KALLIKREIN KININ SYSTEM IN INFLAMMATORY BOWEL DISEASE

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The mechanisms underlying the pathological changes in inflammatory bowel disease are not well understood. We have found that bacterial products found in the lower bowel have the ability to produce the chronic granulomatous inflammation similar to Crohn's disease (regional ileitis) in genetically susceptible hosts. Moreover, systemic absorption of these products could explain the associated finding of arthritis and anemia. We have demonstrated that bacterial products known to activate the kallikrein-kinin system in shock associated with severe infection may initiate the local changes important in experimental intestinal inflammation. The kallikrein-kinin system is a series of enzymatic factions which release bradykinin, a peptide which induces pain, swelling, diarrhea, and-muscle contraction, all of which are characteristic symptoms of Crohn's disease. We have first documented the occurrence of activation of this system in a rat model of arthritis induced by a bacterial product, peptidoglycan-polysaccharide (PG-APS). Further, we have recently demonstrated that a specific kallikrein inhibitor can not only block contact activation in a rat model of arthritis, but also ameliorates the arthritis, anemia and acute phase reaction. Further, we have shown that the contact activation only occurs in the Lewis rat but not in the Buffalo rat, which falls to respond to PG-APS. We also have preliminary data that a specific kallikrein inhibitor blocks the contact, activation, gut inflammation and neutrophil infiltration in rats given intramural injection of PG-APS into the caecum. To delineate the mechanisms by which the contact system relates to the inflammatory changes, we propose to study 1) an additional specific kallikrein inhibitor, a novel recombinant mutant Kunitz-type protease inhibitor, 2) aprotonin, which inhibits both kallikrein and plasmin, 3) a bradykinin receptor antagonist, and 4) a recombinant elastase inhibitor. These agents will be tested for their ability to inhibit the acute and chronic phases of inflammation. In addition, we will investigate the mechanism of the differential activation of the contact system in genetically susceptible and resistant rats, including in vitro and in vivo activation of the contact system by PG-PS, endotoxin, IL-1 and lL-6. We will study the molecular genetic basis of the defect in kininogen cleavage in resistant rats. These studies should demonstrate important mechanisms in the pathogenesis of inflammatory bowel disease. Assays of the contact system could distinguish active from inactive disease, or serve as an index for therapy. In addition, the inhibitors used alone or in combination could serve in the future as potential therapeutic agents of human inflammatory bowel disease.