CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

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The major objective of this collaborative and synergistic effort continues to be to characterize in physiologic, cellular, and molecular terms the regulation of mast cell diversity and function. There is compelling evidence that mast cells, arising from bone marrow, circulate as committed progenitors with minimal granulation and undergo tissue-dependent maturation and differentiation with further modulation during an inflammatory tissue event. With the cDNA and genes have been isolated and characterized for secretory granule mast cell tryptases, LTC4 synthase, and gp49B1 and with recognition of their functions, gene regulation, regulatory cell biology, segregated pathways of eicosanoid generation and cytokine regulation of effector pathways in committed mast cell progenitors can now be addressed. The regulation of tryptases for which selective functions and availability after exocytosis have been established will be defined in terms of chromosome structure, transcriptional regulation, and transcript stability. Similarly, the expression of LTC4 synthase, the terminal pathway protein committed to biosynthesis of the cysteinyl leukotrienes, will be characterized at transcriptional and post-transcriptional levels. The complexity of the cystein-enriched low molecular weight phospholipase A2 superfamily and the role of the various phospholipase A2 enzymes in supplying arachidonic acid for cysteinyl leukotrienes and segregated, prostaglandin endoperoxide synthase-1 and -2 dependent, PGD2 synthesis will be assessed with selective molecular and immunochemical probes. The mast cell appears enriched with counter-regulatory for mast cell-associated members and for biochemical differences between members, including gp49Bl and PIR-B (p91). The development of mouse bone marrow-derived mast cell progenitors with stem cell factors, interleukin-6 (IL-6), and IL-10 has provided progenitor mast cells (PrMC) deficient in secretory granule proteases and unable to proliferate to IL-3 in the absence of continued sem cell factor stimulation for further characterization of cytokine effects. The genetic loci associated with naturally occurring airway reactivity, which is decreased in mast cell-deficient mice, will be more narrowly localized by repetitive back crosses with a newly available functional assay to conveniently recognize high responders. Taken together, these studies will provide specific information on the regulated expression of key mast cell genes defining critical effector functions with the intent of providing further insights into the tissue-regulated determination of mast cell phenotype/function under physiologic and pathobiologic stimuli.