and Specific Aims.) Pulmonary alveolar macrophages (PAM) are involved in the phagocytosis of IgG- coated microorganisms and are important in the defense of the lung infection. Furthermore, stimulation of Fc-gamma(g) receptors can release inflammatory cytokines and superoxide. The excessive release of these molecules from PAM may have deleterious effects on the lung. In addition, depressed PAM Fc-g receptor function may increase the likelihood of infection. The goal is to examine the function of each of the PAM Fc-g receptors and determine their alterations in the acute respiratory distress syndrome (ARDS), a pulmonary disorder associated with lung injury and infectious complications. The hypothesis is that each PAM Fc-g receptor differs in its function and in how it transmits signals, e.g. one PAM Fc-g receptor may function primarily in IL- 1 production and another in phagocytosis. Structure/function relationships in signal transduction will be studied utilizing Fc-gRIIIA transfectants.
The Specific Aims are to address the following areas: 1) relationship between PAM Fc-g receptor expression and function, including a) the ability of each PAM Fc receptor class stimulated with monoclonal antibodies (mAbs) to initiate superoxide production and the release of IL-6, IL-1, and TNF, b) PAM Fc-gRIII signal transduction and identification of substrates phosphorylated on tyrosine, c) effect of lipopolysaccharide (LPS) sensitization of PAM on Fc-g receptor function, d) correlation of PAM Fc-g receptor expression and function with the clinical course in ARDS, and e) cytokine and superoxide release following stimulation of PAM Fc-g receptors from ARDS patients; 2) structure/function relationships of the Fc-g receptor, Fc-gRIIIA in signal transduction, including, a) examination of sequence requirements for Ca2+ signaling and phagocytosis, b) examination of the function of chimeric Fc-gRIIIA/g molecules, c) the role of the tyrosine kinase Src in Fc-gRIIIA activation, and d) construction of murine macrophage cell lines permanently transfected with human Fc-gRIIIA/g.
Showing the most recent 10 out of 59 publications
