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Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling

Ramis, Jopeth; Middlewick, Robert; Pappalardo, Francesco; Cairns, Jennifer T.; Stewart, Iain D.; John, Alison E.; Naveed, Shams Un Nisa; Krishnan, Ramaswamy; Miller, Suzanne; Shaw, Dominick E.; Brightling, Christopher E.; Buttery, Lee; Rose, Felicity; Jenkins, Gisli; Johnson, Simon R.; Tatler, Amanda L.

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Authors

Jopeth Ramis

Robert Middlewick

Francesco Pappalardo

Jennifer T. Cairns

Iain D. Stewart

Alison E. John

Shams Un Nisa Naveed

Ramaswamy Krishnan

Dr SUZANNE MILLER suzanne.miller@nottingham.ac.uk
Senior Clinical Studies and Project Manager

Dominick E. Shaw

Christopher E. Brightling

LEE BUTTERY lee.buttery@nottingham.ac.uk
Associate Professor

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FELICITY ROSE FELICITY.ROSE@NOTTINGHAM.AC.UK
Professor of Biomaterials and Tissue Engineering

Gisli Jenkins

SIMON JOHNSON simon.johnson@nottingham.ac.uk
Professor of Respiratory Medicine

AMANDA TATLER AMANDA.TATLER@NOTTINGHAM.AC.UK
Principal Research Fellow



Abstract

BACKGROUND: Airway smooth muscle (ASM) cells are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyperresponsiveness and airway remodelling. The extracellular matrix (ECM) can influence tissue remodelling pathways; however, to date no study has investigated the effect of ASM ECM stiffness and cross-linking on the development of asthmatic airway remodelling. We hypothesised that transforming growth factor-β (TGF-β) activation by ASM cells is influenced by ECM in asthma and sought to investigate the mechanisms involved. METHODS: This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGF-β activation and expression of ECM cross-linking enzymes. Human bronchial biopsies from asthmatic and nonasthmatic donors were used to confirm lysyl oxidase like 2 (LOXL2) expression in ASM. A chronic ovalbumin (OVA) model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. RESULTS: We found that asthmatic ASM cells activated more TGF-β basally than nonasthmatic controls and that diseased cell-derived ECM influences levels of TGF-β activated. Our data demonstrate that the ECM cross-linking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGF-β activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an OVA mouse model of asthma. CONCLUSION: These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.

Citation

Ramis, J., Middlewick, R., Pappalardo, F., Cairns, J. T., Stewart, I. D., John, A. E., …Tatler, A. L. (2022). Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling. European Respiratory Journal, 60(1), Article 2004361. https://doi.org/10.1183/13993003.04361-2020

Journal Article Type Article
Acceptance Date Nov 8, 2021
Online Publication Date Jul 7, 2022
Publication Date Jul 1, 2022
Deposit Date Dec 13, 2021
Publicly Available Date Jul 1, 2022
Journal European Respiratory Journal
Print ISSN 0903-1936
Electronic ISSN 1399-3003
Publisher European Respiratory Society
Peer Reviewed Peer Reviewed
Volume 60
Issue 1
Article Number 2004361
DOI https://doi.org/10.1183/13993003.04361-2020
Keywords Pulmonary and Respiratory Medicine
Public URL https://nottingham-repository.worktribe.com/output/7014700
Publisher URL https://erj.ersjournals.com/content/early/2021/11/18/13993003.04361-2020

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