Novel mechanisms of endothelial Injury in the pathogenesis of ARDS

急性呼吸窘迫综合征（ARDS）是一种复杂的多因素综合征， 肺微血管渗漏、蛋白质含量高的水肿和顽固性低氧血症。鉴于最近的研究 从人类和动物研究中已经证明了微血管渗漏在 决定脓毒症和ARDS的结果，维持内皮屏障的完整性代表了一种治疗方法， 预防和治疗ARDS的新的、有效的治疗方法。然而，分子 脓毒症后介导内皮屏障破坏的机制仍然知之甚少，特别是， 对内皮屏障的关键分子和信号通路知之甚少 导致ARDS患者的高死亡率。我们的支持数据显示， ARDS患者血浆SDF 1水平与高死亡率呈正相关。在小鼠中，我们观察到， SDF 1治疗增加了脓毒症诱导的肺损伤和死亡率，在小鼠中， Cxcr 4的可诱导EC特异性破坏（Cxcr 4 iEC）。重要的是，我们的机制研究表明， SDF 1处理诱导内皮细胞焦亡，导致严重的内皮屏障功能障碍。 因此，我们假设血浆SDF 1水平升高是严重肺损伤的预后生物标志物 和更高的ARDS患者死亡率，这归因于SDF 1诱导的压倒性内皮 脓毒症后的焦亡和导致的严重内皮屏障功能障碍。拟议的研究 我们将致力于以下具体目标。目标1中的研究将验证循环SDF 1水平作为 ARDS患者的预后生物标志物，并定义介导SDF 1-夸大的信号通路 脓毒症激发后的肺损伤和死亡率。目标2中的研究将描述分子和 SDF 1通过激活内皮细胞增强脓毒症诱导的肺损伤的细胞机制 探讨抑制焦亡治疗ARDS的可能性。与 从这些全面的研究数据，我们将描绘内皮细胞的基本机制， 损伤，确定ARDS严重程度和死亡率的预后生物标志物，并提供新的 有效治疗ARDS和提高生存率的治疗方法。这些创新 机制研究具有很高的转化潜力。

Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome which manifest itself by leaky lung microvessels, protein rich edema, and intractable hypoxemia. Given that recent studies from both human and animal studies has demonstrated the key role of microvascular leakage in determining the outcome of sepsis and ARDS, maintaining the endothelial barrier integrity represents a novel, effective therapeutic approach for the prevention and treatment of ARDS. However, the molecular mechanisms mediating endothelial barrier disruption after sepsis remain poorly understood, especially, little is known about the key molecules and signaling pathways responsible for endothelial barrier dysfunction resulting in high mortality in ARDS patients. Our Supporting Data show that higher levels of plasma SDF1 in ARDS patients are positively associated with high mortality. In mice, we observed that SDF1 treatment augmented sepsis-induced lung injury and mortality, which were attenuated in mice with inducible EC-specific disruption of Cxcr4 (Cxcr4iEC). Importantly, our mechanistic studies demonstrate that SDF1 treatment induces endothelial cell pyroptosis leading to severe endothelial barrier dysfunction. Thus, we hypothesize that elevated plasma SDF1 levels is a prognostic biomarker of severe lung injury and greater mortality of ARDS patients which is ascribed to SDF1-induced overwhelming endothelial pyroptosis and resultant severe endothelial barrier dysfunction following sepsis. The proposed studies will address the following Specific Aims. Studies in Aim 1 will validate circulating SDF1 level as a prognostic biomarker of ARDS patients and define the signaling pathway mediating SDF1-exaggerated lung injury and mortality following sepsis challenge. Studies in Aim 2 will delineate the molecular and cellular mechanisms of SDF1 in augmenting sepsis-induced lung injury through activation of endothelial pyroptosis and explore the therapeutic potential of inhibiting pyroptosis for treatment of ARDS. With the data from these comprehensive studies, we will delineate the fundamental mechanisms of endothelial injury, identify a prognostic biomarker for the severity and mortality of ARDS, and provide novel therapeutic approaches for effective treatment of ARDS and promotion of survival. Thus, these innovative mechanistic studies have high translational potential.