The overall objective of this SCCOR proposal is to identify pathophysiological mechanisms that initiate and perpetuate acute lung injury (ALl). The central hypothesis of this application is that concurrent induction of pro-inflammatory and anti-inflammatory cytokines occurs in the lungs of patients with ALI/ARDS. A cytokine imbalance in these factors triggers the acute exudative phase of ALI/ARDS and creates an alveolar milieu which favors impaired pulmonary innate immune responses and fibroproliferative repair responses. This SCCOR will utilize a bench-to-bedside approach to test the following project hypotheses: 1. The expression of the chemokine TARC and it's receptor CCR4 by structural cells and leukocytes represent key regulatory components of the septic response by modulating early cytokine production, toll-like receptor expression, and leukocyte activation/recruitment. 2. ALl induces the systemic release of the CC chemokine MCP-1, which mediates the recruitment of fibroblast progenitor cells (fibrocytes) to the alveolus, resulting in fibrocyte maturation, collagen deposition, and fibroproliferation. 3. The activation state of the alveolar macrophage (AM) in ALl is regulated by peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and the magnitude of PPAR-gamma expression/activation is predictive of the clinical course in patients with ALI/ARDS. 4. Fibroblast progenitor cells are present in the alveolus of patients with ALl, and the phenotype of these cells is controlled by both genetic and microenvironmental factors. Furthermore, the presence and/or phenotype of alveolar mesenchymal cells is predictive of acute and long-term outcomes in patients with ALI/ARDS. 5. The administration of GM-CSF will improve clinical outcomes in patients with ALI/ARDS. Our SCCOR represents a unique multidisciplinary and multicenter collaboration that unites a diverse group of investigators with expertise in the clinical and basic investigation of ALl, as well as provides access to a large population of ARDS patients to ensure successful completion of the proposed studies. These studies will provide important insights into the regulation of pulmonary inflammation and repair in ALl, which may lead to novel approaches in both the assessment and treatment of this devastating disease.
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