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.

Citation

Ramis, J., Middlewick, R., Pappalardo, F., Cairns, J. T., Stewart, I. D., John, A. E., Naveed, S. U. N., Krishnan, R., Miller, S., Shaw, D. E., Brightling, C. E., Buttery, L., Rose, F., Jenkins, G., Johnson, S. R., & 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