This application represents a consortial effort by a group of investigators with considerable expertise in the area of inflammation, immunopathology, leukocyte pathophysiology, and mechanisms of lung injury. The efforts are focused on the mechanisms of activation of phagocytic cells and the role of these cells in bringing about acute and/or progressive injury within the vascular, interstitial, and alveolar compartments of the lung. The studies will be facilitated by the fact that all investigators have an established record of collaborative interactions and have their research laboratories within the Department of Pathology. Section 1 deals with acute lung injury within the alveolar compartment (produced by deposition of immune complexes) and injury of the lung vascular compartment (following systemic complement activation), the role of arachidonate metabolites in neutrophils in the facilitation of these outcomes and pharmacological manipulations designed to alter the production of these metabolites and, thereby, protect the lung from injury. A detailed in vitro analysis of arachidonate metabolites produced by neutrophils after interaction by a variety of soluble and particulate stimuli, and the modulation of these by various drugs will also be carried out. Section 2 is a study of lung granulomatous inflammatory reactions using the T-cell dependent model with Schistosomal egg antigen. Granuloma macrophages will be analyzed for Ia content, production of O2, and arachidonate metabolites and the effects of lipoxygenase and cyclooxygenase inhibitors determined, followed by the in vivo application of these drugs to suppress granuloma formation. The roles of complement factors, T-cells, lymphokines and platelets in the outcome of the granuloma will also be probed. In Section 3, evidence for in vivo leukocyte activation will be sought in ARDS patients and in other clinical situations using a combination of techniques (immunochemical, flow cytometric, membrane polarization, etc.). Parallel reference studies will be carried out in the cobra venom factor model (Section 1), where acute lung injury is known to be related to complement-induced activation of neutrophils. Section 4 involves a probing of lung macrophages, their activation, and their production of factors related to bleomycin-induced pulmonary fibrosis. Supporting Core Units (1-3) provide administrative, immunochemical, and morphological support for all Sections.
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