Airway and parenchymal transcriptomics in a novel model of asthma and COPD overlap.

Autor:	Tu X; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Kim RY; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, Australia., Brown AC; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., de Jong E; Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands, Australia., Jones-Freeman B; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia., Ali MK; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Gomez HM; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Budden KF; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Starkey MR; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia., Cameron GJM; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Loering S; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Nguyen DH; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Nair PM; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Haw TJ; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Alemao CA; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Faiz A; Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, Australia., Tay HL; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Wark PAB; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Knight DA; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Providence Health Care Research Institute, Vancouver, British Columbia, Canada., Foster PS; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Bosco A; Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands, Australia., Horvat JC; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia., Hansbro PM; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, Australia. Electronic address: Philip.Hansbro@uts.edu.au., Donovan C; Priority Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, Australia; Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, Australia. Electronic address: Chantal.Donovan@uts.edu.au.
Jazyk:	angličtina
Zdroj:	The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Oct; Vol. 150 (4), pp. 817-829.e6. Date of Electronic Publication: 2022 May 25.
DOI:	10.1016/j.jaci.2022.04.032
Abstrakt:	Background: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic respiratory diseases, and some patients have overlapping disease features, termed asthma-COPD overlap (ACO). Patients characterized with ACO have increased disease severity; however, the mechanisms driving this have not been widely studied. Objectives: This study sought to characterize the phenotypic and transcriptomic features of experimental ACO in mice induced by chronic house dust mite antigen and cigarette smoke exposure. Methods: Female BALB/c mice were chronically exposed to house dust mite antigen for 11 weeks to induce experimental asthma, cigarette smoke for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Lung inflammation, structural changes, and lung function were assessed. RNA-sequencing was performed on separated airway and parenchyma lung tissues to assess transcriptional changes. Validation of a novel upstream driver SPI1 in experimental ACO was assessed using the pharmacological SPI1 inhibitor, DB2313. Results: Experimental ACO recapitulated features of both asthma and COPD, with mixed pulmonary eosinophilic/neutrophilic inflammation, small airway collagen deposition, and increased airway hyperresponsiveness. Transcriptomic analysis identified common and distinct dysregulated gene clusters in airway and parenchyma samples in experimental asthma, COPD, and ACO. Upstream driver analysis revealed increased expression of the transcription factor Spi1. Pharmacological inhibition of SPI1 using DB2313, reduced airway remodeling and airway hyperresponsiveness in experimental ACO. Conclusions: A new experimental model of ACO featuring chronic dual exposures to house dust mite and cigarette smoke mimics key disease features observed in patients with ACO and revealed novel disease mechanisms, including upregulation of SPI1, that are amenable to therapy. (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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