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.

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.

• 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 (ERS)
• 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