To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or COX-2 isoform. We treated wild-type, COX-1–/–, COX-2–/–, and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E2, and interleukin-1β. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE2 production in COX-1–/– mice. Both COX-1–/– and COX-2–/– mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2–/– mice were more susceptible than COX-1–/– mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1–/– mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE2 intestinal secretion in all groups except COX-2–/– mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli.
Olivier Morteau, Scott G. Morham, Rance Sellon, Levinus A. Dieleman, Robert Langenbach, Oliver Smithies, R. Balfour Sartor
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