S-nitrosothiols, NF-KappaB and Inflammation in Acute Lung Injury

描述（由申请人提供）：急性肺损伤（ALI）的致病进展涉及气道炎症、上皮损伤和气体交换受损。尽管有协调一致的公共卫生努力，但没有有效的治疗方法来预防ALI，死亡率仍然> 30%。S-亚硝基硫醇（SNO）是由呼吸上皮产生的内源性分子，在肺中以高浓度存在。SNO通过抑制免疫应答途径（包括NF-kB）的活化而发挥抗炎作用。SNO通过靶向激活异源二聚体（p50-p65）的p65亚基进行S-亚硝基化来抑制NF-kB。使用小鼠LPS模型，我们已经表明肺SNO在ALI过程的早期被耗尽，这与p65去亚硝基化、NF-kB活化和气道炎症一起发生。增强肺SNO通过抑制NF-κ B去亚硝基化来预防肺部炎症/损伤，强调了该机制的病理生理学重要性。最近，我们已经表明细胞因子类似地诱导呼吸道上皮中的p65去亚硝基化，该过程由硫氧还蛋白（Trx）调节。Trx抑制剂阻止p65去亚硝基化、NF-κ B活化和细胞因子在ALI模型中的表达，表明Trx是SNO耗竭的介体。这些数据支持我们的假设，即SNO耗竭是ALI发病机制中的一个关键因素。为了验证这一假设，我们制定了以下目标：1。确定Trx是否调节肺SNO代谢并启动ALI中的炎症反应。2.确定肺SNO增加是否抑制肺炎和脓毒症相关ALI的发展。3.量化ALI/ARDS患者的气道SNO，并与疾病严重程度/结局相关。我们预计，完成所提出的目标将提供翻译数据，这是必不可少的支持气道SNO充盈作为预防和发展ALI的治疗的临床试验。

DESCRIPTION (provided by applicant): The pathogenic progression of acute lung injury (ALI) involves airway inflammation, epithelial injury, and the impairment of gas exchange. Despite concerted public health efforts, no effective therapy exists to prevent ALI and mortality remains >30%. S-nitrosothiols (SNOs) are endogenous molecules produced by the respiratory epithelium that are found in high concentration in the lung. SNOs serve an anti-inflammatory role by inhibiting activation of immune response pathways, including NF-kB. SNOs inhibit NF-kB by targeting the p65 subunit of the activating heterodimer (p50-p65) for S-nitrosylation. Using a mouse LPS model, we have shown that lung SNOs are depleted early in the course of ALI which occurs in conjunction with p65 denitrosylation, NF-kB activation, and airway inflammation. Augmenting lung SNOs prevents lung inflammation/injury by inhibiting NF-kB denitrosylation, emphasizing the pathophysiological importance of this mechanism. Recently, we have shown cytokines similarly induce p65 denitrosylation in the respiratory epithelium with this process regulated by thioredoxin (Trx). Trx inhibitors prevent p65 denitrosylation, NF-kB activation, and cytokine expression in the ALI model, suggesting Trx to be the mediator of SNO depletion. These data support our hypothesis that SNO depletion is a critical factor in ALI pathogenesis. To test this hypothesis, we formulated the following aims: 1. Determine if Trx regulates lung SNO metabolism and initiates the inflammatory response in ALI. 2. Determine if lung SNO augmentation inhibits the development of pneumonia- and sepsis-related ALI. 3. Quantify airway SNOs in ALI/ARDS patients and correlate with disease severity/outcomes. We anticipate that completion of the proposed aims will provide the translational data that is essential to support the clinical testing of airway SNO repletion as treatment for the prevention and development of ALI.