J L Wallace1, W McKnight, B K Reuter, N Vergnolle. 1. Mucosal Inflammation Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. wallacej@ucalgary.ca
Abstract
BACKGROUND & AIMS: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested this hypothesis in rats by using a selective COX-1 inhibitor (SC-560). METHODS: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combination of both inhibitors on gastric damage and prostaglandin synthesis were determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1-preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed. RESULTS: SC-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 activity, but spared COX-2 and did not cause gastric damage. Celecoxib did not affect gastric prostaglandin E(2) synthesis and did not cause gastric damage. However, the combination of SC-560 and celecoxib invariably caused hemorrhagic erosion formation, comparable to that seen with indomethacin. Ketorolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly increased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gastric blood flow. CONCLUSIONS: Inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.
BACKGROUND & AIMS: Selective cyclooxygenase (COX)-2 inhibitors produce less gastric damage than conventional nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that NSAIDs cause damage by inhibiting COX-1. We tested this hypothesis in rats by using a selective COX-1 inhibitor (SC-560). METHODS: The effects of SC-560, celecoxib (selective COX-2 inhibitor), or a combination of both inhibitors on gastric damage and prostaglandin synthesis were determined. Selectivity of the drugs for COX-1 vs. COX-2 was assessed in the carrageenan-airpouch model. A COX-1-preferential inhibitor, ketorolac, was also evaluated. The effects of these inhibitors on leukocyte adherence to vascular endothelium and on gastric blood flow were assessed. RESULTS:SC-560 markedly reduced gastric prostaglandin synthesis and platelet COX-1 activity, but spared COX-2 and did not cause gastric damage. Celecoxib did not affect gastric prostaglandin E(2) synthesis and did not cause gastric damage. However, the combination of SC-560 and celecoxib invariably caused hemorrhagic erosion formation, comparable to that seen with indomethacin. Ketorolac caused damage only at doses that inhibited both COX isoforms, or when given with a COX-2 inhibitor. Celecoxib, but not SC-560, significantly increased leukocyte adherence, whereas SC-560, but not celecoxib, reduced gastric blood flow. CONCLUSIONS: Inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury in the rat.
Authors: Laura E Fredenburgh; Margarita M Suárez Velandia; Jun Ma; Torsten Olszak; Manuela Cernadas; Joshua A Englert; Su Wol Chung; Xiaoli Liu; Cynthia Begay; Robert F Padera; Richard S Blumberg; Stephen R Walsh; Rebecca M Baron; Mark A Perrella Journal: J Immunol Date: 2011-10-03 Impact factor: 5.422
Authors: Sonia Gallego-Sandín; Jesús Novalbos; Aránzazu Rosado; Javier P Gisbert; María-Angeles Gálvez-Múgica; Antonio G García; José María Pajares; Francisco Abad-Santos Journal: Dig Dis Sci Date: 2004-09 Impact factor: 3.199