ACTIVATION OF THE KALLIKREIN-KININ SYSTEM IN ARTHRITIS AND ENTEROCOLITIS IN GENETICALLY SUSCEPTIBLE RATS - MODULATION BY A SELECTIVE PLASMAKALLIKREIN INHIBITOR

We have developed models of acute and chronic inflammatory arthritis a nd enterocolitis using peptidoglycan-polysaccharide injected intraperi toneally or subserosally (intramurally) into the distal ileum and cecu m. Acute inflammation occurs in both Buffalo and Lewis rats, character ized by inflammation of the injected areas of the intestine. However, only the genetically susceptible Lewis rat develops chronic synovitis and joint erosion or adhesions and granulomatous enterocolitis. In the Lewis rat but not the Buffalo rat, these changes are accompanied by a decrease in plasma prekallikrein and high-molecular-weight kininogen, reflecting activation of the kallikrein-kinin system. Pretreatment wi th a specific plasma kallikrein inhibitor modulates the acute and chro nic arthritis. The same inhibitor partially abrogates the acute change s characteristic of enterocolitis, and preliminary data suggest simila r results in the chronic model. The results of these studies indicate that the kallikrein-kinin system plays an important role in arthritis and enterocolitis induced by bacterial products and that kallikrein in hibitors are potential therapeutic agents for inflammatory arthritis a nd inflammatory bowel disease.