Chronic cyclooxygenase-2 inhibition does not cause gastrointestinal damage in the rat

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Background: It is known that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause gastric and duodenal ulceration, but over the past decades it has become increasingly recognized that the distal parts of the small intestine are also harmed. The pathomechanism of this enteropathy is still poorly understood. Previous studies demonstrated that the inhibition of cyclooxygenase (COX) -1 enzyme and the "topical effect" of the compounds both play a role in the damage of intestinal mucosa. However, it still remains controversial whether long-term and selective inhibition of the COX-2 enzyme causes enteropathy. Thus, in the present study, we aimed to analyze the gastrointestinal effects of chronic, selective COX-2 inhibition in the rat. Methods: Male Wistar rats were treated with either rofecoxib, which is a non-acidic, selective COX-2 inhibitor (5.12 mg/kg once daily) or with its vehicle (1% methylcellulose) for 4 weeks. The non-selective COX inhibitor indomethacin (5 mg/kg once daily) was used as a positive control. The examination of small intestinal mucosal injury was performed by macroscopic and histological methods. In order to determine the protein concentrations of four pro- or anti-inflammatory cytokines in the small intestine (interleukin (IL)-1 beta, IL-6, IL-10 and tumor necrosis factor-alpha (TNF-alpha)), ELISA and Luminex xMAP technology were used. Results: Indomethacin-induced severe enteropathy with marked weight loss, high mortality rate and pronounced shortening of the small intestine length. In contrast, long-term treatment with rofecoxib did not cause any of the above-described inflammatory changes. It did not induce any tissue damage, neither macroscopically, nor histologically. Furthermore, it failed to significantly alter the protein levels of the tested inflammatory cytokines. Conclusions: This study demonstrates that chronic and selective cyclooxygenase-2 inhibition by rofecoxib does not cause mucosal damage in the distal segments of the small intestine. These findings suggest that pure COX-2 inhibition is safe for the lower gastrointestinal tract, even long-term, and mucosal injury develops only if additional effects (e.g. topical effect or COX-1 inhibition) coexist. The research was supported by the European Foundation for Disease Research (EFSD) New Horizons Collaborative Research Initiative and National Research, Development and Innovation Office of Hungary (NKFI FK 124878; NVKP-16-1-2016-0017 National Heart Program).

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