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

Abstract

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.Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin have been widely used for their anti-inflammatory effects, but they are known to produce gastric damage. More recently, with the development of capsule endoscopy and double-balloon endoscopy, it has become possible to examine the small intestine endoscopically, and NSAID-induced damage in the small intestine has been clarified (Allison et al., 1992;Maiden et al., 2005). We recently proposed the possibilities of the therapeutic targets in NSAID-induced small intestinal damage (Higuchi et al., 2009). However, the mechanism of NSAID-induced small intestinal damage has been still unclear, and useful medications have not been identified.Matrix metalloproteinases (MMPs) play a crucial role in physiological turnover of extracellular matrix with degradation and remodeling during inflammation. MMPs are a family of zinc-and calcium-dependent endopeptidases, divided into different subgroups: collagenases, gelatinases, stromilysins, membrane-type MMPs, and other MMPs. Among the MMPs, MMP-9 is known as a gelatinase, and it was recently documented that MMP-9 plays an important role i...

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