mechanisms of airflow-induced mechanoreception/-transduction and their impacts on ventilation associated lung injury

呼吸机相关性肺损伤是危重病患者的严重并发症，其特征在于肺泡上皮屏障功能紊乱以及肺泡液体重吸收受损。呼吸机相关性肺损伤通常被描述为基于肺泡上皮细胞牵张诱导的机械感受和机械转导的炎症反应。然而，关于气流引起的支气管和肺泡水平的切应力却知之甚少.本研究的目的是描述存在的上皮机械感受和随后的信号转导在远端气道上皮细胞作为气流诱导的剪切应力的结果。为此，我们开发了一种腔室，用于对远端气道上皮细胞施加气流诱导的剪切应力。为了转化这些发现，计划在动物实验中确认结果。培养的肺泡上皮细胞的初步结果表明，气流诱导的剪切应力导致活性氧介导的Ca2+内流和线粒体活性氧释放增加。我们可以证明，上皮glycocalix的降解，这在血流诱导的内皮剪切应力的mechanoreception中起着重要作用，增加了气流诱导的Ca2+信号。已显示糖杯的降解是细菌诱导的炎症的结果。因此，我们也想研究在glycocalix降解后如何产生增加的Ca2+信号，以及这种机制是否可以解释在初始炎症刺激后肺更容易受到呼吸机相关肺损伤的观察结果。

Ventilator associated lung injury is a serious complication in critical ill patients and is characterized by a disturbed alveolo-epithelial barrier function as well as a compromised alveolar fluid reabsorption. Ventilator associated lung injury is typically described as an inflammatory response based on cell stretch induced mechanoreception and mechanotransduction in the alveolar epithelium. However, little is known about the airflow- induced shear stress at the bronchial and alveolar level. This study proposal aims to describe the existence of the epithelial mechanoreception and subsequent signal transduction in distal airway epithelial cells as a consequence of airflow induced shear stress. For this purpose we developed a chamber to apply airflow induced shear stress on distal airway epithelial cells. To translate these findings it is planned to confirm the results in animal experiments. Preliminary results in cultured alveolar epithelial cells suggest that airflow induced shear stress leads to a reactive oxygen species mediated Ca2+ influx and increased liberation of mitochondrial reactive oxygen species. We could demonstrate that the degradation of the epithelial glycocalix, which plays a major role in the mechanoreception of blood flow induced endothelial shear stress, increased the airflow induced Ca2+ signal. A degradation of the glycocalix has been shown to be a consequence of bacterial induced inflammation. Therefore we would like to investigate as well how the increased Ca2+ signal after glycocalix degradation is generated and if this mechanism can explain the observation that the lungs are more susceptible to ventilator associated lung injury after an initial inflammatory stimulus.