An intensive review of the broad intellectual and physical resources potentially available to this SCOR renewal has resulted in a proposal which includes five interrelated Projects--two new and three continuing and four continuing Cores. In Project One, study will continue of a unique """"""""human model"""""""" of acute lung injury; namely, patients who develop, predictably, lung injury following pulmonary thromboendarterectomy (PT- E). One pilot intervention study, using a specific inhibitor of human neutrophil elastase, is underway. Other interventions (e.g., inhalation of nitric oxide) are planned. In Project 2, will continue investigations focused on the potential role of cytokines, particularly Interleukin - 8 and TNF.
Among specific aims are a detailed structure-function analysis of IL-8; studies of the influence of inhibition of IL-8 upon the inflammatory sequence; and studies of blood/BALF from acute lung injury patients to determine the impact of surfactant on cytokine behavior. In Project 3, fundamental observations regarding the biochemical alterations of surfactant in acute lung inflammation will continue. From prior studies in SCOR has emerged a synthetic surfactant (KL4) which will be available for intervention studies. Studies of optimal delivery modes, surfactant pharmacokinetics, and, surfactant modulation of clinical- physiologic-cellular behavior in animal models and patients go forward. In the new Project 4, will study the role of selectin-carbohydrate interactions, with the ultimate goal to determine whether blockade of selectin-dependent adhesion of leukocytes will inhibit acute lung injury. Antibody, peptide and oligosaccharide-based approaches will be used to block the molecular interactions of selectins and their ligands in vitro, in a murine model of acute lung injury and, ultimately, in human, In the new Project 5, will explore bacterial lipopolysaccharide (LPS)-LPS- binding protein (LPB) - CD14 relationships in acute lung injury will focus on the relatively unexplored molecular mechanisms by which such interactions activate endothelial cells, how such activation may be blocked and whether blockade modulates lung injury. The four existing Cores will continue their supportive roles. The Administrative Core will be responsible for fiscal-budgetary and administrative-coordinating functions within the SCOR and with other SCORS. The Clinical Core will be responsible for subject identification, sample collection/handling, SCOR activities. The Biochemistry Core will continue to provide analytical resources to the Projects; and the Pathology Core will provide morphologic, morphometric and other specialized analyses required by the Projects. All Project/Cores are led by experienced, well recognized investigators with established laboratories.
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