Abstract
BackgroundAirway 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.MethodsThis 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.ResultsWe 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.ConclusionThese 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.
Highlights
Airway remodelling is a common feature in asthma and can include epithelial shedding, increased airway smooth muscle (ASM) mass and subepithelial fibrosis
We have investigated how extracellular matrix (ECM) influences TGFβ activation in ASM cells and identified a novel and important role for the matrix crosslinking enzyme Lysyl oxidase like-2 (LOXL2) in asthmatic airway remodelling
TGFβ is a key driver of asthmatic airway remodelling and we have previously shown that ASM cells activate TGFβ in response to contractile agonists [21]
Summary
Airway remodelling is a common feature in asthma and can include epithelial shedding, increased airway smooth muscle (ASM) mass and subepithelial fibrosis. Proteins present within asthmatic ECM can influence the secretory profile of ASM cells and promote their proliferation [4, 5], and influence airway remodelling, hyper-responsiveness and inflammation [6]. In the lung increased ECM stiffness initiates epithelial-mesenchymal transition and causes fibroblasts to synthesise collagen [9, 10]. Increased matrix stiffness can increase ASM cell proliferation and contractile force [11, 12]. Together these studies suggest that increased ECM stiffness may contribute to the development of airway remodelling
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