Trauma to a tissue with impairment and reestablishment of the blood supply, ischemiareperfusion, or after a burn, can lead to an injury that is augmented by the body's own immune system. Mast cells (MC) play an important role in progression of such an autologous inflammatory response in skeletal muscle and small intestine and after a cutaneous burn, possibly contributing to irreversible injury with scarring. Through the use of mice lacking specific secretory granule neutral proteases, mouse MC protease 5 (mMCP-5) has been found to participate in each of these models of immune injury. In addition, mMCP-4 which has a substrate specificity different from mMCP-5 has been found to also participlate in burn injury. This genetic evidence will be extended by more detailed characterization of the MC response and tissue pathobiology and confirmed by pharmacologic approaches using active site inhibitors and recombinant mMCP-5. The mechanism for MC activation, presumed to be via generation of complement fragments, C3a 6 C5a, will be established by showing protection against autologous immune injury in a strain deficient in one receptor and pharmacologically blocked at the other or by using a strain deficient in both receptors. The possibility that irreversible injury requires the action of the terminal cytotoxic complex of five complement proteins and a MC protease will be addressed by showing protection in a new strain generated so as to be deficient in MC and in formation of the complement complex but intact for the activating portion of the complement pathway. In each of these three aims the final proof for involvement of a particular protein will be by reconstituting injury in a deficient strain with adoptive transfer of wild type MC but not deficient MC.
. Understanding the mechanism of MC activation in autologous immune inflammation, the specificity of the mMCPs involved, and the interplay of the mMCPs with the cytotoxic complement complex in irreversible injury with scarring should provide therapeutic targets.
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