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

描述（由申请人提供）：急性肺损伤（ALI）的病原进展包括气道炎症、上皮损伤和气体交换障碍。尽管协调一致的公共卫生努力，但没有有效的治疗方法来预防急性呼吸道感染，死亡率仍然高达30%。s -亚硝基硫醇（SNOs）是由呼吸道上皮细胞产生的内源性分子，在肺中存在高浓度。SNOs通过抑制包括NF-kB在内的免疫反应通路的激活而发挥抗炎作用。SNOs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。通过小鼠LPS模型，我们发现肺SNOs在ALI过程中早期被耗尽，这与p65脱硝基化、NF-kB激活和气道炎症同时发生。增加肺SNOs通过抑制NF-kB脱硝基化来预防肺部炎症/损伤，强调了这一机制的病理生理学重要性。最近，我们发现细胞因子在呼吸上皮中类似地诱导p65脱硝基化，这一过程由硫氧还蛋白（Trx）调节。在ALI模型中，Trx抑制剂可阻止p65脱硝基化、NF-kB活化和细胞因子表达，表明Trx是SNO耗竭的介质。这些数据支持我们的假设，即SNO耗竭是ALI发病的关键因素。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代谢并引发ALI患者的炎症反应。2. 确定肺SNO升高是否抑制肺炎和败血症相关ALI的发展。3. 量化ALI/ARDS患者气道SNOs并与疾病严重程度/结局相关。我们预计，完成拟议的目标将为支持气道SNO补充作为预防和发展ALI治疗的临床试验提供必要的转化数据。

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.