COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice

Background & Aims: The pathogenesis of nonsteroidal anti-inflammatory drug-induced enteropathy is controversial, but it is thought that cyclooxygenase-1 (COX-1) inhibition is of pivotal importance. We compared small intestinal function and morphology in untreated wildtype, COX-1- and COX-2- deficient mice and the effect of indomethacin, selective COX-1 (SC-560), and COX-2 (celecoxib) inhibition. Methods: Intestinal permeability ((51)CrEDTA), inflammation (fecal granulocyte marker protein), prostaglandin E-2 (PGE(2)) levels, and macroscopic and microscopic appearances were assessed at baseline and after the drugs. Results: COX-1(-/-) animals were normal except for a 97% decrease in intestinal PGE2 levels. COX-1(+/+) and COX-1(-/-) animals reacted in a similar way to indomethacin. However, celecoxib, having caused no damage in COX-1(+/+) animals, caused small bowel ulcers in COX-1(-/-) animals. Selective inhibition of COX-I decreased intestinal PGE2 levels in COX-2(+/+) and COX-2(-/-) animals by 95%-97%, but caused only small bowel ulcers in the latter group. Dual inhibition of COX-1 and COX-2 in wild-type animals resulted in similar small bowel damage. Between 40% and 50% of untreated COX-2(-/-) animals had increased intestinal permeability and inflammation. Some had ileal ulcers that were distinctively different from indomethacin-induced ulcers. Furthermore, long-term celecoxib administration in wildtype animals was associated with similar damage as in the COX-2(-/-) mice. Conclusions: COX-1 deficiency or inhibition and short-term COX-2 inhibition are compatible with normal small intestinal integrity. Dual inhibition of the COX enzymes leads to damage similar to that seen with indomethacin. Long-term COX-2 deficiency or inhibition is associated with significant intestinal pathology despite normal intestinal PGE2 levels, suggesting a role for COX-2 in the maintenance of small intestinal integrity in the mouse.