赖氨酰氧化酶样2在哮喘中增加，并有助于哮喘气道重塑
2022/01/28
摘要
气道平滑肌细胞（ASM）是哮喘发病的基础，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，然而，迄今为止，没有研究探讨ASM ECM硬度和交联对哮喘气道重塑发展的影响。我们假设哮喘患者ASM激活TGFβ受ECM影响，并试图研究其相关机制。本研究结合了体外和体内方法：体外使用人ASM细胞研究基础TGFβ激活和ECM交联酶的表达。来自哮喘和非哮喘供体的人支气管活检用于确认LOXL2的表达。采用慢性卵清蛋白哮喘模型研究LOXL2抑制对气道重塑的影响。我们发现哮喘患者的ASM细胞比非哮喘对照组的基底部激活更多TGFβ，并且病变细胞源性ECM影响TGFβ激活水平。我们的数据表明，哮喘ASM细胞和支气管活检中的ECM交联酶LOXL2增加。关键的是，在卵清蛋白哮喘小鼠模型中，我们发现LOXL2抑制可在体外降低ECM硬度和TGFβ活化，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。这些数据首次强调了LOXL2在哮喘气道重塑发展中的作用，并表明LOXL2抑制作为减少严重哮喘气道重塑的潜在疗法值得进一步研究。
Lysyl oxidase-like 2 is increased in asthma and contributes to asthmatic airway remodelling
Jopeth Ramis, Robert Middlewick, Francesco Pappalardo, Jennifer T Cairns, Iain D Stewart, Alison E John, Shams-Un-Nisa Naveed, Ramaswamy Krishnan, Suzanne Miller, Dominick E Shaw, Christopher E Brightling, Lee Buttery, Felicity Rose, Gisli Jenkins, Simon R Johnson, Amanda L Tatler
Abstract
Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin 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.
气道平滑肌细胞（ASM）是哮喘发病的基础，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，然而，迄今为止，没有研究探讨ASM ECM硬度和交联对哮喘气道重塑发展的影响。我们假设哮喘患者ASM激活TGFβ受ECM影响，并试图研究其相关机制。本研究结合了体外和体内方法：体外使用人ASM细胞研究基础TGFβ激活和ECM交联酶的表达。来自哮喘和非哮喘供体的人支气管活检用于确认LOXL2的表达。采用慢性卵清蛋白哮喘模型研究LOXL2抑制对气道重塑的影响。我们发现哮喘患者的ASM细胞比非哮喘对照组的基底部激活更多TGFβ，并且病变细胞源性ECM影响TGFβ激活水平。我们的数据表明，哮喘ASM细胞和支气管活检中的ECM交联酶LOXL2增加。关键的是，在卵清蛋白哮喘小鼠模型中，我们发现LOXL2抑制可在体外降低ECM硬度和TGFβ活化，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。这些数据首次强调了LOXL2在哮喘气道重塑发展中的作用，并表明LOXL2抑制作为减少严重哮喘气道重塑的潜在疗法值得进一步研究。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Eur Respir J. 2022 Jan 7;2004361. doi: 10.1183/13993003.04361-2020.)
(Eur Respir J. 2022 Jan 7;2004361. doi: 10.1183/13993003.04361-2020.)
Lysyl oxidase-like 2 is increased in asthma and contributes to asthmatic airway remodelling
Jopeth Ramis, Robert Middlewick, Francesco Pappalardo, Jennifer T Cairns, Iain D Stewart, Alison E John, Shams-Un-Nisa Naveed, Ramaswamy Krishnan, Suzanne Miller, Dominick E Shaw, Christopher E Brightling, Lee Buttery, Felicity Rose, Gisli Jenkins, Simon R Johnson, Amanda L Tatler
Abstract
Airway smooth muscle cells (ASM) are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyper-responsiveness, and airway remodelling. Extracellular matrix (ECM) can influence tissue remodelling pathways, however, to date no study has investigated the effect of ASM ECM stiffness and crosslinking on the development of asthmatic airway remodelling. We hypothesised that TGFβ activation by ASM is influenced by ECM in asthma and sought to investigate the mechanisms involved. This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGFβ activation and expression of ECM crosslinking enzymes. Human bronchial biopsies from asthmatic and non-asthmatic donors were used to confirm LOXL2 expression ASM. A chronic ovalbumin model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. We found that ASM cells from asthmatics activated more TGFβ basally than non-asthmatic controls and that diseased cell-derived ECM influences levels of TGFβ activated. Our data demonstrate that the ECM crosslinking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGFβ activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an ovalbumin 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.
