we review applications involving EBC sampling for the analysis of COPD biomarkers and discuss its future potential.
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Affiliation(s)
- Somayeh Kazeminasab
- Pharmaceutical Analysis Research Center & Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran
- Liver & Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14756, Iran
| | - Babak Emamalizadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences,Tabriz, Iran
| | - Abolghasem Jouyban
- Pharmaceutical Analysis Research Center & Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran
- Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 14117-13135, Iran
| | - Mohammadali M Shoja
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Maryam Khoubnasabjafari
- Tuberculosis & Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 51656-65811, Iran
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz 51666-14756, Iran
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37
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Su W, Liang Y, Meng Z, Chen X, Lu M, Han X, Deng X, Zhang Q, Zhu H, Fu T. Inhalation of Tetrandrine-hydroxypropyl-β-cyclodextrin Inclusion Complexes for Pulmonary Fibrosis Treatment. Mol Pharm 2020; 17:1596-1607. [PMID: 32142292 DOI: 10.1021/acs.molpharmaceut.0c00026] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/12/2022]
Abstract
Pulmonary fibrosis (PF) is a kind of interstitial lung disease with the features of progressive and often fatal dyspnea. Tetrandrine (TET) is the major active constituent of Chinese herbal Stephania tetrandra S. Moore, which has already applied clinically to treat rheumatism, lung cancer, and silicosis. In this work, a tetrandrine-hydroxypropyl-β-cyclodextrin inclusion compound (TET-HP-β-CD) was developed for the treatment of pulmonary fibrosis via inhalation administration. TET-HP-β-CD was prepared by the freeze-drying method and identified using the cascade impactor, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectrum (FT-IR). A bleomycin-induced pulmonary fibrosis rat model was used to assess the effects of inhaled TET and TET-HP-β-CD. Animal survival, hydroxyproline content in the lungs, and lung histology were detected. The results showed that inhalation of TET-HP-β-CD alleviated inflammation and fibrosis, limited the accumulation of hydroxyproline in the lungs, regulated protein expression in PF development, and improved postoperative survival. Moreover, nebulized delivery of TET-HP-β-CD accumulated chiefly in the lungs and limited systemic distribution compared with intravenous administration. The present results indicated that inhalation of TET-HP-β-CD is an attractive candidate for the treatment of pulmonary fibrosis.
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Affiliation(s)
- Wenqiang Su
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Yinmei Liang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Zhiping Meng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Xuanyu Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Manqi Lu
- Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing 210023, China
| | - Xingxing Han
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Xiaomin Deng
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Qichun Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China
| | - Huaxu Zhu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China.,Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, China
| | - Tingming Fu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.,Jiangsu Botanical Medicine Refinement Engineering Research Center, Nanjing 210023, China.,Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing 210023, China
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38
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Vorsprach M, Arens C, Knipping S, Jechorek D, Stegemann-Koniszewski S, Lücke E, Schreiber J. Expression of COX-1, COX-2, 5-LOX and CysLT 2 in nasal polyps and bronchial tissue of patients with aspirin exacerbated airway disease. Allergy Asthma Clin Immunol 2019; 15:83. [PMID: 31889962 PMCID: PMC6933683 DOI: 10.1186/s13223-019-0395-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/22/2019] [Accepted: 12/10/2019] [Indexed: 11/10/2022] Open
Abstract
Background Aspirin exacerbated respiratory disease (AERD) is a disease of the upper and lower airways. It is characterized by severe asthma, chronic sinusitis with nasal polyps (CRSwNP) and intolerance towards nonsteroidal analgesics (NSAR). Arachidonic acid (AA) metabolites play an important role in the pathogenesis of AERD. It is still unknown, whether metabolism of AA is comparable between the upper and lower airways as well as between patients with and without NSAR intolerance. Objective We sought to analyze differences in the expression of cyclooxygenases type 1 and 2 (COX-1, COX-2), arachidonate 5-lipoxygenase (5-LOX) and cysteinyl leukotriene receptor type 2 ( CysLT 2 ) in nasal polyps and the bronchial mucosa of patients with aspirin intolerant asthma (AIA, n = 23 ) as compared to patients with aspirin tolerant asthma (ATA, n = 17 ) and a control group with nasal polyps, but without asthma (NPwA, n = 15 ). Methods Tissue biopsies from nasal polyps and bronchial mucosa were obtained during surgical treatment of nasal polyps by endonasal functional endoscopic sinus surgery (FESS) under general anesthesia from intubated patients. Immunohistochemistry was used to analyze the expression of COX-1, COX-2, 5-LOX and CysLT 2 in nasal and bronchial mucosa. Categorization into the different patient groups was performed according to the patient history, clinical and laboratory data, pulmonary function and provocation tests, as well as allergy testing. Results We observed a stronger expression of 5-LOX and CysLT 2 in submucosal glands of nasal and bronchial tissue compared to epithelial expression. The expression of COX-1 and COX-2 was stronger in epithelia compared to submucosal glands. There was a similar expression of the enzymes and CysLT 2 between upper and lower airways in all patient groups. We did not detect any significant differences between the patient groups. Conclusions The AA-metabolizing enzymes and the CysLT 2 were expressed in a very similar way in different microscopic structures in samples of the upper and lower airways of individual patients. We did not detect differences between the patient groups indicating the pathogenetic role of AA metabolism in these disorders is independent of the presence of NSAR-intolerance.
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Affiliation(s)
- Monique Vorsprach
- 1Departmemt of Pneumology, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Christoph Arens
- 2Department of Otorhinolaryngology, Head- and Neck Surgery, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Stephan Knipping
- 3Department of Otorhinolaryngology, Head- and Neck Surgery, Plastical Surgery, Dessau Medical Center, Martin-Luther-University Halle, Auenweg 38, 06847 Dessau, Germany
| | - Dörte Jechorek
- 4Department of Pathology, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Sabine Stegemann-Koniszewski
- 1Departmemt of Pneumology, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Eva Lücke
- 1Departmemt of Pneumology, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
| | - Jens Schreiber
- 1Departmemt of Pneumology, University Hospital Magdeburg, Medical Faculty, Otto-von-Guericke-University, Leipziger Straße 44, 39120 Magdeburg, Germany
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Hamrin J, Perez‐Manzo M, Idborg H, Jakobsson P, Björk L, Eriksson M, Nilsson A, Herlenius E. Urinary PGE 2 metabolite levels in hospitalised infants with infections compared to age-matched controls. Acta Paediatr 2019; 108:1879-1886. [PMID: 30933389 DOI: 10.1111/apa.14807] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/30/2018] [Revised: 02/05/2019] [Accepted: 03/29/2019] [Indexed: 12/11/2022]
Abstract
AIM To determine the urinary tetranor-prostaglandin E2 metabolite in healthy infants and in hospitalised infants with upper and lower respiratory tract as well as gastrointestinal infections. METHODS A prospective cross-sectional study to determine baseline concentrations of urinary tetranor-prostaglandin E2 metabolite was conducted in 81 healthy infants aged one week to one year and in 142 hospitalised infants with infections. Prostaglandin metabolite levels were measured by liquid chromatography tandem mass spectrometry. RESULTS In healthy infants, urinary prostaglandin E2 metabolite levels decreased with age and did not differ between girls and boys. Infections of the lower respiratory (n = 78) and gastrointestinal tract (n = 12) correlated with increased levels of the prostaglandin E2 metabolite. In contrast, infants hospitalised with upper respiratory tract infections (n = 23) exhibited similar levels as healthy, age-matched controls. Lower prostaglandin E2 levels were found after treatment with acetaminophen in hospitalised children. Prostaglandin E2 metabolite levels did not correlate with length of hospitalisation or need for respiratory support. CONCLUSION This study first provides normal levels of urinary prostaglandin E2 metabolite in infants and secondly demonstrates elevated levels in hospitalised children with lower respiratory tract and gastrointestinal infections.
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Affiliation(s)
- Johan Hamrin
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden
| | - Monica Perez‐Manzo
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
| | - Helena Idborg
- Department of Medicine Karolinska Institutet Stockholm Sweden
- Rheumatology Karolinska University Hospital Stockholm Sweden
| | - Per‐Johan Jakobsson
- Department of Medicine Karolinska Institutet Stockholm Sweden
- Rheumatology Karolinska University Hospital Stockholm Sweden
| | - Lars Björk
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
| | - Margareta Eriksson
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden
| | - Anna Nilsson
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden
| | - Eric Herlenius
- Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden
- Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden
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40
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Wasnik S, Lakhan R, Baylink DJ, Rundle CH, Xu Y, Zhang J, Qin X, Lau KHW, Carreon EE, Tang X. Cyclooxygenase 2 augments osteoblastic but suppresses chondrocytic differentiation of CD90 + skeletal stem cells in fracture sites. SCIENCE ADVANCES 2019; 5:eaaw2108. [PMID: 31392271 PMCID: PMC6669009 DOI: 10.1126/sciadv.aaw2108] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 11/28/2018] [Accepted: 06/21/2019] [Indexed: 05/07/2023]
Abstract
Cyclooxygenase 2 (COX-2) is essential for normal tissue repair. Although COX-2 is known to enhance the differentiation of mesenchymal stem cells (MSCs), how COX-2 regulates MSC differentiation into different tissue-specific progenitors to promote tissue repair remains unknown. Because it has been shown that COX-2 is critical for normal bone repair and local COX-2 overexpression in fracture sites accelerates fracture repair, this study aimed to determine the MSC subsets that are targeted by COX-2. We showed that CD90+ mouse skeletal stem cells (mSSCs; i.e., CD45-Tie2-AlphaV+ MSCs) were selectively recruited by macrophage/monocyte chemoattractant protein 1 into fracture sites following local COX-2 overexpression. In addition, local COX-2 overexpression augmented osteoblast differentiation and suppressed chondrocyte differentiation in CD90+ mSSCs, which depended on canonical WNT signaling. CD90 depletion data demonstrated that local COX-2 overexpression targeted CD90+ mSSCs to accelerate fracture repair. In conclusion, CD90+ mSSCs are promising targets for the acceleration of bone repair.
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Affiliation(s)
- Samiksha Wasnik
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Ram Lakhan
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - David J. Baylink
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Charles H. Rundle
- Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, CA, USA
| | - Yi Xu
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Jintao Zhang
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Henan, China
| | - Xuezhong Qin
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
- Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, CA, USA
| | - Kin-Hing William Lau
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
- Musculoskeletal Disease Center, Jerry L. Pettis Memorial Veterans Affairs Medical Center, Loma Linda, CA, USA
| | - Edmundo E. Carreon
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Xiaolei Tang
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, USA
- Corresponding author.
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Saadat S, Beheshti F, Askari VR, Hosseini M, Mohamadian Roshan N, Boskabady MH. Aminoguanidine affects systemic and lung inflammation induced by lipopolysaccharide in rats. Respir Res 2019; 20:96. [PMID: 31113409 PMCID: PMC6530199 DOI: 10.1186/s12931-019-1054-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/15/2018] [Accepted: 04/22/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Nitric oxide is a mediator of potential importance in numerous physiological and inflammatory processes in the lung. Aminoguanidine (AG) has been shown to have anti-inflammation and radical scavenging properties. This study aimed to investigate the effects of AG, an iNOS inhibitor, on lipopolysaccharide (LPS)-induced systemic and lung inflammation in rats. METHODS Male Wistar rats were divided into control, LPS (1 mg/kg/day i.p.), and LPS groups treated with AG 50, 100 or 150 mg/kg/day i.p. for five weeks. Total nitrite concentration, total and differential white blood cells (WBC) count, oxidative stress markers, and the levels of IL-4, IFN-γ, TGF-β1, and PGE2 were assessed in the serum or bronchoalveolar lavage fluid (BALF). RESULTS Administration of LPS decreased IL-4 level (p < 0.01) in BALF, total thiol content, superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.001) in BALF and serum, and increased total nitrite, malondialdehyde (MDA), IFN-γ, TGF-β1 and PGE2 (p < 0.001) concentrations in BALF. Pre-treatment with AG increased BALF level of IL-4 and total thiol as well as SOD and CAT activities (p < 0.05 to p < 0.001), but decreased BALF levels of total nitrite, MDA, IFN-γ, TGF-β1, and PGE2 (p < 0.01 to p < 0.001). AG treatment decreased total WBC count, lymphocytes and macrophages in BALF (p < 0.01 to p < 0.001) and improved lung pathological changes including interstitial inflammation and lymphoid infiltration (p < 0.05 to p < 0.001). CONCLUSIONS AG treatment reduced oxidant markers, inflammatory cytokines and lung pathological changes but increased antioxidants and anti-inflammatory cytokines. Therefore, AG may play a significant protective role against inflammation and oxidative stress that cause lung injury.
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Affiliation(s)
- Saeideh Saadat
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
| | - Farimah Beheshti
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Vahid Reza Askari
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
- Student Research Committee, Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Hosseini
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
| | - Nema Mohamadian Roshan
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
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Helmy MM, Helmy MW, El-Mas MM. Upregulation of cystathionine-γ-lyase/hydrogen sulfide pathway underlies the celecoxib counteraction of cyclosporine-induced hypertension and renal insult in rats. Prostaglandins Other Lipid Mediat 2019; 141:1-10. [DOI: 10.1016/j.prostaglandins.2019.01.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/18/2018] [Revised: 01/07/2019] [Accepted: 01/14/2019] [Indexed: 12/16/2022]
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Tavares Pereira M, Gram A, Nowaczyk R, Boos A, Hoffmann B, Janowski T, Kowalewski MP. Prostaglandin-mediated effects in early canine corpus luteum: In vivo effects on vascular and immune factors. Reprod Biol 2019; 19:100-111. [PMID: 30929911 DOI: 10.1016/j.repbio.2019.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/29/2018] [Revised: 01/17/2019] [Accepted: 02/04/2019] [Indexed: 01/17/2023]
Abstract
Prostaglandins (PGs) are important regulators of the early corpus luteum (CL) in the dog. Whereas, initially, CL is gonadotropin independent, in the second half of its lifespan, hypophyseal support is required. The transition period is marked by decreased availability of PGs, in particular of PGE2. We previously reported that inhibition of COX2/PTGS2 in vivo suppressed luteal production of PGE2, lowered circulating progesterone and negatively affected luteal development. Therefore, bitches were treated with a COX2-specific blocker, firocoxib, for 5, 10, 20 and 30 days after ovulation, leading to suppression of the steroidogenic machinery. Control groups received a placebo for the same periods. Considering the wide range of possible modulatory roles of PGs shown in different organ systems, this follow-up project aimed to understand further possible PG-mediated effects in early canine CL. Thirty-four (34) factors related predominantly to vascularization and immune response were screened (mRNAs and proteins) on samples from the above described in vivo study. Most of the effects were observed during the transitional period (days 20 and 30). The inhibition of COX2 diminished the expression of angiopoietin family members ANGPT1, -2, Tie1 and -2 receptors. The expression of endothelin (ET)-1 was increased. Concerning the immune system, increased expression of the pro-inflammatory cytokines, IL1β, IL6 and IL12a, and elevated expression levels of CD4, was observed. Cumulatively, besides its involvement in regulating steroidogenesis, our results indicate a broader role of PGs in the canine CL, including modulation of angiogenesis, vascular stabilization and local immunomodulation. Possible cross-species translational effects are strongly implied.
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Affiliation(s)
- Miguel Tavares Pereira
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Aykut Gram
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Renata Nowaczyk
- Division of Animal Anatomy, Department of Animal Physiology and Biostructure, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
| | - Alois Boos
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - Bernd Hoffmann
- Clinic for Obstetrics, Gynaecology and Andrology, Faculty of Veterinary Medicine, Justus Liebig University, Giessen, Germany
| | - Tomasz Janowski
- Department of Animal Reproduction, Faculty of Veterinary Medicine, University of Warmia and Mazury, Olsztyn, Poland
| | - Mariusz P Kowalewski
- Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
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44
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Bottemanne P, Paquot A, Ameraoui H, Alhouayek M, Muccioli GG. The α/β–hydrolase domain 6 inhibitor WWL70 decreases endotoxin‐induced lung inflammation in mice, potential contribution of 2‐arachidonoylglycerol, and lysoglycerophospholipids. FASEB J 2019; 33:7635-7646. [DOI: 10.1096/fj.201802259r] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/19/2022]
Affiliation(s)
- Pauline Bottemanne
- Bioanalysis and Pharmacology of Bioactive Lipids Research GroupLouvain Drug Research InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Adrien Paquot
- Bioanalysis and Pharmacology of Bioactive Lipids Research GroupLouvain Drug Research InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Hafsa Ameraoui
- Bioanalysis and Pharmacology of Bioactive Lipids Research GroupLouvain Drug Research InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research GroupLouvain Drug Research InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Giulio G. Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research GroupLouvain Drug Research InstituteUniversité Catholique de Louvain (UCLouvain)BrusselsBelgium
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Feng F, Wang Z, Li R, Wu Q, Gu C, Xu Y, Peng W, Han D, Zhou X, Wu J, He H. Citrus alkaline extracts prevent fibroblast senescence to ameliorate pulmonary fibrosis via activation of COX-2. Biomed Pharmacother 2019; 112:108669. [PMID: 30784938 DOI: 10.1016/j.biopha.2019.108669] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/07/2018] [Revised: 01/29/2019] [Accepted: 02/04/2019] [Indexed: 12/14/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with a poor prognosis and limited treatment options. The incidence of IPF increases with age, and the mechanisms related to aging such as cellular senescence have been strongly implicated in disease pathology. Therefore, a better understanding of fibroblasts senescence might provide a new therapeutic strategy to prevent and treat pulmonary fibrosis. In this study, we aimed to explore the effects of citrus alkaline extracts (CAE) on the fibroblasts senescence, and elucidate the underlying mechanism to ameliorate pulmonary fibrosis. We demonstrated that CAE mitigated the collagen deposition by the initial early treatment, suggesting a potential preventive effect of CAE on pulmonary fibrosis. The expression of senescence biomarkers P16INK4a and P21, concomitant with down-regulation of the myofibroblasts marker α-SMA, and the number of senescence-associated β-galactosidase (SA-β-Gal) positive cells were decreased by CAE treatment, indicating a significant inhibitory effect of CAE on fibroblast senescence. Additionally, CAE down-regulated the expression of the senescence-associated secretory phenotype (SASP) in etoposide-induced senescent fibroblasts. Further studies indicated that COX-2 activation was required for CAE to inhibit the lung fibroblast senescence through a P53-dependent pathway. Results showed that the anti-senescence effect of CAE was abrogated when COX-2 was knocked down or inhibited by COX-2 inhibitor NS-398 or indomethacin in lung fibroblasts. Meanwhile, the anti-fibrotic and anti-senescence effect of CAE were abolished due to disruption of COX-2 in vivo. Collectively, our results provided a novel insight into the potential mechanism of CAE to inhibit the fibroblasts activation through preventing cellular senescence.
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Affiliation(s)
- Fanchao Feng
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhichao Wang
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ruofei Li
- Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China; The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Qi Wu
- Department of Physiology, Xuzhou Medical University, Xuzhou, 221009, China
| | - Cheng Gu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yong Xu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wenpan Peng
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Di Han
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xianmei Zhou
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
| | - Jing Wu
- State Key Laboratory of Analytical Chemistry for Life Science and Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
| | - Hailang He
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China; Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
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An JH, Song WJ, Li Q, Kim SM, Yang JI, Ryu MO, Nam AR, Bhang DH, Jung YC, Youn HY. Prostaglandin E 2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res 2018; 14:354. [PMID: 30453939 PMCID: PMC6245895 DOI: 10.1186/s12917-018-1684-9] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/02/2018] [Accepted: 11/01/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an intractable autoimmune disease, relatively common in cats, with chronic vomiting and diarrhea. Previous studies have reported that mesenchymal stem cells (MSCs) alleviate inflammation by modulating immune cells. However, there is a lack of research on cross-talk mechanism between feline adipose tissue-derived mesenchymal stem cells (fAT-MSCs) and immune cells in IBD model. Hence, this study aimed to evaluate the therapeutic effects of fAT-MSC on mice model of colitis and to clarify the therapeutic mechanism of fAT-MSCs. RESULTS Intraperitoneal infusion of fAT-MSC ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea, and inflammation in the colon of Dextran sulfate sodium (DSS)-treated mice (C57BL/6). Since regulatory T cells (Tregs) are pivotal in modulating immune responses and maintaining tolerance in colitis, the relation of Tregs with fAT-MSC-secreted factor was investigated in vitro. PGE2 secreted from fAT-MSC was demonstrated to induce elevation of FOXP3 mRNA expression and adjust inflammatory cytokines in Con A-induced feline peripheral blood mononuclear cells (PBMCs). Furthermore, in vivo, FOXP3+ cells of the fAT-MSC group were significantly increased in the inflamed colon, relative to that in the PBS group. CONCLUSION Our results suggest that PGE2 secreted from fAT-MSC can reduce inflammation by increasing FOXP3+ Tregs in mice model of colitis. Consequently, these results propose the possibility of administration of fAT-MSC to cats with not only IBD but also other immune-mediated inflammatory diseases.
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Affiliation(s)
- Ju-Hyun An
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Woo-Jin Song
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Qiang Li
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Sang-Min Kim
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Ji-In Yang
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Min-Ok Ryu
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - A Ryung Nam
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea
| | - Dong Ha Bhang
- Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon-si, Gyeonggi-do, 16419, Republic of Korea
| | - Yun-Chan Jung
- Chaon Corporation, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13493, Republic of Korea
| | - Hwa-Young Youn
- Labolatory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
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Gouveia-Figueira S, Karimpour M, Bosson JA, Blomberg A, Unosson J, Sehlstedt M, Pourazar J, Sandström T, Behndig AF, Nording ML. Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust. Anal Chim Acta 2018; 1018:62-69. [PMID: 29605135 DOI: 10.1016/j.aca.2018.02.032] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/03/2017] [Revised: 02/08/2018] [Accepted: 02/13/2018] [Indexed: 11/26/2022]
Abstract
Experimental human exposure studies are an effective tool to study adverse health effects from acute inhalation of particulate matter and other constituents of air pollution. In this randomized and double-blinded crossover study, we investigated the systemic effect on bioactive lipid metabolite levels after controlled biodiesel exhaust exposure of healthy humans and compared it to filtered air at a separate exposure occasion. Eicosanoids and other oxylipins, as well as endocannabinoids and related lipids, were quantified in plasma from 14 healthy volunteers at baseline and at three subsequent time points (2, 6, and 24 h) after 1 h exposure sessions. Protocols based on liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) methods were developed to detect temporal changes in circulating levels after biodiesel exhaust exposure. The exhaust was generated by a diesel engine fed with an undiluted rapeseed methyl ester fuel. Among the 51 analyzed lipid metabolites, PGF2α, 9,10-DiHOME, 9-HODE, 5-HETE, 11-HETE, 12-HETE, and DEA displayed significant responsiveness to the biodiesel exhaust exposure as opposed to filtered air. Of these, 9-HODE and 5-HETE at 24 h survived the 10% false discovery rate cutoff (p < 0.003). Hence, the majority of the responsive lipid metabolites were monohydroxy fatty acids. We conclude that it is possible to detect alterations in circulating bioactive lipid metabolites in response to biodiesel exhaust exposure using LC-MS/MS, with emphasis on metabolites with inflammation related properties and implications on cardiovascular health and disease. These observations aid future investigations on air pollution effects, especially with regard to cardiovascular outcomes.
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Affiliation(s)
| | | | - Jenny A Bosson
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Anders Blomberg
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Jon Unosson
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Maria Sehlstedt
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Jamshid Pourazar
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Thomas Sandström
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Annelie F Behndig
- Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, 901 87 Umeå, Sweden
| | - Malin L Nording
- Department of Chemistry, Umeå University, 901 87 Umeå, Sweden.
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Łanocha-Arendarczyk N, Baranowska-Bosiacka I, Kot K, Gutowska I, Kolasa-Wołosiuk A, Chlubek D, Kosik-Bogacka D. Expression and Activity of COX-1 and COX-2 in Acanthamoeba sp.-Infected Lungs According to the Host Immunological Status. Int J Mol Sci 2018; 19:ijms19010121. [PMID: 29301283 PMCID: PMC5796070 DOI: 10.3390/ijms19010121] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/30/2017] [Revised: 12/26/2017] [Accepted: 12/27/2017] [Indexed: 12/20/2022] Open
Abstract
Little is known about the pathomechanism of pulmonary infections caused by Acanthamoeba sp. Therefore, the aim of this study was to determine whether Acanthamoeba sp. may affect the expression and activity of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), resulting in the altered levels of their main products, prostaglandins (PGE₂) and thromboxane B₂ (TXB₂), in lungs of immunocompetent or immunosuppressed hosts. Acanthamoeba sp. induced a strong expression of COX-1 and COX-2 proteins in the lungs of immunocompetent mice, which, however, did not result in significant differences in the expression of PGE₂ and TXB₂. Our immunohistochemical analysis showed that immunosuppression induced by glucocorticoids in Acanthamoeba sp.-infected mice caused a decrease in COX-1 and COX-2 (not at the beginning of infection) in lung tissue. These results suggest that similar to COX-2, COX-1 is an important mediator of the pathophysiology in experimental pulmonary acanthamoebiasis. We suggest that the signaling pathways important for Acanthamoeba sp. induction of lung infection might interact with each other and depend on the host immune status.
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Affiliation(s)
- Natalia Łanocha-Arendarczyk
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Karolina Kot
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Izabela Gutowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Agnieszka Kolasa-Wołosiuk
- Department of Histology and Embryology, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
| | - Danuta Kosik-Bogacka
- Department of Biology and Medical Parasitology, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland.
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Ehrhardt C, Bäckman P, Couet W, Edwards C, Forbes B, Fridén M, Gumbleton M, Hosoya KI, Kato Y, Nakanishi T, Takano M, Terasaki T, Yumoto R. Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs: Summary Proceedings of the First Workshop on Drug Transporters in the Lungs. J Pharm Sci 2017; 106:2234-2244. [DOI: 10.1016/j.xphs.2017.04.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/25/2017] [Revised: 04/07/2017] [Accepted: 04/07/2017] [Indexed: 12/31/2022]
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50
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The Role of PGE 2 in Alveolar Epithelial and Lung Microvascular Endothelial Crosstalk. Sci Rep 2017; 7:7923. [PMID: 28801643 PMCID: PMC5554158 DOI: 10.1038/s41598-017-08228-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2017] [Accepted: 07/06/2017] [Indexed: 12/26/2022] Open
Abstract
Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.
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