The role of the enzyme cyclooxygenase and bile in the damage and repair of intestinal epithelium

Colic describes poorly localized abdominal pain and is treated with nonsteroidal anti-inflammatory drugs (NSAIDs). They inhibit the enzyme cyclooxygenase (COX), which has two isoforms: COX-1, which constitutively produces prostaglandins and COX-2, which is induced by inflammation. Study 1. Hypothesis: A non-specific cyclooxygenase inhibitor, flunixin would retard repair of ischemic intestinal injury, whereas a selective COX-2 inhibitor, etodolac would permit repair. Equine jejunum was subjected to ischemia for 60-minutes, and recovered in Ussing chambers. In ischemic tissue treated with flunixin, production of prostaglandins was inhibited, with evidence of recovery. Untreated ischemic tissues or tissues treated with etodolac had significant elevations in prostaglandins, and significant recovery. Study 2. Hypothesis: A non-selective COX inhibitor, flunixin would retard repair of bile-injured colon, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair. Equine colon was exposed to 1.5mM deoxycholate for 30-minutes, and recovered in Ussing chambers. Recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostaglandin production. Control tissue treated with flunixin had increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Study 3. Hypothesis: Physiologic concentrations of deoxycholic acid (a bile acid) would retard repair of ischemic intestinal injury. Porcine ileum was subjected to 45-minutes of ischemia, mounted in Ussing chambers, and exposed to varying concentrations of deoxycholic acid. The ischemic episode resulted in significant damage which recovered, associated with significant reductions in mucosal permeability. Treatment of ischemic-injured tissues with 10−5 M deoxycholic acid fully inhibited recovery with significant increases in mucosal permeability, whereas 10−6M deoxycholic acid had no effect. Histology revealed complete restitution regardless of treatment, indicating the breakdown in barrier function was due to changes in paracellular permeability. Application of 10−5M taurodeoxycholic acid had similar effects. The effects of deoxycholic acid were reversed with application of the Ca2+ mobilizing agent thapsigargin. These studies show that selective COX-2 inhibitors may be advantageous in the treatment of colic and that bile may retard the repair of ischemic-injured intestine.