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、多因素的综合征 肺微血管渗漏，富含蛋白质的水肿，以及顽固性低氧血症。鉴于最近的研究 从人类和动物研究中都证明了微血管渗漏在 决定脓毒症和ARDS的结局，维持内皮屏障的完整性代表着 防治ARDS的新的、有效的治疗方法。然而，分子 脓毒症后内皮细胞屏障破坏的机制仍不清楚，尤其是， 对内皮屏障的关键分子和信号转导途径知之甚少 功能障碍导致ARDS患者的高死亡率。我们的支持数据显示，更高水平的 ARDS患者血浆SDF1水平与高死亡率呈正相关。在老鼠身上，我们观察到 SDF1治疗增加了脓毒症所致的肺损伤和死亡率，而这种损伤可被 可诱导EC特异性的CXCR4(Cxcr4iEC)中断。重要的是，我们的机械论研究表明 SDF1治疗可诱导内皮细胞下垂，导致严重的内皮屏障功能障碍。 因此，我们假设血浆sdf1水平升高是严重肺损伤的预后生物标志物。 而ARDS患者死亡率更高，这归因于SDF1诱导的压倒性内皮细胞 脓毒症后的上睑下垂和由此导致的严重内皮屏障功能障碍。建议进行的研究 将解决以下具体目标。AIM 1的研究将验证循环SDF1水平作为一种 ARDS患者预后的生物标志物及介导SDF1过度表达的信号通路 脓毒症激发后的肺损伤和死亡率。目标2中的研究将描绘出分子和 SDF1通过激活内皮细胞增强脓毒症肺损伤的细胞机制 目的：探讨抑制上睑下垂治疗ARDS的可能性。与 来自这些综合研究的数据，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和提高存活率的治疗方法。因此，这些创新的 机械论研究具有很高的翻译潜力。

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.