Stiffening of the extracellular matrix is a sufficient condition for airway hyperreactivity.
Stiffening of the extracellular matrix is a sufficient condition for airway hyperreactivity.
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细胞外基质的硬化是气道高反应性的充分条件。
DOI：
10.1152/japplphysiol.00554.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Parameswaran,Harikrishnan
中科院分区：
文献类型：
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作者：
Jamieson,RyanR;Stasiak,SuzanneE;Polio,SamuelR;Augspurg,RalstonD;McCormick,CarolineA;Ruberti,JeffreyW;Parameswaran,Harikrishnan
目前哮喘的治疗方法主要集中在靶向炎症和减少气道平滑肌力量，以防止症状复发。然而，即使炎症得到控制，当暴露于低剂量激动剂时，哮喘患者的气道仍然会过度收缩。这表明，有一些机制可能是由炎症引发的，并最终成为自我维持的，因此，即使气道炎症得到控制，这些替代机制仍会继续驱动哮喘患者气道的高反应性。在这项研究中，我们假设气道细胞外基质的硬化是一种核心病理改变，足以在没有炎症的情况下支持过度支气管收缩。为了验证这一假设，我们利用核黄素（维生素B2）和紫外线a辐射，在新鲜解剖的牛环的气道壁上光交联胶原纤维，增加了气道细胞外基质的刚度。在我们的实验中，胶原交联导致气道细胞外基质硬度增加两倍。当暴露于10 - 5 M乙酰胆碱5分钟时，这种变化足以使气道收缩到更大程度，收缩速度更快。我们的研究结果表明，即使在没有炎症信号的情况下，细胞外基质的硬化也足以驱动过度的气道收缩。
The current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force to prevent the recurrence of symptoms. However, even when inflammation is brought under control, airways in an asthmatic can still hyperconstrict when exposed to a low dose of agonist. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction even in the absence of inflammation. To test this hypothesis, we increased the stiffness of the airway extracellular matrix by photo-crosslinking collagen fibers within the airway wall of freshly dissected bovine rings using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a twofold increase in the stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, and at a faster rate when they were exposed to 10− 5 M acetylcholine for 5 min. Our results show that stiffening of the extracellular matrix is sufficient to drive excessive airway constriction even in the absence of inflammatory signals.