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

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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.