The objective of this SCOR proposal is to further understand the pathogenesis of ARDS as it relates to multiple organ dysfunction. The central hypothesis of this proposal is the pathogenesis of sepsis-induced ARDS is due to the persistence of an imbalance of over-expression of pro- inflammatory/pro-angiogenic mediators, as compared to anti- inflammatory/anti-angiogenic factors. This paradigm predicts that perpetuation of inflammation, angiogenesis, and fibrosis in ARDS, ultimately results in impaired host defense and intra-alveolar fibrosis. An in-depth understanding of the molecular and cellular pathogenesis of ARDS is necessary in order to develop novel treatment strategies. The project hypothesis of this SCOR proposal are as follows: 1. The pathogenesis of intra-alveolar angiogenesis/fibrosis, as compared to angiostatic members of the CXC chemokine family. This paradigm of biological imbalance will favor net angiogenesis leading to intra-alveolar fibrosis and impaired lung function of ARDS patients. 2. The sepsis-induced suppression of lung antibacterial host defense is a result of altered expression of important pro- and anti-inflammatory cytokines; favoring the expression of detrimental Th2-, rather than protective Th1-phenotype cytokines. 3. The cytokine networks established during the pathogenesis of sepsis- shock result in the expression of specific chemokines which can exert either inflammatory or immunoregulatory effects. 4. Acute lung injury occurs during a variety of systemic insults, and that complement activation and chemokine production trigger an inflammatory reaction that injuries the lung. Furthermore, it is postulated that complement products cause synergistic production of chemokines by stimulated alveolar macrophages. This SCOR will utilize a multi-disciplinary approach to test these hypotheses. This expertise consists of investigators trained in Critical Care Medicine, Pathology, Cell and Molecular Biology, and Biostatistics. The strength of this proposal are the investigators, who have a long track-record of collaborative/investigative interests in mechanisms of lung injury. The exceptional institutional resources for biomedical research, the proven commitment to collaborative interaction by both clinicians and basic scientists, and the access to a large population ARDS patients will assure that the studies designed in this proposal will come to fruition.
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