The Acute Respiratory Distress Syndrome (ARDS) is characterized by exuberant pulmonaryinflammation and injury to the alveolar-capillary membrane, which can result in dysregulated lung repair (fibroproliferation) and the development of nosocomial infection, particularly pneumonia. While mechanisms that control intrapulmonary inflammation in acute lung injury (ALl) remain unclear, dysregulation of alveolar macrophage (AM) function is believed to play an important role in the pathogenesis of this disease. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, has been shown to down-regulate the expression of inflammatory mediators from monocytes/macrophages, including AM. The role of PPAR-gamma in regulating pulmonary inflammation in ALl has not been investigated, and is the focus of this application. The central hypothesis of this proposal is that the activation state of AM in ALl is regulated by PPAR-gamma, which functions to dampen the magnitude of AM inflammatory responses in ALl. Furthermore, determining the activation state of AM during the course of ALl may serve as an independent predictor of subsequent clinical outcomes in this disease.In this application, we will employ a bench-to-bedside approach utilizing both animal models and human studies involving patients with ALI/ARDS to address the following Specific Aims: 1) to assess the expression and regulation of PPAR-gamma in AM during experimental murine FITC-induced ALl; 2) to determine the role of PPAR-gamma in regulating AM activation state in murine FITC-induced ALl; 3) to prospectively correlate PPAR-gamma expression/activity with the magnitude of pulmonary inflammation, the expression of endogenous ligands, and clinical outcomes in patients with ALI/ARDS; 4) to determine the contribution of PPAR-gamma tofunctional AM phenotypic changes in patients with ALI/ARDS; and 5) to determine whether PPAR-gamma polymorphisms alter disease susceptibility and/or the clinical course of disease in patients with ALI/ARDS. The performance of studies proposed in this application will provide important insights into the control of pulmonary inflammation in ALl, which may lead to novel approaches to both the assessment and treatment of this devastating disease.
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