학술논문
Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling.
Document Type
Academic Journal
Author
Ramis J; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Dept of Chemical Engineering, Technological Institute of the Philippines, Manila, Philippines.; Middlewick R; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Pappalardo F; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Cairns JT; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Stewart ID; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK.; John AE; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK.; Naveed SU; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK.; Krishnan R; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.; Miller S; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Shaw DE; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Brightling CE; Institute for Lung Health, Leicester NIHR Biomedical Research Centre, University of Leicester, Leicester, UK.; Buttery L; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Rose F; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Jenkins G; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK.; Johnson SR; Biodiscovery Institute, University of Nottingham, Nottingham, UK.; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.; Tatler AL; Centre for Respiratory Research/NIHR Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, UK amanda.tatler@nottingham.ac.uk.
Source
Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Conflict of interest: J. Ramis has a patent “Industrial Synthesis of Modified Crosslinkable Biopolymer” pending. Conflict of interest: R. Middlewick has nothing to disclose. Conflict of interest: F. Pappalardo has nothing to disclose. Conflict of interest: J.T. Cairns has nothing to disclose. Conflict of interest: I.D. Stewart has nothing to disclose. Conflict of interest: A.E. John has nothing to disclose. Conflict of interest: S-U-N. Naveed has nothing to disclose. Conflict of interest: R. Krishnan has nothing to disclose. Conflict of interest: S. Miller has nothing to disclose. Conflict of interest: D.E. Shaw has nothing to disclose. Conflict of interest: C.E. Brightling has nothing to disclose. Conflict of interest: L. Buttery has nothing to disclose. Conflict of interest: F. Rose has nothing to disclose. Conflict of interest: G. Jenkins reports personal fees and other (sponsored research agreement paid to institution) from Biogen, GlaxoSmithKline and MedImmune, personal fees from Galapagos, Heptares, Boehringer Ingelheim, Pliant, Roche/InterMune, PharmAkea, Bristol Myers Squibb, Chiesi and Roche/Promedior, other (sponsored research agreement paid to institution) from Galecto, other (collaborative awards) from RedX and Nordic Biosciences, other (advisory board membership) from NuMedii, outside the submitted work; is supported by a National Institute of Health Research Professorship (RP-2017-08-ST2-014); and is a trustee for Action for Pulmonary Fibrosis. Conflict of interest: S.R. Johnson reports grants from the Medical Research Council (MRC), during the conduct of the study; grants from the National Institute of Health Research, MRC and Pfizer, personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A.L. Tatler reports personal fees for consultancy from Pliant Therapeutics, outside the submitted work.
(Copyright ©The authors 2022.)
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.
Competing Interests: Conflict of interest: J. Ramis has a patent “Industrial Synthesis of Modified Crosslinkable Biopolymer” pending. Conflict of interest: R. Middlewick has nothing to disclose. Conflict of interest: F. Pappalardo has nothing to disclose. Conflict of interest: J.T. Cairns has nothing to disclose. Conflict of interest: I.D. Stewart has nothing to disclose. Conflict of interest: A.E. John has nothing to disclose. Conflict of interest: S-U-N. Naveed has nothing to disclose. Conflict of interest: R. Krishnan has nothing to disclose. Conflict of interest: S. Miller has nothing to disclose. Conflict of interest: D.E. Shaw has nothing to disclose. Conflict of interest: C.E. Brightling has nothing to disclose. Conflict of interest: L. Buttery has nothing to disclose. Conflict of interest: F. Rose has nothing to disclose. Conflict of interest: G. Jenkins reports personal fees and other (sponsored research agreement paid to institution) from Biogen, GlaxoSmithKline and MedImmune, personal fees from Galapagos, Heptares, Boehringer Ingelheim, Pliant, Roche/InterMune, PharmAkea, Bristol Myers Squibb, Chiesi and Roche/Promedior, other (sponsored research agreement paid to institution) from Galecto, other (collaborative awards) from RedX and Nordic Biosciences, other (advisory board membership) from NuMedii, outside the submitted work; is supported by a National Institute of Health Research Professorship (RP-2017-08-ST2-014); and is a trustee for Action for Pulmonary Fibrosis. Conflict of interest: S.R. Johnson reports grants from the Medical Research Council (MRC), during the conduct of the study; grants from the National Institute of Health Research, MRC and Pfizer, personal fees from AstraZeneca, outside the submitted work. Conflict of interest: A.L. Tatler reports personal fees for consultancy from Pliant Therapeutics, outside the submitted work.
(Copyright ©The authors 2022.)