Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois.
Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Am J Physiol Lung Cell Mol Physiol. 2021 Apr 1;320(4):L568-L582. doi: 10.1152/ajplung.00472.2020. Epub 2021 Feb 10.
Ventilator-induced lung injury is associated with an increase in mortality in patients with respiratory dysfunction, although mechanical ventilation is an essential intervention implemented in the intensive care unit. Intrinsic molecular mechanisms for minimizing lung inflammatory injury during mechanical ventilation remain poorly defined. We hypothesize that Yes-associated protein (YAP) expression in endothelial cells protects the lung against ventilator-induced injury. Wild-type and endothelial-specific YAP-deficient mice were subjected to a low (7 mL/kg) or high (21 mL/kg) tidal volume () ventilation for 4 h. Infiltration of inflammatory cells into the lung, vascular permeability, lung histopathology, and the levels of inflammatory cytokines were measured. Here, we showed that mechanical ventilation with high upregulated YAP protein expression in pulmonary endothelial cells. Endothelial-specific YAP knockout mice following high ventilation exhibited increased neutrophil counts and protein content in bronchoalveolar lavage fluid, Evans blue leakage, and histological lung injury compared with wild-type littermate controls. Deletion of YAP in endothelial cells exaggerated vascular endothelial (VE)-cadherin phosphorylation, downregulation of vascular endothelial protein tyrosine phosphatase (VE-PTP), and dissociation of VE-cadherin and catenins following mechanical ventilation. Importantly, exogenous expression of wild-type VE-PTP in the pulmonary vasculature rescued YAP ablation-induced increases in neutrophil counts and protein content in bronchoalveolar lavage fluid, vascular leakage, and histological lung injury as well as VE-cadherin phosphorylation and dissociation from catenins following ventilation. These data demonstrate that YAP expression in endothelial cells suppresses lung inflammatory response and edema formation by modulating VE-PTP-mediated VE-cadherin phosphorylation and thus plays a protective role in ventilator-induced lung injury.
呼吸机相关性肺损伤与呼吸功能障碍患者的死亡率增加有关，尽管机械通气是重症监护病房实施的一项重要干预措施。在机械通气过程中，最大限度减少肺炎症损伤的内在分子机制仍未得到很好的定义。我们假设内皮细胞中 Yes 相关蛋白（YAP）的表达可以保护肺免受呼吸机相关性损伤。野生型和内皮细胞特异性 YAP 缺陷型小鼠分别接受小潮气量（7 mL/kg）或大潮气量（21 mL/kg）通气 4 小时。测量炎症细胞浸润肺部、血管通透性、肺组织病理学和炎症细胞因子水平。结果表明，高 机械通气可上调肺内皮细胞中的 YAP 蛋白表达。与野生型同窝对照相比，高 通气后的内皮细胞特异性 YAP 敲除小鼠的中性粒细胞计数和支气管肺泡灌洗液中的蛋白含量增加，伊文思蓝渗漏和组织学肺损伤增加。内皮细胞中 YAP 的缺失加剧了机械通气后血管内皮（VE）-钙粘蛋白的磷酸化、血管内皮蛋白酪氨酸磷酸酶（VE-PTP）的下调以及 VE-钙粘蛋白和连环蛋白的解离。重要的是，外源性表达野生型 VE-PTP 可挽救 YAP 缺失引起的中性粒细胞计数和支气管肺泡灌洗液中的蛋白含量增加、血管渗漏和组织学肺损伤，以及通气后 VE-钙粘蛋白的磷酸化和与连环蛋白的解离。这些数据表明，内皮细胞中 YAP 的表达通过调节 VE-PTP 介导的 VE-钙粘蛋白磷酸化来抑制肺炎症反应和水肿形成，从而在呼吸机相关性肺损伤中发挥保护作用。
