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. Mastcells (MC) play an important role in progression of such an autologous inflammatory response in skeletalmuscle and small intestine and after a cutaneous burn, possibly contributing to irreversible injury withscarring. Through the use of mice lacking specific secretory granule neutral proteases, mouse MC protease5 (mMCP-5) has been found to participate in each of these models of immune injury. In addition, mMCP-4which 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 tissuepathobiology and confirmed by pharmacologic approaches using active site inhibitors and recombinantmMCP-5. The mechanism for MC activation, presumed to be via generation of complement fragments, C3a6 C5a, will be established by showing protection against autologous immune injury in a strain deficient inone receptor and pharmacologically blocked at the other or by using a strain deficient in both receptors. Thepossibility that irreversible injury requires the action of the terminal cytotoxic complex of five complementproteins and a MC protease will be addressed by showing protection in a new strain generated so as to bedeficient in MC and in formation of the complement complex but intact for the activating portion of thecomplement pathway. In each of these three aims the final proof for involvement of a particularprotein will be by reconstituting injury in a deficient strain with adoptive transfer of wild type MC but notdeficient MC.
. Understanding the mechanism of MC activation in autologous immuneinflammation, the specificity of the mMCPs involved, and the interplay of the mMCPs with the cytotoxiccomplement complex in irreversible injury with scarring should provide therapeutic targets.
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