Essential role of macrophage-related matrix metalloproteinases in indomethacin-induced enteropathy in rats *
Background andAims : Matrix metalloproteinases (MMPs) play a key role in degradation and remodeling of the extracellular matrix in various inflammatory diseases. Intrarectal administration of indomethacin induces longitudinal ulcers of the small intestine in rats, similar to those in Crohn's diseases. The aim of this study was to investigate the role of macrophage-related MMPs in the development of indomethacin-induced small intestinal ulcers in male Wistar rats. Materials and Methods : In the first experiment, we investigated serial changes in small intestinal ulcers and assessed the production of MMP-2, -3, and -9 by Western blotting, zymography, and immunohistochemistry. In the second experiment, we assessed the effect of a broad spectrum MMP inhibitor, GM6001 , which was given intraperioneally three hours after indomethacin administration. We evaluated small intestinal injury 24 hours after indomethacin administration by the methods used in the first experiment. In the third experiment, we administered selective MMP-3 inhibitor VI three hours after intrarectal indomethacin and assessed the small intestinal ulcers. Results : In the first experiment, the ulcer index of the small intestine and the histological damage score during the acute phase were at their peak at 24 hours after indomethacin administration. MMP-3 production was also at its peak at 24 hours after indomethacin administration. In the second experiment, intraperitonal GM6001 inhibited the small intestinal ulcers in a dose-dependent fashion. The change in MMP-3, but not in MMP-2, and MMP-9, correlated positively with the change in the small intestinal ulcers after GM6001 treatment. In the third experiment, selective MMP-3 inhibitor VI also suppressed the small intestinal ulcers in a dose-dependent fashion. Conclusions : MMP-3 plays an essential role in indomethacin-induced enteropathy in rats. Regarding the equal efficacy of selective MMP-3 inhibitor VI and the broad-spectrum MMP inhibitor GM6001 against the experimental longuitudinal ulcers of the small intestine, selective inhibition of MMP-3 may become a strong alternative in the management of Crohn's disease. (Accepted on October 6 , 2003)
