Endoplasmic reticulum-unfolded protein response signalling is altered in severe eosinophilic and neutrophilic asthma.

Autor:	Pathinayake PS; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia., Waters DW; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia., Nichol KS; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia., Brown AC; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia., Reid AT; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia., Hsu AC; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia., Horvat JC; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia., Wood LG; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia., Baines KJ; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia., Simpson JL; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia.; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia., Gibson PG; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia.; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.; NHMRC Centre for Clinical Research Excellence in Severe Asthma, New Lambton Heights, New South Wales, Australia., Hansbro PM; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, New South Wales, Australia.; Centre for Inflammation, Centenary Institute, and Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia., Wark PAB; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia peter.wark@newcastle.edu.au.; Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia.; NHMRC Centre for Clinical Research Excellence in Severe Asthma, New Lambton Heights, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	Thorax [Thorax] 2022 May; Vol. 77 (5), pp. 443-451. Date of Electronic Publication: 2021 Sep 11.
DOI:	10.1136/thoraxjnl-2020-215979
Abstrakt:	Introduction: The significance of endoplasmic reticulum (ER) stress in asthma is unclear. Here, we demonstrate that ER stress and the unfolded protein response (UPR) are related to disease severity and inflammatory phenotype. Methods: Induced sputum (n=47), bronchial lavage (n=23) and endobronchial biopsies (n=40) were collected from participants with asthma with varying disease severity, inflammatory phenotypes and from healthy controls. Markers for ER stress and UPR were assessed. These markers were also assessed in established eosinophilic and neutrophilic murine models of asthma. Results: Our results demonstrate increased ER stress and UPR pathways in asthma and these are related to clinical severity and inflammatory phenotypes. Genes associated with ER protein chaperone ( BiP, CANX, CALR ), ER-associated protein degradation ( EDEM1, DERL1) and ER stress-induced apoptosis ( DDIT3, PPP1R15A ) were dysregulated in participants with asthma and are associated with impaired lung function (forced expiratory volume in 1 s) and active eosinophilic and neutrophilic inflammation. ER stress genes also displayed a significant correlation with classic Th2 (interleukin-4, IL-4/13) genes, Th17 (IL-17F/CXCL1) genes, proinflammatory (IL-1b, tumour necrosis factor α, IL-8) genes and inflammasome activation (NLRP3) in sputum from asthmatic participants. Mice with allergic airway disease (AAD) and severe steroid insensitive AAD also showed increased ER stress signalling in their lungs. Conclusion: Heightened ER stress is associated with severe eosinophilic and neutrophilic inflammation in asthma and may play a crucial role in the pathogenesis of asthma. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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