Objective: Tumor necrosis factor (TNF)-alpha-converting enzyme (TACE), which has been purified, regulates maturity of TNF-alpha. Matrix metalloproteinases (MMPs) play a key role in various inflammatory conditions. The incidence of intestinal damage has increased, but the mechanism and treatment have not been well understood. The purpose of this study was to investigate the roles of TACE and MMP in indomethacin (Indo)-induced intestinal damage as well as the therapeutic effects of TACE inhibitor and selective MMP inhibitor (sMMPi) on this intestinal damage in rats.
Material and methods: In the first experiment, serial changes in intestinal ulcers and the production of MMP were investigated. In the second experiment, we assessed the effect of three TACE and/or MMP inhibitors and the production of TNF-alpha, TACE, MMP-3, -9 and tissue inhibitor of MMP (TIMP)-1. The rats were divided into five groups: a control group, and four groups that received Indo alone, Indo plus TACE inhibitor (GM6001), Indo plus a selective MMP-3 inhibitor and Indo plus an MMP-9/13 inhibitor, respectively.
Results: MMP-3 was overexpressed at 24 h after Indo administration, when intestinal injury was most prominent macroscopically and microscopically. GM6001 significantly decreased ulcer severity and suppressed MMP-3 in a dose-dependent fashion. The selective MMP-3 inhibitor dose-dependently ameliorated intestinal damage to the same degree as GM6001, but the MMP-9 inhibitor had no effect on the injury.
Conclusions: MMP-3 inhibition ameliorates intestinal damage without apparently affecting either TNF-alpha or TACE production and the dose-response curve suggests that the beneficial effect of the so-called TACE inhibitor is actually mainly mediated via MMP-3 inhibition rather than TNF-alpha inhibition.