CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

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The major objective of this collaborative effort continues to be to characterize in biochemical and functional terms certain cells and chemical mediators considered to be involved in bronchial asthma. Characterization of cell-specific proteins and development of specific cDNA probes will allow studies of the regulation of murine mast cells phenotypes in vitro and in vivo. Companion studies of the role of the fibroblast in determining the mast cell in the associated proliferation of the fibroblasts will serve as the background for in vitro studies of pulmonary fibrosis in a mouse model. The studies of normal and mast cell-deficient strains of mice will utilize the mast cell-specific probes in immunochemical and hybridization analyses to define mast cell phenotypes in lung of normal and reconstituted mast cell-deficient strains in association with the assessment of the pulmonary mechanical response to IgE-dependent mast cell activation in vivo. The mast cells in various human tissues, including lung, require ultrastructural and immunochemical characterization by available techniques with further definition of putative phenotypes with gene-specific cDNA probes as the latter become available. In vitro studies of human mast cells will use retrovirus technology to establish immortalized cell lines as a source of a cDNA library for development of mast cell-specific probes for characterization of human mast cells in vitro and in vivo. The companion in vitro studies of human eosinophils will focus on the isolation structural characterization and cloning of the enzyme LTC4 synthase which forms LTC4 from LTA4 and glutathione and on the further definition of the role of specific cytokines in maintaining the post-mitotic viability of human eosinophils and in augmenting their agonist-initiated formation and release of LTC4. The target cell function of LTC4, whether direct or via conversion to LTD4, will be further analyzed in vitro and in vivo in animal systems and in normal and asthmatic humans. The relationships among airway responsiveness, the effects of a deep inhalation on airway caliber, and the inflammatory state of the lungs and airways based on measurements of mediators, cell types, and microvascular permeability will be assessed for asthmatic humans.