NSAID-induced small intestinal damage: Role of COX inhibition

Indomethacin, the nonselective COX inhibitor, decreased mucosal PGE2 content and caused damage in the intestine within 24 h, accompanied by increase in intestinal motility, bacterial number and MPO, as well as iNOS activity, together with the up-regulation of COX-2 and iNOS mRNA expression. Neither SC-560 nor rofecoxib alone caused intestinal damage, but their combined administration produced lesions. SC-560, but not rofecoxib, caused intestinal hypermotility, bacterial invasion and COX-2 as well as iNOS mRNA expression, yet the iNOS and MPO activity was increased only when rofecoxib was also administered. Although SC-560 inhibited the PG production, the level of PGE2 was recovered, in a rofecoxib-dependent manner. Thus, inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion and iNOS expression, up-regulates the expression of COX-2, and the the COX-2/PGE2 counteracts deleterious events and maintains the mucosal integrity. This sequence of events explains why intestinal damage occurs when both COX-1 and COX-2 are inhibited.