PM2.5通过激肽释放酶介导气道高反应性的作用及机制

Fine particulate matter 2.5 (PM2.5) in the air could increase the airway responsiveness and cause asthma exacerbation. However, the exact mechanism of airway hyperresponsiveness induced by PM2.5 is not clear. Kallikrein could mediate the release of bradykinin (BK) and plays an important role in the inflammatory reaction in vivo. No studies have been reported for the role of kallikrein in PM2.5-induced inflammation and airway hyperresponsiveness. Our preliminary work showed that PM2.5 could induce airway hyperresponsiveness, elevate BK levels in the serum and bronchoalveolar lavage fluid and increase the kallikrein expression in bronchial-lung, while the specific inhibitor of kallikrein could significantly decrease the airway hyperresponsiveness induced by PM2.5. Based on these findings, we hypothesize that kallikrein plays an important role in the occurrence of airway hyperresponsiveness and PM2.5 mediates airway hyperresponsiveness through kallikrein. This proposal will focus on the role of kallikrein in PM2.5-induced airway hyperresponsiveness and the related molecular mechanism. This study will help to clarify the significance of PM2.5-induced airway hyperresponsiveness and the related molecular mechanism, and provide new possible targets for clinical treatment of airway hyperresponsiveness related disease.

空气中细颗粒物PM2.5可以使气道反应性增高，使哮喘患者出现急性加重，但是PM2.5引起气道高反应性的机制尚不明确。激肽释放酶（kallikrein）可以介导缓激肽BK释放，在机体炎症反应过程中起重要作用，但其在PM2.5诱发气道炎症及气道高反应性中的作用尚无研究。我们的前期工作发现PM2.5可以诱发气道高反应，升高血清和肺泡灌洗液中BK水平，增加支气管-肺部kallikrein的表达，而kallikrein特异性阻断剂可以显著降低PM2.5诱发的气道高反应。据此我们提出假设：kallikrein在气道高反应发生中起重要作用，且PM2.5通过kallikrein介导气道高反应性。本申请拟在此基础之上深入研究kallikrein在PM2.5致气道高反应性中的作用及分子机制。此研究对深入认识PM2.5致气道高反应性发生及其机制具有重要意义，同时为临床治疗气道高反应性相关疾病提供新的靶点。

气道平滑肌细胞的异常收缩和气道炎症是导致气道高反应的重要原因。本研究的目的是探讨激肽释放酶在PM2.5诱发的气道高反应中的作用及机制。我们利用PM2.5在线富集口鼻暴露系统来进行小鼠气道高反应模型的建立。结果显示，PM2.5在线富集口鼻暴露后，小鼠气道反应性升高，肺部病理显示炎症反应加重，肺泡灌洗液中IL-4、IL-13及IL-33水平显著升高，且支气管-肺组织激肽释放酶表达升高，肺泡灌洗液中缓激肽分泌水平升高。此外，激肽释放酶的特异性阻断剂可以显著降低气道反应性。 我们在人气道平滑肌细胞上观察了PM2.5对细胞收缩的影响，结果表明PM2.5可以显著促进人气道平滑肌细胞收缩，增加激肽释放酶14，缓激肽受体B2R蛋白表达水平，PM2.5也可以促进细胞缓激肽分泌以及胞内钙离子水平升高。而激肽释放酶14基因特异性敲低可以抑制人气道平滑肌细胞收缩，降低激肽释放酶14表达，并降低上清液中缓激肽分泌水平和胞浆中钙离子水平。总之，研究结果提示激肽释放酶在PM2.5诱发的气道高反应中发挥了重要作用。本研究将为临床防治PM2.5诱发气道高反应提供理论依据和潜在药物靶点。