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Wang Z, Zhao P, Yan G, Sun A, Xu L, Li J, Zhai X, Liu X, Mei T, Xuan Y, Nie Y. Neuropeptide S and its receptor aggravated asthma via TFEB dependent autophagy in bronchial epithelial cells. Respir Res 2025; 26:50. [PMID: 39930427 PMCID: PMC11812264 DOI: 10.1186/s12931-025-03125-9] [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] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/27/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Asthma is a prevalent respiratory disorder with limited treatment strategy. Neuropeptide S (NPS) is a highly conserved peptide via binding to its receptor NPSR, a susceptibility gene for asthma from genomics studies. However, little is known about the role of NPS-NPSR in the pathogenesis of asthma. This study was performed to determine the effect and underlying mechanism of NPS-NPSR on asthma. METHODS NPSR knockdown was verified to affect asthma through autophagy by transcriptome sequencing and molecular biology experiments in animal models. Silencing of transcription factor EB in a bronchial epithelial cell line and validation of NPS-NPSR activation of autophagy dependent on transcription factor EB. RESULTS Our results showed that NPSR expression was markedly increased in asthmatic humans and mice, mainly localized in bronchial epithelial cells. Using ovalbumin (OVA) and papain-induced asthma mouse models, NPSR-deficient mice exhibited significantly alleviated asthma, with reduced small airway lesions and inflammatory infiltration compared with wild-type mice. OVA and papain promoted TFEB-mediated autophagy with increased ATG5 and LC3 II expression, and NPS effectively regulated the activation of TFEB and autophagy. In turn, specific TFEB knockdown could restore the effect of exogenous NPS and its receptor antagonist on the autophagy and cytokines secretion in bronchial epithelial cells. Furthermore, Prkcg may be the key upstream targeting of the TFEB-autophagy pathway involved in asthma. CONCLUSIONS NPS-NPSR exacerbated asthma by regulating the TFEB-autophagy axis in airway epithelial injury, which may be a potential target for asthma therapy.
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Affiliation(s)
- Zhixu Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Peng Zhao
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Gen Yan
- Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, 361000, China
| | - Aijuan Sun
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Department of Pathology, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center of Nanjing Medical University, Wuxi People's Hospital, Wuxi, 214023, Jiangsu, China
| | - Li Xu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Jiao Li
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Xiaorun Zhai
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Xiangcen Liu
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Tingting Mei
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Yinghua Xuan
- Department of Microbiology and Immunology, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Yunjuan Nie
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China.
- MOE Medical Basic Research Innovation Center for Gut Microbiota and Chronic Diseases, School of Medicine, Jiangnan University, Wuxi, 214122, China.
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Zhang C, Xu H, Netto KG, Sokulsky LA, Miao Y, Mo Z, Meng Y, Du Y, Wu C, Han L, Zhang L, Liu C, Zhang G, Li F, Yang M. Inhibition of γ-glutamyl transferase suppresses airway hyperresponsiveness and airway inflammation in a mouse model of steroid resistant asthma exacerbation. Front Immunol 2023; 14:1132939. [PMID: 37377967 PMCID: PMC10292800 DOI: 10.3389/fimmu.2023.1132939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
Introduction Despite recent advances, there are limited treatments available for acute asthma exacerbations. Here, we investigated the therapeutic potential of GGsTop, a γ-glutamyl transferase inhibitor, on the disease with a murine model of asthma exacerbation. Methods GGsTop was administered to mice that received lipopolysaccharide (LPS) and ovalbumin (OVA) challenges. Airway hyperresponsiveness (AHR), lung histology, mucus hypersecretion, and collagen deposition were analyzed to evaluate the hallmark features of asthma exacerbation. The level of proinflammatory cytokines and glutathione were determined with/without GGsTop. The transcription profiles were also examined. Results GGsTop attenuates hallmark features of the disease with a murine model of LPS and OVA driven asthma exacerbation. Airway hyperresponsiveness (AHR), mucus hypersecretion, collagen deposition, and expression of inflammatory cytokines were dramatically inhibited by GGsTop treatment. Additionally, GGsTop restored the level of glutathione. Using RNA-sequencing and pathway analysis, we demonstrated that the activation of LPS/NFκB signaling pathway in airway was downregulated by GGsTop. Interestingly, further analysis revealed that GGsTop significantly inhibited not only IFNγ responses but also the expression of glucocorticoid-associated molecules, implicating that GGsTop profoundly attenuates inflammatory pathways. Conclusions Our study suggests that GGsTop is a viable treatment for asthma exacerbation by broadly inhibiting the activation of multiple inflammatory pathways.
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Affiliation(s)
- Cancan Zhang
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Huisha Xu
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Keilah G. Netto
- Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Leon A. Sokulsky
- Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, Callaghan, New South Wales, Australia
| | - Yiyan Miao
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhongyuan Mo
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yan Meng
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yingying Du
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chengyong Wu
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Liyou Han
- Institute for Liberal Arts and Sciences, Kyoto University, Kyoto, Japan
| | - Lirong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chi Liu
- Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, China
| | - Guojun Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fuguang Li
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Ming Yang
- Academy of Medical Sciences & Department of Immunology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, Callaghan, New South Wales, Australia
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Kantar A, Marchant JM, Song WJ, Shields MD, Chatziparasidis G, Zacharasiewicz A, Moeller A, Chang AB. History Taking as a Diagnostic Tool in Children With Chronic Cough. Front Pediatr 2022; 10:850912. [PMID: 35498777 PMCID: PMC9051232 DOI: 10.3389/fped.2022.850912] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/21/2022] [Indexed: 11/17/2022] Open
Abstract
Chronic cough is a common symptom of many underlying respiratory and non-respiratory disorders and may be associated with less serious causes, such as gastroesophageal reflux and nasal diseases. Chronic cough in children differs from that in adults with respect to its etiologies and management since it can indicate a symptom of an underlying disease in children. Guidelines for managing chronic cough in children are based on recording the history, followed by physical examination, chest radiography, and spirometry. Thus, taking accurate respiratory history for coughing helps delineate the pathophysiological basis of the cause of chronic cough. Detailed history taking enhances the evaluation and treatment, and facilitates a tailored diagnostic identification of likely diagnoses. While studies have described evidence-based red flags in children with chronic cough, the value of skilled physicians regarding history taking has received less attention for the best patient care. In the present article, we outline the major questions comprising a detailed history taking for chronic cough in children.
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Affiliation(s)
- Ahmad Kantar
- Paediatric Asthma and Cough Centre, Gruppo Ospedaliero San Donato, Bergamo, Italy.,Department of Paediatrics, University Vita Salute San Raffaele, Milano, Italy
| | - Julie M Marchant
- Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia.,Center for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia
| | - Woo-Jung Song
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Michael D Shields
- Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom.,Royal Belfast Hospital for Sick Children, Belfast, United Kingdom
| | | | - Angela Zacharasiewicz
- Department of Pediatrics, Adolescent Medicine, Teaching Hospital of the University of Vienna, Wilhelminen Hospital, Klinikum Ottakring, Vienna, Austria
| | - Alexander Moeller
- Division of Respiratory Medicine and Childhood Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Anne B Chang
- Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia.,Center for Children's Health Research, Queensland University of Technology, Brisbane, QLD, Australia.,Child Health Division, Menzies School of Health Research, Darwin, NT, Australia
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Probable positive effects of the photobiomodulation as an adjunctive treatment in COVID-19: A systematic review. Cytokine 2020; 137:155312. [PMID: 33128927 PMCID: PMC7550078 DOI: 10.1016/j.cyto.2020.155312] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/17/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022]
Abstract
Photobiomodulation (PBM) can reduce lung edema, cytokines in bronchoalveolar parenchyma, neutrophil influx. PBM reduces TNF-α, IL-1β, IL-6, ICAM-1, MIP-2 and Reactive oxygen species. Transthoracic approach is the direct methods for reducing lung inflammation. Intravenous approach increases the oxygenation of red blood cells. Background COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one –third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. Methodology The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. Results Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). Conclusion Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.
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Banu N, Panikar SS, Leal LR, Leal AR. Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications. Life Sci 2020; 256:117905. [PMID: 32504757 PMCID: PMC7832382 DOI: 10.1016/j.lfs.2020.117905] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/25/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023]
Abstract
In light of the outbreak of the 2019 novel coronavirus disease (COVID-19), the international scientific community has joined forces to develop effective treatment strategies. The Angiotensin-Converting Enzyme (ACE) 2, is an essential receptor for cell fusion and engulfs the SARS coronavirus infections. ACE2 plays an important physiological role, practically in all the organs and systems. Also, ACE2 exerts protective functions in various models of pathologies with acute and chronic inflammation. While ACE2 downregulation by SARS-CoV-2 spike protein leads to an overactivation of Angiotensin (Ang) II/AT1R axis and the deleterious effects of Ang II may explain the multiorgan dysfunction seen in patients. Specifically, the role of Ang II leading to the appearance of Macrophage Activation Syndrome (MAS) and the cytokine storm in COVID-19 is discussed below. In this review, we summarized the latest research progress in the strategies of treatments that mainly focus on reducing the Ang II-induced deleterious effects rather than attenuating the virus replication.
Protective role of ACE2 in the organs and system Downregulation of ACE2 expression by SARS-CoV-2 leads to Ang II-induced organ damage. The appearance of MAS in COVID-19 patient Suggested treatment to diminish the deleterious effect of Ang II or appearance of MAS
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Affiliation(s)
- Nehla Banu
- Instituto de Enfermedades Crónico-Degenerativas, Departamento de Biología Molecular y Genómica, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sandeep Surendra Panikar
- Centro de Física Aplicada y Tecnología Avanzada, Universidad Nacional Autonoma de México (UNAM), Apartado Postal 1-1010, Queretaro, Queretaro 76000, Mexico
| | - Lizbeth Riera Leal
- Hospital General Regional número 45, Instituto Mexicano del Seguro Social (IMSS), Guadalajara, Jalisco, Mexico
| | - Annie Riera Leal
- UC DAVIS Institute for Regenerative Cure, Department of Dermatology, University of California, 2921 Stockton Blvd, Rm 1630, 95817 Sacramento, CA, USA.
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Use of glucocorticoids in the critical care setting: Science and clinical evidence. Pharmacol Ther 2020; 206:107428. [DOI: 10.1016/j.pharmthera.2019.107428] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/02/2019] [Indexed: 02/07/2023]
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Looi K, Evans DJ, Garratt LW, Ang S, Hillas JK, Kicic A, Simpson SJ. Preterm birth: Born too soon for the developing airway epithelium? Paediatr Respir Rev 2019; 31:82-88. [PMID: 31103368 DOI: 10.1016/j.prrv.2018.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/31/2018] [Accepted: 11/23/2018] [Indexed: 12/17/2022]
Abstract
Birth prior to term interrupts the normal development of the respiratory system and consequently results in poor respiratory outcomes that persist throughout childhood. The mechanisms underpinning these poor respiratory outcomes are not well understood, but intrinsic abnormalities within the airway epithelium may be a contributing factor. Current evidence suggests that the airway epithelium is both structurally and functionally abnormal after preterm birth, with reports of epithelial thickening and goblet cell hyperplasia in addition to increased inflammation and apoptosis in the neonatal intensive care unit. However, studies focusing on the airway epithelium are limited and many questions remain unanswered; including whether abnormalities are a direct result of interrupted development, a consequence of exposure to inflammatory stimuli in the perinatal period or a combination of the two. In addition, the difficulty of accessing airway tissue has resulted in the majority of evidence being collected in the pre-surfactant era which may not reflect contemporary preterm birth. This review examines the consequences of preterm birth on the airway epithelium and explores the clinical relevance of currently available models whilst highlighting the need to develop a clinically relevant in vitro model to help further our understanding of the airway epithelium in preterm birth.
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Affiliation(s)
- Kevin Looi
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Denby J Evans
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Luke W Garratt
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Sherlynn Ang
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Jessica K Hillas
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia
| | - Anthony Kicic
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia; Occupation and Environment, School of Public Health, Curtin University, Bentley 6845, Western Australia, Australia; Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, Nedlands 6009, Western Australia, Australia; Department of Respiratory and Sleep Medicine, Perth Children's Hospital, Nedlands, WA 6009, Australia; UWA Centre for Child Health Research & School of Biomedical Sciences, Nedlands 6009, Western Australia, Australia
| | - Shannon J Simpson
- Telethon Kids Institute, Nedlands 6009, Western Australia, Australia.
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Takahashi T, Kato A, Berdnikovs S, Stevens WW, Suh LA, Norton JE, Carter RG, Harris KE, Peters AT, Hulse KE, Grammer LC, Welch KC, Shintani-Smith S, Tan BK, Conley DB, Kern RC, Bochner BS, Schleimer RP. Microparticles in nasal lavage fluids in chronic rhinosinusitis: Potential biomarkers for diagnosis of aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2017; 140:720-729. [PMID: 28238741 PMCID: PMC5568994 DOI: 10.1016/j.jaci.2017.01.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 12/09/2016] [Accepted: 01/05/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to evaluate cell injury or activation in patients with pathological conditions. OBJECTIVE We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). METHODS We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule [EpCAM](+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1[EMR1](+)MPs), mast cell MPs (high-affinity IgE receptor [FcεRI](+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(-)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs. RESULTS Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP (P < .002) and AERD (P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control (P = .91) and lower than those in patients with CRSsNP (P < .02) and AERD (P < .002). CONCLUSIONS Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.
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Affiliation(s)
- Toru Takahashi
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Atsushi Kato
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Sergejs Berdnikovs
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Whitney W Stevens
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Lydia A Suh
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - James E Norton
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Roderick G Carter
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Kathleen E Harris
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Anju T Peters
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Kathryn E Hulse
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Leslie C Grammer
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Kevin C Welch
- Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | | | - Bruce K Tan
- Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - David B Conley
- Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Robert C Kern
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Bruce S Bochner
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
| | - Robert P Schleimer
- Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill; Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, Ill.
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Larose MC, Archambault AS, Provost V, Laviolette M, Flamand N. Regulation of Eosinophil and Group 2 Innate Lymphoid Cell Trafficking in Asthma. Front Med (Lausanne) 2017; 4:136. [PMID: 28848734 PMCID: PMC5554517 DOI: 10.3389/fmed.2017.00136] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/27/2017] [Indexed: 12/17/2022] Open
Abstract
Asthma is an inflammatory disease usually characterized by increased Type 2 cytokines and by an infiltration of eosinophils to the airways. While the production of Type 2 cytokines has been associated with TH2 lymphocytes, increasing evidence indicates that group 2 innate lymphoid cells (ILC2) play an important role in the production of the Type 2 cytokines interleukin (IL)-5 and IL-13, which likely amplifies the recruitment of eosinophils from the blood to the airways. In that regard, recent asthma treatments have been focusing on blocking Type 2 cytokines, notably IL-4, IL-5, and IL-13. These treatments mainly result in decreased blood or sputum eosinophil counts as well as decreased asthma symptoms. This supports that therapies blocking eosinophil recruitment and activation are valuable tools in the management of asthma and its severity. Herein, we review the mechanisms involved in eosinophil and ILC2 recruitment to the airways, with an emphasis on eotaxins, other chemokines as well as their receptors. We also discuss the involvement of other chemoattractants, notably the bioactive lipids 5-oxo-eicosatetraenoic acid, prostaglandin D2, and 2-arachidonoyl-glycerol. Given that eosinophil biology differs between human and mice, we also highlight and discuss their responsiveness toward the different eosinophil chemoattractants.
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Affiliation(s)
- Marie-Chantal Larose
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, Québec City, QC, Canada
| | - Anne-Sophie Archambault
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, Québec City, QC, Canada
| | - Véronique Provost
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, Québec City, QC, Canada
| | - Michel Laviolette
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, Québec City, QC, Canada
| | - Nicolas Flamand
- Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculté de Médecine, Département de Médecine, Université Laval, Québec City, QC, Canada
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Wang B, Yan L, Yao Z, Roskos LK. Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2017; 6:249-257. [PMID: 28109128 PMCID: PMC5397562 DOI: 10.1002/psp4.12160] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 11/10/2016] [Accepted: 11/13/2016] [Indexed: 01/22/2023]
Abstract
Benralizumab is a humanized, afucosylated, anti‐interleukin‐5 receptor α, immunoglobulin G (IgG) 1 κ monoclonal antibody. We developed a population pharmacokinetic (PK)/pharmacodynamic (PD) model for benralizumab by analyzing PK and blood eosinophil count data from two healthy volunteer studies (N = 48) and four studies in patients with asthma (N = 152). Benralizumab PK was dose‐proportional and adequately described by a two‐compartment model with first‐order elimination from the central compartment and first‐order absorption from the subcutaneous dosing site. The estimated systemic clearance and volume of distribution were typical for human IgG. Body weight and high‐titer antidrug antibodies were identified as relevant covariates influencing the PK of benralizumab. Depletion of blood eosinophil counts was depicted by a modified transit model in which benralizumab induced depletion of eosinophils in each age compartment. Stochastic simulations supported an every‐8‐week dosing schedule of benralizumab for a phase IIb study in patients with uncontrolled asthma.
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Affiliation(s)
- B Wang
- MedImmune LLC, Mountain View, California, USA
| | - L Yan
- MedImmune LLC, Mountain View, California, USA
| | - Z Yao
- MedImmune LLC, Mountain View, California, USA.,Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - L K Roskos
- MedImmune LLC, Gaithersburg, Maryland, USA
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11
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Diao X, Wang J, Zhu H, He B. Overexpression of programmed cell death 5 in a mouse model of ovalbumin-induced allergic asthma. BMC Pulm Med 2016; 16:149. [PMID: 27846830 PMCID: PMC5109699 DOI: 10.1186/s12890-016-0317-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 11/10/2016] [Indexed: 11/10/2022] Open
Abstract
Background Programmed cell death 5 (PDCD5) was first identified as an apoptosis-promoting protein and involved in some autoimmune diseases and inflammatory processes. Our previous study demonstrated greater expression of serum PDCD5 in asthmatic patients than controls. This study aimed to further explore the significance of PDCD5 in mice with induced allergic asthma. Methods We divided 16 female mice into 2 groups: control (n = 8) and allergen (ovalbumin, OVA)-challenged mice (n = 8). The modified ovalbumin inhalation method was used to generate the allergic asthma mouse model, and the impact of OVA was assessed by histology of lung tissue and morphometry. The number of cells in bronchoalveolar lavage fluid (BALF) was detected. Pulmonary function was measured by pressure sensors. PDCD5 and active caspase-3 levels were detected. Results The expression of PDCD5 was higher with OVA challenge than for controls (p < 0.05). PDCD5 level was correlated with number of inflammatory cells in BALF and lung function. Moreover, active caspase-3 level was increased in the OVA-challenged mice (p < 0.001) and correlated with PDCD5 level (p = 0.000). Conclusions These data demonstrate an association between level of PDCD5 and asthma severity and indicate that PDCD5 may play a role in allergic asthma. Electronic supplementary material The online version of this article (doi:10.1186/s12890-016-0317-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaolin Diao
- Department of Respiratory Medicine, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - Juan Wang
- Department of Respiratory Medicine, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - Hong Zhu
- Department of Respiratory Medicine, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing, 100191, China
| | - Bei He
- Department of Respiratory Medicine, Peking University Third Hospital, No. 49 Huayuan North Road, Haidian District, Beijing, 100191, China.
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12
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Fang P, Shi HY, Wu XM, Zhang YH, Zhong YJ, Deng WJ, Zhang YP, Xie M. Targeted inhibition of GATA-6 attenuates airway inflammation and remodeling by regulating caveolin-1 through TLR2/MyD88/NF-κB in murine model of asthma. Mol Immunol 2016; 75:144-50. [PMID: 27289030 DOI: 10.1016/j.molimm.2016.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/20/2016] [Accepted: 05/23/2016] [Indexed: 12/11/2022]
Abstract
The purpose of this study was to evaluate the effects of GATA-6 on airway inflammation and remodeling and the underlying mechanisms in a murine model of chronic asthma. Female BALB/c mice were randomly divided into four groups: phosphate-buffered saline control (PBS), ovalbumin (OVA)-induced asthma group (OVA), OVA+ siNC and OVA+ siGATA-6. In this mice model, GATA-6 expression level was significantly elevated and the expression in Caveolin-1 (Cav-1) inversely correlated with the abundance of GATA-6 in OVA-induced asthma of mice. Silencing of GATA-6 gene expression upregulated Cav-1 expression. Additionally, downregulation of GATA-6 dramatically decreased OVA-challenged inflammation, infiltration, and mucus production. Moreover, silencing of GATA-6 resulted in decreased levels of immunoglobulin E (IgE) and inflammatory mediators and reduced inflammatory cell accumulation, as well as inhibiting the expression of important mediators including matrix metalloproteinase (MMP)-2 and MMP-9, TGF-β1, and a disintegrin and metalloproteinase 8 (ADAM8) and ADAM33, which is related to airway remodeling. Further analysis confirmed that silencing of GATA-6 attenuated OVA-induced airway inflammation and remodeling through the TLR2/MyD88 and NF-κB pathway. In conclusion, these findings indicated that the downregulation of GATA-6 effectively inhibited airway inflammation and reversed airway remodeling via Cav-1, at least in part through downregulation of TLR2/MyD88/NF-κB, which suggests that GATA-6 represents a promising therapeutic strategy for human allergic asthma.
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Affiliation(s)
- Ping Fang
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China.
| | - Hong-Yang Shi
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
| | - Xiao-Ming Wu
- Key Laboratory, Biochemical Information Engineering of Ministry of Education Xi'an Jiaotong University School of Life Science and Technology, Xi'an 710049, Shaanxi, PR China
| | - Yong-Hong Zhang
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
| | - Yu-Jie Zhong
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
| | - Wen-Jing Deng
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
| | - Yu-Ping Zhang
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
| | - Mei Xie
- Respiratory Department, The Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, Shaanxi, PR China
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13
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Li Y, Li J, Huang H, Yang M, Zhuang D, Cheng X, Zhang H, Fu X. Microcystin-LR induces mitochondria-mediated apoptosis in human bronchial epithelial cells. Exp Ther Med 2016; 12:633-640. [PMID: 27446254 PMCID: PMC4950845 DOI: 10.3892/etm.2016.3423] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 04/11/2016] [Indexed: 12/15/2022] Open
Abstract
The present study aimed to investigate the toxicity of microcystin-LR (MC-LR) and to explore the mechanism of MC-LR-induced apoptosis in human bronchial epithelial (HBE) cells. HBE cells were treated with MC-LR (1, 10, 20, 30 and 40 µg/ml) alone or with MC-LR (0, 2.5, 5 and 10 µg/ml) and Z-VAD-FMK (0, 10, 20, 40, 60, 80, 100, 120 and 140 µM), which is a caspase inhibitor, for 24 and 48 h. Cell viability was assessed via an MTT assay and the half maximal effective concentration of MC-LR was determined. The optimal concentration of Z-VAD-FMK was established as 50 µm, which was then used in the subsequent experiments. MC-LR significantly inhibited cell viability and induced apoptosis of HBE cells in a dose-dependent manner, as detected by an Annexin V/propidium iodide assay. MC-LR induced cell apoptosis, excess reactive oxygen species production and mitochondrial membrane potential collapse, upregulated Bax expression and downregulated B-cell lymphoma-2 expression in HBE cells. Moreover, western blot analysis demonstrated that MC-LR increased the activity levels of caspase-3 and caspase-9 and induced cytochrome c release into the cytoplasm, suggesting that MC-LR-induced apoptosis is associated with the mitochondrial pathway. Furthermore, pretreatment with Z-VAD-FMK reduced MC-LR-induced apoptosis by blocking caspase activation in HBE cells. Therefore, the results of the present study suggested that MC-LR is capable of significantly inhibiting the viability of HBE cells by inducing apoptosis in a mitochondria-dependent manner. The present study provides a foundation for further understanding the mechanism underlying the toxicity of MC-LR in the respiratory system.
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Affiliation(s)
- Yang Li
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Jinhui Li
- Henan Science and Technology Exchange Center with Foreign Countries, Zhengzhou University, Zhengzhou, Henan 450003, P.R. China
| | - Hui Huang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Mingfeng Yang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Donggang Zhuang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xuemin Cheng
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xiaoli Fu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
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14
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Kadiyala V, Sasse SK, Altonsy MO, Berman R, Chu HW, Phang TL, Gerber AN. Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects. J Biol Chem 2016; 291:12673-12687. [PMID: 27076634 DOI: 10.1074/jbc.m116.721217] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Indexed: 12/11/2022] Open
Abstract
Antagonism of pro-inflammatory transcription factors by monomeric glucocorticoid receptor (GR) has long been viewed as central to glucocorticoid (GC) efficacy. However, the mechanisms and targets through which GCs exert therapeutic effects in diseases such as asthma remain incompletely understood. We previously defined a surprising cooperative interaction between GR and NF-κB that enhanced expression of A20 (TNFAIP3), a potent inhibitor of NF-κB. Here we extend this observation to establish that A20 is required for maximal cytokine repression by GCs. To ascertain the global extent of GR and NF-κB cooperation, we determined genome-wide occupancy of GR, the p65 subunit of NF-κB, and RNA polymerase II in airway epithelial cells treated with dexamethasone, TNF, or both using chromatin immunoprecipitation followed by deep sequencing. We found that GR recruits p65 to dimeric GR binding sites across the genome and discovered additional regulatory elements in which GR-p65 cooperation augments gene expression. GR targets regulated by this mechanism include key anti-inflammatory and injury response genes such as SERPINA1, which encodes α1 antitrypsin, and FOXP4, an inhibitor of mucus production. Although dexamethasone treatment reduced RNA polymerase II occupancy of TNF targets such as IL8 and TNFAIP2, we were unable to correlate specific binding sequences for GR or occupancy patterns with repressive effects on transcription. Our results suggest that cooperative anti-inflammatory gene regulation by GR and p65 contributes to GC efficacy, whereas tethering interactions between GR and p65 are not universally required for GC-based gene repression.
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Affiliation(s)
- Vineela Kadiyala
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206
| | - Sarah K Sasse
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206
| | - Mohammed O Altonsy
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206,; Department of Zoology, Sohag University, Sohag 825224, Egypt, and
| | - Reena Berman
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206
| | - Hong W Chu
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206
| | - Tzu L Phang
- Department of Medicine, University of Colorado, Denver, Colorado 80045
| | - Anthony N Gerber
- From the Department of Medicine, National Jewish Health, Denver, Colorado 80206,; Department of Medicine, University of Colorado, Denver, Colorado 80045.
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15
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Raoufy MR, Ghafari T, Darooei R, Nazari M, Mahdaviani SA, Eslaminejad AR, Almasnia M, Gharibzadeh S, Mani AR, Hajizadeh S. Classification of Asthma Based on Nonlinear Analysis of Breathing Pattern. PLoS One 2016; 11:e0147976. [PMID: 26824900 PMCID: PMC4732950 DOI: 10.1371/journal.pone.0147976] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 01/10/2016] [Indexed: 11/30/2022] Open
Abstract
Normal human breathing exhibits complex variability in both respiratory rhythm and volume. Analyzing such nonlinear fluctuations may provide clinically relevant information in patients with complex illnesses such as asthma. We compared the cycle-by-cycle fluctuations of inter-breath interval (IBI) and lung volume (LV) among healthy volunteers and patients with various types of asthma. Continuous respiratory datasets were collected from forty age-matched men including 10 healthy volunteers, 10 patients with controlled atopic asthma, 10 patients with uncontrolled atopic asthma, and 10 patients with uncontrolled non-atopic asthma during 60 min spontaneous breathing. Complexity of breathing pattern was quantified by calculating detrended fluctuation analysis, largest Lyapunov exponents, sample entropy, and cross-sample entropy. The IBI as well as LV fluctuations showed decreased long-range correlation, increased regularity and reduced sensitivity to initial conditions in patients with asthma, particularly in uncontrolled state. Our results also showed a strong synchronization between the IBI and LV in patients with uncontrolled asthma. Receiver operating characteristic (ROC) curve analysis showed that nonlinear analysis of breathing pattern has a diagnostic value in asthma and can be used in differentiating uncontrolled from controlled and non-atopic from atopic asthma. We suggest that complexity analysis of breathing dynamics may represent a novel physiologic marker to facilitate diagnosis and management of patients with asthma. However, future studies are needed to increase the validity of the study and to improve these novel methods for better patient management.
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Affiliation(s)
- Mohammad Reza Raoufy
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- * E-mail: (MRR); (SH)
| | - Tara Ghafari
- Department of Physiology, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Darooei
- Department of Biomedical Engineering, Faculty of Electrical and Computer Engineering, Tarbiat Modares University, Tehran, Iran
| | - Milad Nazari
- Faculty of Electrical Engineering, Sharif University of Technology, Tehran, Iran
| | - Seyed Alireza Mahdaviani
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Reza Eslaminejad
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Almasnia
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahriar Gharibzadeh
- Department of Bioelectric, Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran
| | - Ali R. Mani
- Division of Medicine, UCL, London, United Kingdom
| | - Sohrab Hajizadeh
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- * E-mail: (MRR); (SH)
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16
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Urae S, Tsuruoka K, Kuroya S, Shibagaki Y. Tumor Lysis-like Syndrome in Eosinophilic Disease of the Lung: A Case Report and Review of the Literature. Intern Med 2016; 55:3029-3034. [PMID: 27746444 PMCID: PMC5109574 DOI: 10.2169/internalmedicine.55.6659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tumor lysis syndrome (TLS) is a metabolic disorder that is generally associated with a malignancy leading to hyperuricemia, hyperphosphatemia, and acute kidney injury. On the other hand, we sometimes encounter these phenomena in nonmalignant disease, which has been referred to as tumor lysis-like syndrome in some studies. We herein experienced a case in which tumor lysis-like syndrome occurred in the course of therapy for eosinophilic disease of the lung, a nonmalignant disease. Even in nonmalignant disease, massive cell lysis induced by therapy can cause phenomena such as TLS or tumor lysis-like syndrome.
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Affiliation(s)
- Seiya Urae
- Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Japan
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17
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Lee HJ, Lee EK, Seo YE, Shin YH, Kim HS, Chun YH, Yoon JS, Kim HH, Han MY, Kim CK, Kim KE, Koh YY, Kim JT. Roles of Bcl-2 and caspase-9 and -3 in CD30-induced human eosinophil apoptosis. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2015; 50:145-152. [PMID: 26254825 DOI: 10.1016/j.jmii.2015.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 04/01/2015] [Accepted: 05/28/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND/PURPOSE Activation of cell surface CD30 by immobilized anti-CD30 monoclonal antibodies (mAb) induces strong apoptosis in human eosinophils. This anti-CD30 mAb-induced eosinophil apoptosis is inhibited by the addition of inhibitors of p38, ERK1/2 mitogen-activated protein kinases, and phosphatidylinositol 3-kinase. However, there is little data investigating the role of Bcl-2 and caspases in eosinophil apoptosis induced by anti-CD30 mAb. We sought to determine whether anti-CD30 mAb induces human eosinophil apoptosis via Bcl-2 and caspase pathways. METHODS Peripheral blood was drawn from 37 healthy volunteers. The CD30 expression on eosinophils was measured at various time points. Eosinophils were then cultured in plates precoated with anti-CD30 mAb (clone Ber-H8), isotype control immunoglobulin G1, interleukin (IL)-5, or dexamethasone. Western blot analysis was performed to determine the expression of Bcl-2, procaspase-8, -9, and -3, and caspase-8, -9, and -3 after cross-linking of CD30. Human eosinophils were also cultured in plates precoated with anti-CD30 mAb (clone Ber-H8) in the presence or absence of caspase-9 or -3 inhibitors. Eosinophil apoptosis was assessed using flow cytometry. RESULTS The addition of anti-CD30 mAb significantly increased eosinophil apoptosis compared with controls. In western blot analysis, the addition of anti-CD30 mAb significantly decreased the expression of Bcl-2 and procaspase-9 and -3 and increased the expression of caspase-9 and -3. The addition of caspase-9 or -3 inhibitors decreased anti-CD30 mAb-induced human eosinophil apoptosis. Procaspase-8 or caspase-8 expression was not changed in response to various stimuli. CONCLUSION Anti-CD30 mAb-induced human eosinophil apoptosis is likely to be mediated through Bcl-2 and caspase-9 and -3.
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Affiliation(s)
- Hye Jin Lee
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun-Kyoung Lee
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young Eun Seo
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Youn Ho Shin
- Department of Medicine, The Graduate School, Yonsei University, Seoul, Republic of Korea; Department of Pediatrics, CHA University School of Medicine, Seoul, Republic of Korea
| | - Hwan Soo Kim
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Hong Chun
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong-Seo Yoon
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Hee Kim
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Man Yong Han
- Department of Pediatrics, CHA University School of Medicine, Seoul, Republic of Korea
| | - Chang-Keun Kim
- Asthma and Allergy Center, Department of Pediatrics, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea
| | - Kyu-Earn Kim
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Yull Koh
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jin Tack Kim
- Department of Pediatrics, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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18
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Abstract
Twenty cattle (14 Holstein-Friesian, 3 Japanese Black, 3 Aberdeen Angus) ranging in age from 3 months to 8 years exhibited, at slaughter, emphysematous thickening of the ruminal submucosa owing to the appearance of numerous, contiguous, small gas bubbles. Microscopic changes in the ruminal submucosa consisted of (1) multiple cystic (emphysematous) lymphangiectasis that was frequently lined or occluded by granulomatous inflammatory infiltrates including macrophages, multinucleate giant cells, and eosinophils; (2) intralymphatic phagocytosis by macrophages and giant cells of eosinophils that showed positive labeling with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay; and (3) an inflammatory infiltrate extending from the area of lymphangitis into surrounding tissue, as well as edema, hemorrhage, fibrin exudation, fibroplasia, or capillary proliferation throughout the lesional submucosa. In addition, 15 (75%) of the cattle had globular leukocyte infiltrates in the mucosal epithelia of the rumen.
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Affiliation(s)
- S. Ohfuji
- Department of Histopathology, Diagnostic Animal Pathology Office, Hokkaido, Japan
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19
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Xu J, Zhu YT, Wang GZ, Han D, Wu YY, Zhang DX, Liu Y, Zhang YH, Xie XM, Li SJ, Lu JM, Liu L, Feng W, Sun XZ, Li MX. The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma. Acta Pharmacol Sin 2015; 36:171-8. [PMID: 25619395 DOI: 10.1038/aps.2014.128] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 11/07/2014] [Indexed: 01/13/2023]
Abstract
AIM Rosiglitazone is one of the specific PPARγ agonists showing potential therapeutic effects in asthma. Though PPARγ activation was considered protective in inhibiting airway inflammation and remodeling in asthma, the specific mechanisms are still unclear. This study was aimed to investigate whether heme oxygenase-1 (HO-1) related pathways were involved in rosiglitazone-activated PPARγ signaling in asthma treatment. METHODS Asthma was induced in mice by multiple exposures to ovalbumin (OVA) in 8 weeks. Prior to every OVA challenge, the mice received rosiglitazone (5 mg/kg, p.o.). After the mice were sacrificed, the bronchoalveolar lavage fluid (BALF), blood samples and lungs were collected for analyses. The activities of HO-1, MMP-2 and MMP-9 in airway tissue were assessed, and the expression of PPARγ, HO-1 and p21 proteins was also examined. RESULTS Rosiglitazone administration significantly attenuated airway inflammation and remodeling in mice with OVA-induced asthma, which were evidenced by decreased counts of total cells, eosinophils and neutrophils, and decreased levels of IL-5 and IL-13 in BALF, and by decreased airway smooth muscle layer thickness and reduced airway collagen deposition. Furthermore, rosiglitazone administration significantly increased PPARγ, HO-1 and p21 expression and HO-1 activity, decreased MMP-2 and MMP-9 activities in airway tissue. All the therapeutic effects of rosiglitazone were significantly impaired by co-administration of the HO-1 inhibitor ZnPP. CONCLUSION Rosiglitazone effectively attenuates airway inflammation and remodeling in OVA-induced asthma of mice by activating PPARγ/HO-1 signaling pathway.
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20
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Stein J, Maxeiner JH, Montermann E, Höhn Y, Raker V, Taube C, Sudowe S, Reske-Kunz AB. Non-eosinophilic airway hyper-reactivity in mice, induced by IFN-γ producing CD4(+) and CD8(+) lung T cells, is responsive to steroid treatment. Scand J Immunol 2015; 80:327-38. [PMID: 25124713 DOI: 10.1111/sji.12217] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 08/06/2014] [Indexed: 01/22/2023]
Abstract
Non-eosinophilic asthma is characterized by infiltration of neutrophils into the lung and variable responsiveness to glucocorticoids. The pathophysiological mechanisms have not been characterized in detail. Here, we present an experimental asthma model in mice associated with non-eosinophilic airway inflammation and airway hyper-responsiveness (AHR). For this, BALB/c mice were sensitized by biolistic DNA immunization with a plasmid encoding the model antigen β-galactosidase (pFascin-βGal mice). For comparison, eosinophilic airway inflammation was induced by subcutaneous injection of βGal protein (βGal mice). Intranasal challenge of mice in both groups induced AHR to a comparable extent as well as recruitment of inflammatory cells into the airways. In contrast to βGal mice, which exhibited extensive eosinophilic infiltration in the lung, goblet cell hyperplasia and polarization of CD4(+) T cells into Th2 and Th17 cells, pFascin-βGal mice showed considerable neutrophilia, but no goblet cell hyperplasia and a predominance of Th1 and Tc1 cells in the airways. Depletion studies in pFascin-βGal mice revealed that CD4(+) and CD8(+) cells cooperated to induce maximum inflammation, but that neutrophilic infiltration was not a prerequisite for AHR induction. Treatment of pFascin-βGal mice with dexamethasone before intranasal challenge did not affect neutrophilic infiltration, but significantly reduced AHR, infiltration of monocytes and lymphocytes as well as content of IFN-γ in the bronchoalveolar fluid. Our results suggest that non-eosinophilic asthma associated predominantly with Th1/Tc1 cells is susceptible to glucocorticoid treatment. pFascin-βGal mice might represent a mouse model to study pathophysiological mechanisms proceeding in the subgroup of asthmatics with non-eosinophilic asthma that respond to inhaled steroids.
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Affiliation(s)
- J Stein
- Clinical Research Unit Allergology, Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
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Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF, Good JT, Gelfand EW, Martin RJ, Leung DYM. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med 2014; 188:1193-201. [PMID: 24024497 DOI: 10.1164/rccm.201304-0775oc] [Citation(s) in RCA: 272] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
RATIONALE The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. METHODS 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. MEASUREMENTS AND MAIN RESULTS Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-β-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. CONCLUSIONS A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.
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Chen CG, Wang HY, Dai Y, Wang JL, Xu WH. Tripterygium polyglycosid attenuates the established airway inflammation in asthmatic mice. Chin J Integr Med 2013; 19:282-288. [PMID: 23321997 DOI: 10.1007/s11655-013-1410-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Indexed: 01/08/2023]
Abstract
OBJECTIVE To investigate the effect of Tripterygium polyglycosid on establishing airway eosinophil infiltration and related airway hyperresponsiveness of asthmatic mice. METHODS A mature murine asthmatic model was made with ovabulmin sensitized and challenged C57BL/6 mice. Forty mice were divided into four groups with 10 mice in each group: mice sensitized and challenged with saline (WS group), mice sensitized and challenged with ovalbumin (WO group), mice sensitized and challenged with ovalbumin and treated with Tripterygium polyglycosid (TP group) and Dexamethasone (DXM group). The mice were intraperitoneally injected with 20 μg chicken ovabulmin emulsified in injected alum on days 0 and 14, then were challenged with an aerosol generated from 1% ovabulmin on days 24, 25 and 26. Tripterygium polyglycosid was injected intraperitoneally at 50 mg/kg on days 25, 26 and 27 after ovabulmin challenge. Dexamethasone was administrated to mice at 2 mg/kg on day 21, 23 before ovabulmin challenge. The airway hyperresponsiveness, mucus production, eosinophils in parabronchial area and bronchoalveolar lavage fluid and the level of interleukin-5, granulo-macrophage clone stimulating factor in bronchoalveolar lavage fluid were measured as indexes of inflammation. RESULTS Tripterygium polyglycosid treatment after ovabulmin challenge completely inhibited eosinophil infiltration in bronchoalveolar lavage fluid [(0.63 ± 0.34)× 10(4) vs. (75.0 ± 14.8)× 10(4), P<0.05] and the peribrochial area (12.60 ± 3.48 mm(2) vs. 379.0 ± 119.3 mm(2), P<0.05), mucus overproduction in airway (2.8 ± 1.7 vs. 7.1±5.6, P<0.05), and increased interleukin-5 levels in bronchoalveolar lavage fluid (28.8 ± 2.8 pg/mL vs. 7.5 ± 3.5 pg/mL, P<0.05). Meanwhile, Tripterygium polyglycosid treatment after ovabulmin challenge also partially inhibited airway hyperresponsiveness. The level of granulo-macrophage clone stimulating factor in bronchoalveolar lavage fluid didn't change with drugs intervention. CONCLUSIONS The administration of Tripterygium polyglycosid could inhibit the established airway inflammation and reduce the airway hyperresponsiveness of allergic asthmatic mice. It provides a possible alternative therapeutic for asthma.
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Affiliation(s)
- Chang-Gui Chen
- Department of General Practice, the Second Affiliated Hospital of Zhejiang University Medical College, Hangzhou 310006, China
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Lee JJ, Jacobsen EA, Ochkur SI, McGarry MP, Condjella RM, Doyle AD, Luo H, Zellner KR, Protheroe CA, Willetts L, Lesuer WE, Colbert DC, Helmers RA, Lacy P, Moqbel R, Lee NA. Human versus mouse eosinophils: "that which we call an eosinophil, by any other name would stain as red". J Allergy Clin Immunol 2012; 130:572-84. [PMID: 22935586 DOI: 10.1016/j.jaci.2012.07.025] [Citation(s) in RCA: 156] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 07/25/2012] [Accepted: 07/25/2012] [Indexed: 12/20/2022]
Abstract
The respective life histories of human subjects and mice are well defined and describe a unique story of evolutionary conservation extending from sequence identity within the genome to the underpinnings of biochemical, cellular, and physiologic pathways. As a consequence, the hematopoietic lineages of both species are invariantly maintained, each with identifiable eosinophils. This canonical presence nonetheless does not preclude disparities between human and mouse eosinophils, their effector functions, or both. Indeed, many books and reviews dogmatically highlight differences, providing a rationale to discount the use of mouse models of human eosinophilic diseases. We suggest that this perspective is parochial and ignores the wealth of available studies and the consensus of the literature that overwhelming similarities (and not differences) exist between human and mouse eosinophils. The goal of this review is to summarize this literature and in some cases provide experimental details comparing and contrasting eosinophils and eosinophil effector functions in human subjects versus mice. In particular, our review will provide a summation and an easy-to-use reference guide to important studies demonstrating that although differences exist, more often than not, their consequences are unknown and do not necessarily reflect inherent disparities in eosinophil function but instead species-specific variations. The conclusion from this overview is that despite nominal differences, the vast similarities between human and mouse eosinophils provide important insights as to their roles in health and disease and, in turn, demonstrate the unique utility of mouse-based studies with an expectation of valid extrapolation to the understanding and treatment of patients.
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Affiliation(s)
- James J Lee
- Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
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Simoes DCM, Psarra AMG, Mauad T, Pantou I, Roussos C, Sekeris CE, Gratziou C. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma. PLoS One 2012; 7:e39183. [PMID: 22761735 PMCID: PMC3384641 DOI: 10.1371/journal.pone.0039183] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 05/21/2012] [Indexed: 01/21/2023] Open
Abstract
Mitochondrial glucocorticoid (mtGR) and estrogen (mtER) receptors participate in the coordination of the cell's energy requirement and in the mitochondrial oxidative phosphorylation enzyme (OXPHOS) biosynthesis, affecting reactive oxygen species (ROS) generation and induction of apoptosis. Although activation of mtGR and mtER is known to trigger anti-inflammatory signals, little information exists on the presence of these receptors in lung tissue and their role in respiratory physiology and disease. Using a mouse model of allergic airway inflammation disease and applying confocal microscopy, subcellular fractionation, and Western blot analysis we showed mitochondrial localization of GRα and ERβ in lung tissue. Allergic airway inflammation caused reduction in mtGRα, mtERβ, and OXPHOS enzyme biosynthesis in lung cells mitochondria and particularly in bronchial epithelial cells mitochondria, which was accompanied by decrease in lung mitochondrial mass and induction of apoptosis. Confirmation and validation of the reduction of the mitochondrial receptors in lung epithelial cells in human asthma was achieved by analyzing autopsies from fatal asthma cases. The presence of the mitochondrial GRα and ERβ in lung tissue cells and especially their reduction in bronchial epithelial cells during allergic airway inflammation suggests a crucial role of these receptors in the regulation of mitochondrial function in asthma, implicating their involvement in the pathophysiology of the disease.
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Affiliation(s)
- Davina C. M. Simoes
- “G.P. Livanos and M. Simou” Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens Medical School, Athens, Greece
| | - Anna-Maria G. Psarra
- University of Thessaly, Department of Biochemistry and Biotechnology, Larissa, Greece
- Biomedical Research Foundation of the Academy of Athens, Center for Basic Research, Laboratory of Biochemistry, Athens, Greece
| | - Thais Mauad
- Department of Pathology, Sao Paulo University Medical School, Sao Paulo, Brazil
| | - Ioanna Pantou
- “G.P. Livanos and M. Simou” Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens Medical School, Athens, Greece
| | - Charis Roussos
- “G.P. Livanos and M. Simou” Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens Medical School, Athens, Greece
| | - Constantine E. Sekeris
- National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, Laboratory of Molecular Endocrinology, Athens, Greece
| | - Christina Gratziou
- “G.P. Livanos and M. Simou” Laboratories, Evangelismos Hospital, Department of Critical Care and Pulmonary Services, University of Athens Medical School, Athens, Greece
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25
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Neural inflammation and the microglial response in diabetic retinopathy. J Ocul Biol Dis Infor 2012; 4:25-33. [PMID: 23614055 DOI: 10.1007/s12177-012-9086-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 03/16/2012] [Indexed: 01/27/2023] Open
Abstract
This chapter reviews the function of microglia and their potential roles in neural inflammation and pathological changes during diabetic retinopathy.
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Janka-Junttila M, Hasala H, Adcock I, Moilanen E, Kankaanranta H. Dexamethasone and RU24858 Induce Survival and Growth Factor Receptor Bound Protein 2, Leukotriene B4 Receptor 1 and Annexin-1 Expression in Primary Human Neutrophils. J Cell Death 2012; 5:21-9. [PMID: 26448690 PMCID: PMC4583096 DOI: 10.4137/jcd.s9097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Glucocorticoids are widely used anti-inflammatory medication in diseases like asthma and chronic obstructive pulmonary disease. Glucocorticoids can either activate (transactivation) or inhibit (transrepression) transcription. RU24858 was introduced as a “dissociated” glucocorticoid and it has been reported to transrepress but not to transactivate. The aim of this study was to compare the effects of RU24858 and dexamethasone in human neutrophils. RU24858 delayed spontaneous neutrophil apoptosis and further enhanced GM-CSF- induced neutrophil survival to a similar extent as dexamethasone. Like dexamethasone RU24858 also reduced CXCL8 and MIP-1α. Unexpectedly however, RU24858 increased the expression of the glucocorticoid-inducible genes BLT-1, Annexin-1 and Grb-2 in neutrophils to a similar level as seen with dexamethasone. We have shown here that dexamethasone and RU24858 both increase Grb-2, BLT1 and Annexin-1 expression and inhibit CXCL8 and MIP-1α production. This suggests that RU24858 was not able to dissociate between transactivation and transrepression in human neutrophils but enhanced neutrophil survival.
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Affiliation(s)
- Mirkka Janka-Junttila
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital Tampere Finland
| | - Hannele Hasala
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital Tampere Finland
| | - Ian Adcock
- Airways Disease, National Heart and Lung Institute, Imperial College, London, UK
| | - Eeva Moilanen
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital Tampere Finland
| | - Hannu Kankaanranta
- The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital Tampere Finland. ; Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
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Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy 2011; 42:712-37. [PMID: 22092535 DOI: 10.1111/j.1365-2222.2011.03854.x] [Citation(s) in RCA: 161] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 07/26/2011] [Accepted: 07/28/2011] [Indexed: 12/17/2022]
Abstract
Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils, in addition to basophils and mast cells. The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts in conformationally dynamic ways with the receptor's βc subunit, an aggregate of domains it shares with binding sites of IL-3 and granulocyte-macrophage colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune responses characterizing numerous diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis. Although corticosteroid therapy is the primary treatment for these diseases, a substantial number of patients exhibit incomplete responses and suffer side-effects. Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. One additional monoclonal antibody, benralizumab (MEDI-563), has been developed to target IL-5R and attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All three monoclonal antibodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common βc IL-5R subunit is also being used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small interfering RNA technology has also been used therapeutically to inhibit the expression of IL-5 in animal models. This review summarizes the structural interactions between IL-5 and IL-5R and the functional consequences of such interactions, and describes the pre-clinical and clinical evidence supporting IL-5R as a therapeutic target.
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Affiliation(s)
- N A Molfino
- MedImmune, LLC, Gaithersburg, MD 20878, USA.
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28
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Kanoh S, Tanabe T, Rubin BK. IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells. Clin Exp Allergy 2011; 41:1747-56. [PMID: 22092504 DOI: 10.1111/j.1365-2222.2011.03852.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2011] [Revised: 07/20/2011] [Accepted: 07/25/2011] [Indexed: 11/28/2022]
Abstract
BACKGROUND Glucocorticosteroids (GCS) are used to treat bronchial asthma, but are not uniformly effective, especially in severe asthma. IL-13 is a T helper type 2 cytokine implicated in the pathogenesis of asthma, and IL-13 induces mucus production and goblet cell hyperplasia in airway epithelial cells. The effect of GCS on IL-13-induced mucin production is not well characterized. OBJECTIVE The aim of this study was to evaluate the effect of dexamethasone (Dex), a potent synthetic GCS, on IL-13-induced MUC5AC mucin expression and goblet cell proliferation in differentiated normal human bronchial epithelial cells (NHBECs). METHODS NHBECs were cultured for 14 days at an air-liquid interface with IL-13, with or without Dex. MUC5AC protein secretion and mRNA expression was determined using ELISA and quantitative real-time PCR. IL-8 production was assayed using ELISA. Histochemical analysis was performed using H&E and periodic acid-Schiff stain, and MUC5AC immunostaining. RESULTS Although Dex dose dependently inhibited IL-8 release induced by 5 ng/mL IL-13, Dex 0.001-1 μg/mL had no effect on IL-13 induced MUC5AC protein secretion or mRNA expression. Dex paradoxically increased MUC5AC induced by IL-13 at 0.5 and 1 ng/mL, but had no effect alone or with IL-13 at 0.1 ng/mL. Dex 0.001-1 μg/mL did not inhibit the differentiation of cells into goblet cells and MUC5AC-positive cells induced by IL-13. CONCLUSION AND CLINICAL RELEVANCE Dex at therapeutic concentrations did not inhibit the effects of IL-13 on goblet cell differentiation, characteristic of severe asthma. Paradoxically, MUC5AC production was increased with lower dose IL-13 exposure. This may lead to airway mucus obstruction commonly seen in life-threatening asthma.
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Affiliation(s)
- S Kanoh
- Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
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Kankaanranta H, Parkkonen J, Ilmarinen-Salo P, Giembycz MA, Moilanen E. Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism. Pulm Pharmacol Ther 2011; 24:394-400. [PMID: 21396479 DOI: 10.1016/j.pupt.2011.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2010] [Revised: 12/14/2010] [Accepted: 03/01/2011] [Indexed: 11/27/2022]
Abstract
Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). β(2)-Adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective β(2)-agonist salbutamol. Isolated human peripheral blood eosinophils were cultured in the absence or presence of a β(2)-agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding. Salbutamol prolonged survival of human eosinophils and it was inhibited by a β-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl- and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC(50) for the salbutamol effect was 13.6 ± 4.0 and 8.1 ± 3.1 nM in the absence and presence of rolipram, respectively; p=0.0142, n=10). In contrast, inhibition of Ca(2+)-activated K(+)-channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival. Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical β(2)-receptor-adenylyl cyclase-cAMP-protein kinase A pathway.
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Affiliation(s)
- Hannu Kankaanranta
- The Immunopharmacology Research Group, Medical School/B, FIN-33014 University of Tampere, Tampere, Finland.
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Wagner M, Lampinen M, Sangfelt P, Agnarsdottir M, Carlson M. Budesonide treatment of patients with collagenous colitis restores normal eosinophil and T-cell activity in the colon. Inflamm Bowel Dis 2010; 16:1118-26. [PMID: 20027654 DOI: 10.1002/ibd.21188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The aim of this study was to assess the activity of eosinophils, neutrophils, and CD4+ as well as CD8+ T-cells in 11 patients with active collagenous colitis (CC) before and after 8 weeks of budesonide treatment (9 mg once daily) compared to 10 healthy individuals. METHODS Clinical symptoms were recorded and intestinal biopsy samples were taken and analyzed by flow cytometry. Eosinophils with a high surface expression of CD44 and low CD9 expression were classified as activated. Neutrophil activity was assessed by their expression of CD66b, and CD69 was used as an activation marker for T-cells. RESULTS All patients responded to the treatment. The eosinophils in active CC showed increased activity compared to controls. The activity was back to control levels after treatment. Neutrophils were not activated in CC patients before or after treatment. CD8+ T-cells from untreated CC patients had a lower activity than controls, and a tendency of lower activity was observed on CD4+ T-cells. After treatment, the activity was increased on both types of T-cells and was not different from controls. CONCLUSIONS In the present study we demonstrated that the inflammation in CC is characterized by activated eosinophils but there is no neutrophil activity. CD4+ and CD8+ T-cells are increased in numbers in active CC but, surprisingly, they had a lower grade of activity than in control subjects. The major finding of this study is that budesonide treatment restores the normal activation of eosinophils and T-cells, accompanied by clinical remission.
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Affiliation(s)
- Michael Wagner
- Department of Medical Sciences, Gastroenterology Research Group, University Hospital, Uppsala, Sweden.
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31
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Kato M, Suzuki M, Hayashi Y, Kimura H. Role of eosinophils and their clinical significance in allergic inflammation. Expert Rev Clin Immunol 2010; 2:121-33. [PMID: 20477093 DOI: 10.1586/1744666x.2.1.121] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Eosinophils are believed to play roles in the pathophysiology of allergic inflammation, such as bronchial asthma. However, recent studies on anti-interleukin-5 monoclonal antibody treatment of asthmatic patients raised the possibility that eosinophils may play only a limited role. More recent studies established that eosinophils are essentially involved in the development of airway remodeling. Moreover, it is theoretically conceivable that eosinophils are a cellular source of lipid mediators, such as cysteinyl leukotrienes or platelet-activating factor in asthma. Even in the absence of interleukin-5, it is likely that the 'T-helper Type 2 network', including a cascade of vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, CC chemokines, granulocyte-macrophage colony-stimulating factor, for example, can maintain sufficient eosinophilic infiltration and effector functions, such as superoxide anion generation and degranulation. Long-term studies, wherein tissue eosinophils are eliminated effectively will be required to establish the exact roles of these cells in asthma. Finally, the authors will demonstrate that eosinophils have the potential for not only playing detrimental roles but also beneficial ones.
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Affiliation(s)
- Masahiko Kato
- Gunma Children's Medical Center, Department of Allergy and Immunology, Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu, Gunma 377-8577, Japan.
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Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, Coyle AJ, Koike M, Spitalny GL, Kiener PA, Geba GP, Molfino NA. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor α antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol 2010; 125:1237-1244.e2. [DOI: 10.1016/j.jaci.2010.04.005] [Citation(s) in RCA: 229] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 03/03/2010] [Accepted: 04/12/2010] [Indexed: 01/21/2023]
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Brown-Whitehorn TF, Spergel JM. The link between allergies and eosinophilic esophagitis: implications for management strategies. Expert Rev Clin Immunol 2010; 6:101-9. [PMID: 20161677 DOI: 10.1586/eci.09.74] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Eosinophilic esophagitis (EE) has an increased incidence of diagnosis similar to other atopic diseases. We present a recent literature review of the common features between atopic diseases (i.e., asthma, allergic rhinitis and atopic dermatitis) and EE. All of the disorders have allergen triggers and evidence of a possible Th2 inflammation at the site of disease. Murine models have also shown similar features with the importance of T cells and Th2 cytokines for the development of disease. The diseases share underlying inflammation with the potential for remodeling with an increase in TGF-beta expression in asthma and EE. However, differences do exist between the diseases in treatment and pathogenesis. For EE, there are two basic treatment options: avoidance of the food triggers or treatment of the eosinophilic inflammation with corticosteroids.
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Affiliation(s)
- Terri F Brown-Whitehorn
- Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, 3550 Market Street, Philadelphia, PA 19104, USA.
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Kankaanranta H, Janka-Junttila M, Ilmarinen-Salo P, Ito K, Jalonen U, Ito M, Adcock IM, Moilanen E, Zhang X. Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils. JOURNAL OF INFLAMMATION-LONDON 2010; 7:9. [PMID: 20181093 PMCID: PMC2841159 DOI: 10.1186/1476-9255-7-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2009] [Accepted: 02/04/2010] [Indexed: 11/24/2022]
Abstract
Background Granulocytes are important in the pathogenesis of several inflammatory diseases. Apoptosis is pivotal in the resolution of inflammation. Apoptosis in malignant cells is induced by histone deacetylase (HDAC) inhibitors, whereas HDAC inhibitors do not usually induce apoptosis in non-malignant cells. The aim of the present study was to explore the effects of HDAC inhibitors on apoptosis in human eosinophils and neutrophils. Methods Apoptosis was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. HDAC activity in nuclear extracts was measured with a nonisotopic assay. HDAC expression was measured by real-time PCR. Results A HDAC inhibitor Trichostatin A (TSA) induced apoptosis in the presence of survival-prolonging cytokines interleukin-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in eosinophils and neutrophils. TSA enhanced constitutive eosinophil and neutrophil apoptosis. Similar effects were seen with a structurally dissimilar HDAC inhibitor apicidin. TSA showed additive effect on the glucocorticoid-induced eosinophil apoptosis, but antagonized glucocorticoid-induced neutrophil survival. Eosinophils and neutrophils expressed all HDACs at the mRNA level except that HDAC5 and HDAC11 mRNA expression was very low in both cell types, HDAC8 mRNA was very low in neutrophils and HDAC9 mRNA low in eosinophils. TSA reduced eosinophil and neutrophil nuclear HDAC activities by ~50-60%, suggesting a non-histone target. However, TSA did not increase the acetylation of a non-histone target NF-κB p65. c-jun-N-terminal kinase and caspases 3 and 6 may be involved in the mechanism of TSA-induced apoptosis, whereas PI3-kinase and caspase 8 are not. Conclusions HDAC inhibitors enhance apoptosis in human eosinophils and neutrophils in the absence and presence of survival-prolonging cytokines and glucocorticoids.
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Affiliation(s)
- Hannu Kankaanranta
- The Immunopharmacology Research Group, Medical School, FIN-33014, University of Tampere and Research Unit, Tampere University Hospital, Tampere, Finland.
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Duffin R, Leitch AE, Sheldrake TA, Hallett JM, Meyer C, Fox S, Alessandri AL, Martin MC, Brady HJ, Teixeira MM, Dransfield I, Haslett C, Rossi AG. The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by down-regulation of Mcl-1. FEBS Lett 2009; 583:2540-6. [PMID: 19616548 DOI: 10.1016/j.febslet.2009.07.017] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2009] [Revised: 07/10/2009] [Accepted: 07/13/2009] [Indexed: 01/21/2023]
Abstract
Eosinophils are major players in inflammatory allergic diseases such as asthma, hay fever and eczema. Here we show that the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine efficiently and rapidly induces human eosinophil apoptosis using flow cytometric analysis of annexin-V/propidium iodide staining, morphological analysis by light microscopy, transmission electron microscopy and Western immunoblotting for caspase-3 cleavage. We further dissect these observations by demonstrating that eosinophils treated with R-roscovitine lose mitochondrial membrane potential and the key survival protein Mcl-1 is down-regulated. This novel finding of efficacious induction of eosinophil apoptosis by CDKi drugs has potential as a strategy for driving resolution of eosinophilic inflammation.
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Affiliation(s)
- Rodger Duffin
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, Scotland, UK
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36
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Bailey MT, Kierstein S, Sharma S, Spaits M, Kinsey SG, Tliba O, Amrani Y, Sheridan JF, Panettieri RA, Haczku A. Social stress enhances allergen-induced airway inflammation in mice and inhibits corticosteroid responsiveness of cytokine production. THE JOURNAL OF IMMUNOLOGY 2009; 182:7888-96. [PMID: 19494313 DOI: 10.4049/jimmunol.0800891] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Chronic psychosocial stress exacerbates asthma, but the underlying mechanisms remain poorly understood. We hypothesized that psychosocial stress aggravates allergic airway inflammation by altering innate immune cell function. The effects of stress on airway inflammation, lung function, and glucocorticoid responsiveness were studied in a novel in vivo murine model of combined social disruption stress and allergic sensitization. The effects of corticosterone were assessed on cytokine profile and glucocorticoid receptor activation in LPS-stimulated spleen cell cultures in vitro. Airway inflammation resolved 48 h after a single allergen provocation in sensitized control mice, but not in animals that were repeatedly exposed to stress before allergen challenge. The enhanced eosinophilic airway inflammation 48 h after allergen challenge in these mice was associated with increased levels of IL-5, GM-CSF, IgG1, thymus-activated and regulatory chemokine, TNF-alpha, and IL-6 in the airways and a diminished inhibition of these mediators by corticosterone in LPS-stimulated splenocyte cultures in vitro. Stress-induced reduction of the corticosteroid effects paralleled increased p65 expression and a decreased DNA-binding capability of the glucocorticoid receptor in vitro. Furthermore, glucocorticoid receptor mRNA and protein expression in the lungs of mice exposed to both stress and allergen was markedly reduced in comparison with that in either condition alone or in naive mice. Thus, exposure to repeated social stress before allergen inhalation enhances and prolongs airway inflammation and alters corticosterone responsiveness. We speculate that these effects were mediated at least in part by impaired glucocorticoid receptor expression and function.
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Affiliation(s)
- Michael T Bailey
- Department of Oral Biology and Institute for Behavioral Medicine Research, Ohio State University, Columbus, OH 43210, USA
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Wang J, Wang C, Li X, Kong L, Gao K, Liu RY. The effects of anti-asthma drugs on the phagocytic clearance of apoptotic eosinophils by A549 cells. Respir Med 2009; 103:1693-9. [PMID: 19525101 DOI: 10.1016/j.rmed.2009.05.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2008] [Revised: 02/22/2009] [Accepted: 05/05/2009] [Indexed: 01/21/2023]
Abstract
BACKGROUND Phagocytic clearance of apoptotic eosinophils plays an important role in the successful resolution of asthmatic inflammation. To our knowledge, there is limited information available on the effects of anti-asthma drugs on the ingestion of apoptotic eosinophils by bronchial epithelial cells. AIMS To evaluate the effects of dexamethasone, aminophylline and terbutaline on the ingestion of apoptotic eosinophils by A549 cells. METHODS Eosinophils were purified by CD15 and CD16-dependent immunomagnetic selection from peripheral blood of five normal donors. The capacity of phagocytosis of apoptotic eosinophils by A549 cells were assessed under the microscope. IL-6 and IL-8 released from A549 cells to the culture supernatants were measured by RIA. RESULTS Dexamethasone enhanced the phagocytic capacity of A549 cells and inhibited the production of IL-6 and IL-8 from A549 cells stimulated by LPS. Interestingly, aminophylline and terbutaline could not only down-regulate the ingestion of apoptotic eosinophils by A549 cells in a time- and dose-dependent manner, but also decrease IL-6 and IL-8 secretion by A549 cells induced by LPS. CONCLUSIONS The present study showed that all of the investigated anti-asthmatic drugs including dexamethasone, aminophylline and terbutaline play an anti-inflammatory effect by decreasing the release of IL-6 and IL-8 induced by LPS. On the other hand, they may have a different effect on the phagocytosis of apoptotic eosinophils by A549 cells, i.e., dexamethasone promotes the uptake of apoptotic eosinophils while aminophylline and terbutaline inhibit the ingestion of apoptotic eosinophils. These results revealed a novel aspect of dexamethasone, aminophylline and terbutaline in the treatment of asthma.
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Affiliation(s)
- Jiong Wang
- Department of Pulmonary, Anhui Geriatrics Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
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Foster PS, Rosenberg HF, Asquith KL, Kumar RK. Targeting eosinophils in asthma. Curr Mol Med 2008; 8:585-90. [PMID: 18781965 DOI: 10.2174/156652408785748013] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Recruitment of eosinophils has long been recognized as a hallmark of the inflammatory response in asthma. However, the functions of this population of cells in host defense remain poorly understood. Eosinophils play an important part in the inflammatory response and have key regulatory roles in the afferent arm of the immune response. More recently, eosinophils have been demonstrated to participate in host defense against respiratory viruses. The specific contributions of eosinophils to the pathophysiology of asthma remain controversial. However, the balance of evidence indicates that they have a significant role in the disease, suggesting that they may be appropriate targets for therapy. Towards this end, a novel intervention of considerable potential interest is the use of an antibody directed against the beta common chain of the receptor for interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor. However, eliminating eosinophils may not be a risk-free therapeutic strategy, as there is potentially an increased likelihood of respiratory viral infections. This may predispose to the development of acute exacerbations of asthma, an outcome that would have significant clinical implications.
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Affiliation(s)
- Paul S Foster
- Discipline of Immunology & Microbiology, Faculty of Health, University of Newcastle, Newcastle NSW, Australia.
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Tan Y, Lim LHK. trans-Resveratrol, an extract of red wine, inhibits human eosinophil activation and degranulation. Br J Pharmacol 2008; 155:995-1004. [PMID: 18776917 DOI: 10.1038/bjp.2008.330] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND PURPOSE trans-Resveratrol, a non-flavonoid polyphenol found abundantly in red wine possesses antiproliferative and anti-inflammatory activity in various inflammatory disease conditions. However, the effect of trans-resveratrol on eosinophil activation in relation to allergy has not been investigated. EXPERIMENTAL APPROACH Human eosinophils were isolated and purified from whole blood and incubated for 16 h with trans-resveratrol. Eosinophil chemotaxis, activation and degranulation, and apoptosis were investigated. The effect of trans-resveratrol on the inhibition of p38 and ERK1/2 activation was examined. KEY RESULTS Treatment of human eosinophils with trans-resveratrol at concentrations <100 microM for 16 h did not induce eosinophil apoptosis. Similar results were seen after 24 h and 48 h incubations. trans-Resveratrol (<100 microM) significantly inhibited eosinophil peroxidase release after activation with IL-5 (IC(50)=2.9+/-0.9 microM) or C5a (IC(50)=3.9+/-0.5 microM) after 5 min priming with cytochalasin B (CB). Similarly, the production of leukotriene C4 after stimulation with calcium ionophore, and eosinophil chemotaxis in response to eotaxin, as well as CD11b upregulation and CD62 L shedding was also significantly reduced by trans-resveratrol, at concentrations above 5 microM. All the activators induced p38 and ERK1/2 phosphorylation maximal at 2 min of activation. trans-Resveratrol potently inhibited p38 and ERK1/2 activation after calcium ionophore and CB and C5a activation. CONCLUSIONS AND IMPLICATIONS trans-Resveratrol is effective at inhibiting human eosinophil activation and degranulation at concentrations <100 microM, while not inducing apoptosis. This potent anti-inflammatory activity of trans-resveratrol and possibly its metabolites on eosinophils may be worth investigating for the treatment of eosinophil-related allergic diseases.
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Affiliation(s)
- Y Tan
- Inflammation and Cancer Laboratory, Department of Physiology and NUS Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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40
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Van Hove CL, Maes T, Joos GF, Tournoy KG. Chronic inflammation in asthma: a contest of persistence vs resolution. Allergy 2008; 63:1095-109. [PMID: 18616676 DOI: 10.1111/j.1398-9995.2008.01772.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.
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Affiliation(s)
- C L Van Hove
- Department of Respiratory Medicine, Laboratory of Translational Research in Obstructive Pulmonary Diseases, Ghent University, Ghent, Belgium
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41
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Abstract
Increasing evidence places the epithelial cell at the centre of inflammatory processes in human airways. Crucial to this function and the maintenance of inflammatory homoeostasis is a balanced oxidant-antioxidant status in the airway, in part controlled by thioredoxin and thioredoxin reductase, which together can alter the NF-kappaB pathway. PMX464, a thiol-reactive quinol and putative thioredoxin inhibitor, has been investigated in endothelial cells, fibroblasts and colorectal cancer cell lines but in the present issue of the BJP, these investigations were extended to A549 airway epithelial cells. Thioredoxin inhibition was confirmed as was NF-kappaB and IKK suppression but siRNA knockdown of thioredoxin did not alter inflammatory marker expression or activity, suggesting that PMX464 has targets other than thioredoxin. Future consolidation of this evidence will involve concomitant knockdown of thioredoxin reductase, the use of primary airway epithelial cells and, potentially, the employment of three-dimensional (3D) culture systems for both A549 and primary cells.
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Abstract
The respiratory mucosa is responsible for gas exchange and is therefore, of necessity, exposed to airborne pathogens, allergens, and foreign particles. It has evolved a multi-faceted, physical and immune defense system to ensure that in the majority of instances, potentially injurious invaders are repelled. Inflammation, predominantly mediated by effector cells of the granulocyte lineage including neutrophils and eosinophils, is a form of immune defense. Where inflammation proves unable to remove an inciting stimulus, chronic inflammatory disease may supervene because of the potential for tissue damage conferred by the presence of large numbers of frustrated, activated granulocytes. Successful recovery from inflammatory disease and resolution of inflammation rely on the clearance of these cells. Ideally, they should undergo apoptosis prior to phagocytosis by macrophage, dendritic, or epithelial cells. The outcome of inflammation can have serious sequelae for the integrity of the respiratory mucosa leading to disease. Therapeutic strategies to drive resolution of inflammation may be directed at the induction of granulocyte apoptosis and the enhancement of granulocyte clearance.
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Kankaanranta H, Zhang X, Tumelius R, Ruotsalainen M, Haikala H, Nissinen E, Moilanen E. Antieosinophilic activity of simendans. J Pharmacol Exp Ther 2007; 323:31-8. [PMID: 17620456 DOI: 10.1124/jpet.107.124057] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Simendans are novel agents used in the treatment of decompensated heart failure. They sensitize troponin C to calcium and open ATP-sensitive potassium channels and have been shown to reduce cardiac myocyte apoptosis. The aim of the present study was to evaluate whether simendans reduce pulmonary eosinophilia and regulate eosinophil apoptosis. Bronchoalveolar lavage (BAL) eosinophilia was evaluated in ovalbumin-sensitized mice. Effects of simendans on apoptosis in isolated human eosinophils were assessed by relative DNA fragmentation assay, annexin V-binding, and morphological analysis. Dextrosimendan [(+)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl)hydrazono]propanedinitrile] reduced ovalbumin-induced BAL-eosinophilia in sensitized mice. Levosimendan [(-)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile] and dextrosimendan reversed interleukin (IL)-5-afforded survival of human eosinophils by inducing apoptosis in vitro. Even high concentrations of IL-5 were not able to overcome the effect of dextrosimendan. Dextrosimendan further enhanced spontaneous apoptosis as well as that induced by CD95 ligation, without inducing primary necrosis. Dextrosimendan-induced DNA fragmentation was shown to be dependent on caspase and c-Jun NH2-terminal kinase activation, whereas extracellular signal-regulated kinase, p38 mitogen-activated kinase, and ATP-sensitive potassium channels seemed to play no role in its actions. Taken together, our results show that simendans possess antieosinophilic activity and may be useful for the treatment of eosinophilic inflammation.
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Affiliation(s)
- Hannu Kankaanranta
- The Immunopharmacology Research Group, Medical School, University of Tampere, Finland.
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44
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Won TB, Quan SH, Rhee CS, Min YG, Lee CH. Expression of uteroglobin in a murine model of allergic rhinitis. Acta Otolaryngol 2007:83-9. [PMID: 17882576 DOI: 10.1080/03655230701624921] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
CONCLUSION We observed for the first time the expression of Uteroglobin (UGB) in the nasal mucosa of mice. The results of our study suggest that UGB may play an important role in the regulation of inflammation in allergic rhinitis (AR) as well as in the lower airway allergic inflammations. OBJECTIVES Uteroglobin is a protein secreted by epithelial lining of organs communicating with the external environment. Reports of its immunomodulatory effects in allergic disease have been made, but the true physiological role still remains to be elucidated. In this study we tried to observe the expression of UGB in the nasal mucosa of mice and determine its role in AR. MATERIALS AND METHODS Thirty BALB-c mice at 3 weeks of age (10 mice/group) were sensitized systemically by intraperitoneal ovalbumin injection and locally by ovalbumin inhalation. Control group were sensitized with PBS. Treatment group had intraperitoneal dexamethasone injection 1 hour before the initial sensitization while control and AR group were injected with PBS. Symptom scores, eosinophil counts, immunohistochemical staining as well as UGB mRNA expression in the nasal mucosa and lung tissue were analyzed. RESULTS The symptom scores and eosinophil counts between control and treatment group was significantly different from the AR group (P<0.01). On immunohistochemical staining, UGB was localized in the epithelium and submucosal gland of the nasal mucosa as well as in the epithelium of respiratory bronchioles. UGB mRNA expression of the nasal mucosa and lung tissue was decreased in the AR group compared to the control group (P=0.022). In the treatment group UGB expression was increased compared to the AR group (P=0.016). The results of IHC and mRNA expression in the lung tissue correlated with the results in the nasal mucosa.
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Affiliation(s)
- Tae-Bin Won
- Department of Otorhinolaryngology-Head and Neck Surgery, Hallym University College of Medicine, Seoul, Korea
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45
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Wang C, Wang J, Guo HF, Liu RY. Involvement of annexin I in the dexamethasone-mediated upregulation of A549 cells phagocytosis of apoptotic eosinophils. Immunol Lett 2007; 111:103-10. [PMID: 17644190 DOI: 10.1016/j.imlet.2007.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 05/30/2007] [Accepted: 06/05/2007] [Indexed: 10/23/2022]
Abstract
Phagolysis of apoptotic eosinophils plays an important role in the successful resolution of asthmatic inflammation. However, little is known about underlying mechanisms. Our aim is to investigate whether annexin I is involved in the dexamethasone-mediated enhancement of phagolysis of apoptotic eosinophils by A549 cells. Phagocytosis of apoptotic eosinophils by A549 cells was visualized under laser confocal scanning microscopy. The effect of dexamethasone and TNF-alpha treatment on surface annexin I expression on A549 cells was assayed by Western blot. Eosinophils were purified under sterile conditions from periphery blood of five normal donors. A549 cells were visually assessed for apoptotic eosinophil phagocytosis by microscope. The concentration of interleukin 6 (IL-6), IL-8 and TGF-beta(1) released by A549 cells to the culture supernatants was measured by RIA or ELISA. Dexamethasone upregulated apoptotic eosinophils phagocytosis by A549 cells in a time-dependent manner, which correlated with annexin I surface expression. Annexin I mAb abolished dexamethasone-mediated enhancement of apoptotic eosinophil phagocytosis by A549 cells. Phagocytosis of apoptotic eosinophils did not change IL-6, IL-8 and TGF-beta(1) release from A549 cells. These results suggest that annexin I is involved in upregulating of dexamethasone-mediated phagocytosis of apoptotic eosinophils by A549 cells. Furthermore, the phagocytic clearance of apoptotic eosinophils did not increase proinflammatory responses.
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Affiliation(s)
- Cheng Wang
- Department of Pulmonary, Anhui Geriatrics Institute, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei 230022 PR China
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46
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Rosenberg HF, Phipps S, Foster PS. Eosinophil trafficking in allergy and asthma. J Allergy Clin Immunol 2007; 119:1303-10; quiz 1311-2. [PMID: 17481712 DOI: 10.1016/j.jaci.2007.03.048] [Citation(s) in RCA: 300] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Revised: 03/27/2007] [Accepted: 03/28/2007] [Indexed: 02/08/2023]
Abstract
Blood eosinophilia and tissue eosinophilia are characteristic features of allergic inflammation and asthma, conditions associated with prominent production of T(H)2 cytokines IL-4, IL-5, and IL-13. In this review, we will consider recent advances in our understanding of the molecular mechanisms that promote expansion and differentiation of eosinophil progenitors in bone marrow, eosinophil recruitment in response to chemokine receptor 3 agonists eosinophil transit mediated by specific ligand-receptor interactions, and prolonged survival of eosinophils in peripheral tissues. Novel rational therapies including antiselectin and antichemokine receptor modalities designed to block eosinophil development and trafficking are discussed, together with the implications of recent clinical studies that have evaluated the efficacy of humanized anti-IL-5 mAb therapy.
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Affiliation(s)
- Helene F Rosenberg
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Mitsuyama H, Matsuyama W, Watanabe M, Shirahama Y, Higashimoto I, Wada T, Osame M, Arimura K. Increased expression of TRAIL receptor 3 on eosinophils in Churg-Strauss syndrome. ACTA ACUST UNITED AC 2007; 56:662-73. [PMID: 17265502 DOI: 10.1002/art.22387] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE Prolonged survival of eosinophils plays an important role in the pathogenesis of Churg-Strauss syndrome (CSS); however, its detailed molecular mechanism is still unclear. TRAIL and its receptors are expressed on a variety of cells, including eosinophils. In this study, we examined the expression of TRAIL receptors on eosinophils from patients with CSS. METHODS TRAIL receptor expression was assessed on eosinophils from healthy volunteers, patients with CSS, patients with asthma, and patients with hypereosinophilia due to parasitic infection. TRAIL-induced apoptosis of eosinophils was compared between the patients with CSS and patients with asthma. RNA interference was used to assess the effects of suppression of TRAIL receptor 3. RESULTS Expression of TRAIL receptor 3, a decoy receptor that acts as an antiapoptotic receptor, on eosinophils from patients with CSS was significantly higher than that in the other subjects. Moreover, in CSS, serum TRAIL receptor 3 levels showed a significant positive correlation with peripheral eosinophil counts, tissue-infiltrating eosinophils stained positive for this receptor, and peripheral T cells expressed TRAIL on their surface. Compared with asthma patients, eosinophils from CSS patients showed a significantly lower percentage of recombinant TRAIL, less autologous T cell-induced apoptosis, and decreased level of active caspase 3. Suppression of TRAIL receptor 3 through RNA interference significantly increased the recombinant TRAIL-induced apoptosis of eosinophils from CSS patients. CONCLUSION Increased expression of TRAIL receptor 3 on eosinophils from patients with CSS was observed. These alterations in TRAIL receptor 3 expression might be involved in the molecular pathogenesis of CSS eosinophilia.
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48
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Allina J, Hu B, Sullivan DM, Fiel MI, Thung SN, Bronk SF, Huebert RC, van de Water J, LaRusso NF, Gershwin ME, Gores GJ, Odin JA. T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. J Autoimmun 2007; 27:232-41. [PMID: 17222534 PMCID: PMC6200357 DOI: 10.1016/j.jaut.2006.11.004] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2006] [Revised: 11/22/2006] [Accepted: 11/23/2006] [Indexed: 12/21/2022]
Abstract
Primary biliary cirrhosis (PBC) is characterized by loss of tolerance against ubiquitously expressed mitochondrial autoantigens followed by biliary and salivary gland epithelial cell (BEC and SGEC) destruction by autoreactive T cells. It is unclear why BECs and SGECs are targeted. Previous work demonstrated that the reduced form of the major PBC autoantigen predominated in apoptotic BECs and SGECs as opposed to an oxidized form in other apoptotic cells. This led to the hypothesis that presentation of novel self-peptides from phagocytosed apoptotic BECs might contribute to BEC targeting by autoreactive T cells. The effect of autoantigen redox status on self-peptide formation was examined along with the phagocytic ability of BECs. Oxidation of PBC autoantigens first was shown to be due to protein S-glutathionylation of lipoyllysine residues. Absence of protein S-glutathionylation generated novel self-peptides and affected T cell recognition of a lipoyllysine containing peptide. Liver biopsy staining revealed BEC phagocytosis of apoptotic BECs (3.74+/-2.90% of BEC) was present in PBC (7 of 7 cases) but not in normal livers (0 of 3). BECs have the ability to present novel mitochondrial self-peptides derived from phagocytosed apoptotic BECs. Apoptotic cell phagocytosis by non-professional phagocytes may influence the tissue specificity of autoimmune diseases.
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Affiliation(s)
- Jorge Allina
- Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA
| | - Bin Hu
- Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA
| | | | - Maria Isabel Fiel
- Department of Pathology, The Mount Sinai School of Medicine, New York, NY, USA
| | - Swan N. Thung
- Department of Pathology, The Mount Sinai School of Medicine, New York, NY, USA
| | - Steven F. Bronk
- Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Robert C. Huebert
- Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Judy van de Water
- Department of Internal Medicine, School of Medicine of the University of California, Davis, CA, USA
| | | | - M. E. Gershwin
- Department of Internal Medicine, School of Medicine of the University of California, Davis, CA, USA
| | - Gregory J. Gores
- Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Joseph A. Odin
- Department of Medicine, The Mount Sinai School of Medicine, New York, NY, USA
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Laan TTJM, Bull S, van Nieuwstadt RA, Fink-Gremmels J. The effect of aerosolized and intravenously administered clenbuterol and aerosolized fluticasone propionate on horses challenged with Aspergillus fumigatus antigen. Vet Res Commun 2006; 30:623-35. [PMID: 16838204 DOI: 10.1007/s11259-006-3346-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2005] [Indexed: 12/22/2022]
Abstract
Beta-agonists have been shown to display anti-inflammatory properties in several experimental models. The aim of this study was to investigate the anti-inflammatory properties of clenbuterol (CB), administered either intravenously or by aerosol, in comparison with fluticasone propionate (FP) in recurrent airway obstruction (RAO)-susceptible horses. Eight horses, of which five were known to be susceptible to RAO, underwent an inhalation challenge with Aspergillus fumigatus (AF) antigen and were treated with CB intravenously, CB by aerosol, or FP by aerosol. Twenty-four hours after the challenge, bronchoalveolar lavage was performed, the total and differential cell counts were assessed, and cytokines were measured in isolated alveolar macrophages. After challenge with AF, RAO-susceptible horses showed an increase in total cell count, based on an increase in macrophages and lymphocytes, which was inhibited by treatment with intravenous CB, aerosolized CB and aerosolized FP. Neutrophil ratios were decreased when treated with aerosolized CB and FP. Expression of interleukin (IL)-1beta and IL -8 was significantly increased after AF challenge . Interleukin -1beta was significantly decreased following treatment with intravenous CB, aerosolized CB and aerosolized FP, whereas only FP decreased the expression of IL-8. These data suggest that the anti-inflammatory property of CB provide new opportunities in the therapeutic intervention of early inflammation in RAO.
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Affiliation(s)
- T T J M Laan
- Department of Equine Sciences, Internal Medicine Section, Utrecht University, Utrecht, The Netherlands.
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50
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Taha Y, Raab Y, Carlson M, Larsson A, Lördal M, Lööf L, Thörn M. Steroids reduce local inflammatory mediator secretion and mucosal permeability in collagenous colitis patients. World J Gastroenterol 2006; 12:7012-8. [PMID: 17109497 PMCID: PMC4087346 DOI: 10.3748/wjg.v12.i43.7012] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein (ECP), myeloperoxidase (MPO), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and albumin in patients with collagenous colitis (CC).
METHODS: A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice (one and four weeks) after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochemical methods in perfusates and in serum.
RESULTS: Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective well-being at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant.
CONCLUSION: Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.
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Affiliation(s)
- Yesuf Taha
- Departments of Medical Sciences, University Hospital, Uppsala, Sweden.
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