A Uribe1, M Alam, C Soderman. 1. Department of Internal Medicine, Karolinska Institute, Danderyd Hospital, Stockholm, Sweden.
Abstract
OBJECTIVE: To follow the sequence of cell kinetic events leading to the development of ulcerations in the gastrointestinal mucosa to better define primary actions of the drug and secondary phenomena mediated by the mucosal regulatory mechanisms. DESIGN: Sprague-Dawley rats were given 4 mg/kg indomethacin subcutaneously as a single dose and killed 4h later. Additional rats were given three and five doses, twice daily, and were killed at 24h and 48h, respectively. Other groups were treated with indomethacin and oral prostaglandin E2 or placebo. All rats were killed 3h after mitotic arrest with vincristine. METHODS: Histological sections from the oxyntic mucosa and proximal and distal jejunum were evaluated using a light microscope. The total number of arrested mitoses were counted in 250 microm width area of 30 consequent fields. In addition, the thickness and proliferative zone of the mucosa were determined. The cumulative mitotic index (MI%) and the number of cells in the left column of 30 well oriented crypts and villi were estimated in the proximal and distal small intestine. RESULTS: The vast majority of rats given five doses of indomethacin developed small intestinal ulcerations and peritonitis and most of them showed haemorrhagic lesions in the oxyntic mucosa. Indomethacin reduced the number of mitotic cells in the oxyntic mucosa after three and five doses compared to controls (P<0.05). In addition, the thickness was significantly reduced in rats given five doses of indomethacin (P<0.05). These changes were prevented by the concomitant administration of prostaglandin E2. The MI% of the jejunal crypts was not affected by indomethacin but the number of villous cells was significantly lower in rats given five doses of indomethacin than in controls (P<0.05). A slight villous hyperplasia was observed in animals given three doses of indomethacin with prostaglandin E2 (P<0.05). The number of crypt cells was unaffected by treatments. CONCLUSION: Indomethacin reduced cell proliferation in the oxyntic and jejunal epithelium, and increased epithelial cell losses, which are cell kinetic mechanisms leading to development of ulcerations. The regulatory mechanisms that increase DNA synthesis need longer periods of time to be triggered and they were not apparent in this model, in which the marked cell kinetic changes induced by indomethacin produced ulcerations within 48 h.
OBJECTIVE: To follow the sequence of cell kinetic events leading to the development of ulcerations in the gastrointestinal mucosa to better define primary actions of the drug and secondary phenomena mediated by the mucosal regulatory mechanisms. DESIGN:Sprague-Dawley rats were given 4 mg/kg indomethacin subcutaneously as a single dose and killed 4h later. Additional rats were given three and five doses, twice daily, and were killed at 24h and 48h, respectively. Other groups were treated with indomethacin and oral prostaglandin E2 or placebo. All rats were killed 3h after mitotic arrest with vincristine. METHODS: Histological sections from the oxyntic mucosa and proximal and distal jejunum were evaluated using a light microscope. The total number of arrested mitoses were counted in 250 microm width area of 30 consequent fields. In addition, the thickness and proliferative zone of the mucosa were determined. The cumulative mitotic index (MI%) and the number of cells in the left column of 30 well oriented crypts and villi were estimated in the proximal and distal small intestine. RESULTS: The vast majority of rats given five doses of indomethacin developed small intestinal ulcerations and peritonitis and most of them showed haemorrhagic lesions in the oxyntic mucosa. Indomethacin reduced the number of mitotic cells in the oxyntic mucosa after three and five doses compared to controls (P<0.05). In addition, the thickness was significantly reduced in rats given five doses of indomethacin (P<0.05). These changes were prevented by the concomitant administration of prostaglandin E2. The MI% of the jejunal crypts was not affected by indomethacin but the number of villous cells was significantly lower in rats given five doses of indomethacin than in controls (P<0.05). A slight villous hyperplasia was observed in animals given three doses of indomethacin with prostaglandin E2 (P<0.05). The number of crypt cells was unaffected by treatments. CONCLUSION:Indomethacin reduced cell proliferation in the oxyntic and jejunal epithelium, and increased epithelial cell losses, which are cell kinetic mechanisms leading to development of ulcerations. The regulatory mechanisms that increase DNA synthesis need longer periods of time to be triggered and they were not apparent in this model, in which the marked cell kinetic changes induced by indomethacin produced ulcerations within 48 h.