KALLIKREIN-KININOGEN SYSTEM ACTIVATION AND BRADYKININ (B2) RECEPTORS IN INDOMETHACIN-INDUCED ENTEROCOLITIS IN GENETICALLY SUSCEPTIBLE LEWISRATS

Background - The plasma kallikrein-kinin (K-K) system is activated in acute and chronic relapsing intestinal inflammation induced in Lewis r ats by intramural injection of exogenous bacterial components. Aims - To determine whether this effect is model specific, K-K system activat ion was investigated in a modified indomethacin induced enterocolitis model, as well as bradykinin 2 (B2) receptor distribution in the norma l and acutely inflamed intestine. Methods - Lewis rats injected with d aily sublethal doses of indomethacin for two days developed acute (two days) and chronic (14 days) intestinal inflammation. Plasma prekallik rein (amidolytic), high molecular weight kininogen (HK, coagulant) and cleavage of HK (western blot) were assayed to detect K-K activation. Results - Liver and spleen weights were significantly higher, and body weights and haematocrit values were significantly lower in the indome thacin group than in the control group. During both acute and chronic phases, rats displayed K-K system activation manifested by a significa nt decrease in plasma prekallikrein and HK functional levels, and by H K cleavage. Plasma T kininogen (a major acute phase protein) was signi ficantly elevated. B2 receptors were identified in both normal and inf lammatory intestine with more prominent specific immunohistochemical s taining in the acutely inflamed tissue. Conclusions - K-K system activ ation occurs in association with both acute and chronic phases of inte stinal injury, regardless of the triggering agent, suggesting that act ivation of this system is integrally involved in intestinal inflammati on in genetically susceptible hosts. Localisation of B2 receptors acro ss intestinal layers provides a structural basis for the kinin functio n in the intestine.