CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

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The major objective of this collaborative effort continues to be to characterize, in physiological, cellular and molecular terms, the factors that regulate mast cell development and function. Together these factors act to create a pleiotropic cell with several tissue-related phenotypes. Although the mast cell arises from bone marrow stem cells, and presents at tissue sites in phenotypically distinct forms, the intermediate phenotype distributed to the tissues or developing within the tissue to provide the tissue-related mature phenotype, remain to be elucidated. Tissue culture systems, beginning with the bone marrow stem cell, will continue to be used to define the regulatory events modulating phenotype. Parallel studies in reconstituted mast cell deficient animals with the appropriate molecular and immunologic probes will be used to identify early mast cell progenitors in bone marrow, blood and/or lymph, and to assess the subsequent development of mast cells at multiple sites in terms of tissue-directed changes in the expression of neutral proteases and cytokines. As the mast cell possesses the capacity to produce leukotrienes from membrane-derived arachidonic acid, the goal of cloning the cDNA and gene for LTC4 synthase continues, so that the regulation of the steps involved in this pathway can be more fully studied in IgE- dependent mast cell systems, or in the previously developed cytokine regulated human eosinophil system. The role of the mast cell in priming the mouse airway for augmented reactivity to methacholine, will be addressed by modifying mast cell phenotypes, either using pharmacologic inhibition or gene disruption to eliminate neutral proteases. The genetic loci associated with naturally occurring airway hyperresponsiveness in various murine strains will be probed using linkage analysis. The studies will delineate the factors that define mast cell development, distribution, and phenotype; phenotype-related functions in the areas of discrete protease action, arachidonic acid metabolism and cytokine generation; and, finally, phenotype-related functions directed to airway reactivity in the mouse model.