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
Biodiscovery Institute, University of Nottingham, Nottingham, UK.
Dept of Chemical Engineering, Technological Institute of the Philippines, Manila, Philippines.
Eur Respir J. 2022 Jul 7;60(1). doi: 10.1183/13993003.04361-2020. Print 2022 Jul.
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.
This study combines and approaches: human ASM cells were used 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.
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 , and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an OVA mouse model of asthma.
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.
气道平滑肌（ASM）细胞是哮喘发病机制的基础，影响支气管收缩、气道高反应性和气道重塑。细胞外基质（ECM）可影响组织重塑途径；然而，迄今为止，尚无研究调查ASM细胞外基质硬度和交联对哮喘气道重塑发展的影响。我们假设哮喘中ASM细胞对转化生长因子-β（TGF-β）的激活受细胞外基质影响，并试图研究其中涉及的机制。
本研究结合了 和 方法：使用人ASM细胞 来研究基础TGF-β激活和细胞外基质交联酶的表达。使用来自哮喘和非哮喘供体的人支气管活检样本确认ASM中赖氨酰氧化酶样2（LOXL2）的表达。采用哮喘慢性卵清蛋白（OVA）模型研究LOXL2抑制对气道重塑的影响。
我们发现哮喘患者的ASM细胞在基础状态下比非哮喘对照组激活更多的TGF-β，且病变细胞衍生的细胞外基质会影响TGF-β的激活水平。我们的数据表明，哮喘患者的ASM细胞和支气管活检样本中，细胞外基质交联酶LOXL2增加。至关重要的是，我们发现在哮喘的OVA小鼠模型中，抑制LOXL2可降低细胞外基质硬度和TGF-β激活 ，并可减少上皮下胶原沉积和ASM厚度，这是气道重塑的两个特征。
这些数据首次突出了LOXL2在哮喘气道重塑发展中的作用，并表明抑制LOXL2作为一种潜在疗法，有望进一步研究以减少重度哮喘患者气道的重塑。
