WWOX对机械通气相关性肺损伤血管内皮细胞的保护作用及其机制研究

机械通气相关性肺损伤（VILI）是影响危重症患者预后的重要因素。炎症性生物伤是VILI发生的核心环节，但确切机制仍不清。WWOX是新发现参与肺内皮细胞（PVEC）通透性及炎症反应的重要因子，而JAK2/STAT3是调控炎症反应的关键通路。我们前期研究发现，机械通气时WWOX表达升高，而WWOX敲除后显著加重PVEC通透性及炎症反应。因此，我们推测WWOX可能通过抑制JAK2/STAT3信号通路降低炎性损伤及改善PVEC屏障功能，从而减轻VILI。本研究拟在细胞水平和动物水平，明确机械通气对PVEC屏障功能及WWOX表达的影响，阐明WWOX在PVEC屏障功能及炎性损伤中的作用，揭示JAK2/STAT3信号通路在WWOX调控VILI介导的PVEC功能障碍中的作用及分子机制。本研究将为VILI的临床防治提供新思路。

Ventilator induced lung injury (VILI) is an important factor affecting the prognosis of critical patients. Inflammatory injury is the core of VILI while the exact mechanism is still undefined. WWOX is a newly discovered important factor involving in endothelial cell permeability and inflammatory response. JAK2/STAT3 is a key pathway regulating inflammatory response. Our previous study found that mechanical ventilation increased the expression of WWOX, while WWOX knockout significantly increased the permeability of Pulmonary vascular endothelial cell(PVEC) and inflammatory response. Therefore, we speculate that WWOX may reduce inflammatory damage and improve PVEC barrier function by inhibiting JAK2/STAT3 signaling pathway to alleviate VILI. The present proposal aims to clarify the effects of mechanical ventilation on the barrier function of PVEC and WWOX expression at the cellular and animal levels. We will address the role of WWOX in PVEC barrier function and inflammatory injury using inducible endothelial WWOX knockout mice. We will further reveal the role of JAK2/STAT3 signaling pathway in the WWOX's regulation of PVEC dysfunction mediated by VILI. This study will provide new ideas for the clinical prevention and treatment of VILI.