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 (V_T) 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 V_T up-regulated YAP protein expression in pulmonary endothelial cells. Endothelial-specific YAP knockout mice following high V_T ventilation exhibited increased neutrophil counts and protein content in bronchoalveolar lavage fluid, Evans blue leakage and histological lung injury compared to 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.

中文翻译：

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内皮细胞中的 YAP 表达可预防呼吸机引起的肺损伤

呼吸机引起的肺损伤与呼吸功能障碍患者死亡率的增加有关，尽管机械通气是重症监护病房实施的一项基本干预措施。机械通气期间最大限度减少肺部炎症损伤的内在分子机制仍未明确。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引起的损伤。野生型和内皮特异性 YAP 缺陷小鼠接受低 (7 ml/kg) 或高 (21 ml/kg) 潮气量 (V _T) 通风 4 小时。测量炎症细胞向肺的浸润、血管通透性、肺组织病理学和炎症细胞因子的水平。在这里，我们发现具有高 V _T的机械通气上调了肺内皮细胞中 YAP 蛋白的表达。_{高 V T}后内皮特异性 YAP 敲除小鼠与野生型同窝仔对照相比，通气表现出支气管肺泡灌洗液中的中性粒细胞计数和蛋白质含量增加、埃文斯蓝渗漏和组织学肺损伤。内皮细胞中 YAP 的缺失会夸大血管内皮 (VE)-钙粘蛋白磷酸化、血管内皮蛋白酪氨酸磷酸酶 (VE-PTP) 的下调以及机械通气后 VE-钙粘蛋白和连环蛋白的解离。重要的是，肺血管系统中野生型 VE-PTP 的外源性表达挽救了 YAP 消融诱导的支气管肺泡灌洗液中中性粒细胞计数和蛋白质含量的增加、血管渗漏和组织学肺损伤以及 VE-钙粘蛋白磷酸化和从连环蛋白中解离。通风。