SPECIFIC-INHIBITION OF PLASMA KALLIKREIN MODULATES CHRONIC GRANULOMATOUS INTESTINAL AND SYSTEMIC INFLAMMATION IN GENETICALLY SUSCEPTIBLE RATS

The kallilnein-kinin (K-K) (contact) system is activated during acute and chronic relapsing phases of enterocolitis induced in genetically s usceptible Lewis rats by intramural injection of peptidoglycan-polysac charide (PG-APS), Using the selective plasma kallikrein inhibitor P872 0, we investigate whether activation of the K-K system plays a primary role in chronic granulomatous intestinal and systemic inflammation in this model, Group I (negative control) received human serum albumin i ntramurally. Group II (treatment) received PG-APS intramurally and P87 20 orally, Group III (positive control) received PG-APS intramurally a nd albumin orally. P8720 attenuated the consumption of the contact pro teins, high molecular weight kininogen (P<0.03), and factor XI (P<0.04 ) in group LI vs, group III. P8720 decreased chronic intestinal inflam mation measured by blinded gross (P<0.01) and histologic (P<0.0005) sc ores as well as systemic complications (arthritis, splenomegaly, hepat omegaly, leukocytosis, and acute-phase reaction) (P<0.01) in group IT as compared with group m. We conclude that relapsing chronic enterocol itis and systemic complications are in part due to plasma K-K system a ctivation, and that inhibition of this pathway is a potential therapeu tic approach to human inflammatory bowel disease and associated extrai ntestinal manifestations.