Significance of Chymase-Dependent Matrix Metalloproteinase-9 Activation on Indomethacin-Induced Small Intestinal Damages in Rats

The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) include gastrointestinal damage not only in the stomach but also in the small intestine. Chymase converts promatrix metalloproteinase- 9 to matrix metalloproteinase (MMP)-9, which plays an important role in NSAID-induced gastric damage, but it has been unclear whether chymase-dependent MMP-9 activation is involved in the NSAID-induced small intestinal damage. To clarify the involvement of chymase-dependent MMP-9 activation on NSAID-induced small intestinal damage, the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b] thiophen-2-yl)sulfonamido- 3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469), on indomethacin-induced small intestinal damage in rats was evaluated. Until 6 h after oral administration of indomethacin in rats, intestinal MMP-9 activity was unchanged compared with normal rats, but significant increases in MMP-9 activity were observed 12 and 24 h after indomethacin administration. Significant increases in the small intestinal damage score were also observed 12 and 24 h after indomethacin administration. In the extract from the small intestine 24 h after indomethacin administration, the MMP-9 activation was significantly attenuated by TY-51469. Intraperitoneal injection of TY-51469 (10 mg/kg) 3 h before indomethacin administration significantly attenuated the MMP-9 activity in the small intestine compared with placebo treatment. Myeloperoxidase activity, which indicates accumulation of neutrophils, was significantly increased in the small intestine in the placebo-treated rats, but its activity was significantly attenuated by TY-51469 treatment. The area of small intestinal damage was also significantly ameliorated by TY-51469 treatment. These findings suggest that chymase-dependent MMP-9 activation has a significant role in indomethacin-induced small intestinal damage in rats.