Role of Cyclooxygenase (COX)-1 and COX-2 Inhibition in Nonsteroidal Anti-Inflammatory Drug-Induced Intestinal Damage in Rats: Relation to Various Pathogenic Events

Abstract

We recently reported that cyclooxygenase (COX)-2 expression was up-regulated in the rat small intestine after administration of indomethacin, and this may be a key to nonsteroidal antiinflammatory drug (NSAID)-induced intestinal damage. In the present study, we investigated the effect of inhibiting COX-1 or COX-2 on various intestinal events occurring in association with NSAID-induced intestinal damage. Rats without fasting were treated with indomethacin, SC-560 (a selective COX-1 inhibitor), rofecoxib (a selective COX-2 inhibitor), or SC-560 plus rofecoxib, and the following parameters were examined in the small intestine: the lesion score, the enterobacterial number, myeloperoxidase (MPO) and inducible nitric-oxide synthase (iNOS) activity, and intestinal motility. Indomethacin decreased mucosal prostaglandin (PG)E 2 content and caused damage in the intestine within 24 h, accompanied by an increase in intestinal contractility, bacterial numbers, 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 PGE 2 was restored 6 h later, in a rofecoxib-dependent manner. We conclude that inhibition of COX-1, despite causing intestinal hypermotility, bacterial invasion, and iNOS expression, up-regulates the expression of COX-2, and the PGE 2 produced by COX-2 counteracts deleterious events, and maintains the mucosal integrity. This sequence of events explains why intestinal damage occurs only when both COX-1 and COX-2 are inhibited.

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

“…It has been suggested that GI toxicity arises when both COX-1 and COX-2 enzymes are inhibited, and that inhibiting either one alone does not cause injury to the gastrointestinal mucosa (Takeuchi et al, 2003;Tanaka et al, 2002aTanaka et al, , 2002b. Our data presented herein may align with this hypothesis, as rofecoxib did not induce an APR at 250-fold its presumptive efficacious dose (Riendeau et al, 2001).…”

Autophagy Deficiency Diminishes Indomethacin-Induced Intestinal Epithelial Cell Damage through Activation of the ERK/Nrf2/HO-1 Pathway

“…Oral administration of IM was performed as described previously (Tanaka et al, 2002). Briefly, wild-type (WT) and Atg5-conditional knockout (CKO) mice (n 5 5 to 6 for each) were given IM p.o.…”

Differential Effects of Selective Cyclooxygenase (COX)-1 and COX-2 Inhibitors on Anorexic Response and Prostaglandin Generation in Various Tissues Induced by Zymosan

“…7), which may be due to reciprocal induction of COX-2 as reported in rat small intestine. 47) In contrast, meloxicam treatment slightly but significantly augmented PGE 2 content in colon but not in small intestine. The implication of such differential COX-2 and prostaglandin responses in these abdominal organs to the modulation of zymosan-induced anorexic responses by these COX inhibitors are largely unknown.…”