Cyclooxygenase 2-implications on maintenance of gastric mucosal integrity and ulcer healing: controversial issues and perspectives

Abstract

Cyclooxygenase (COX), the key enzyme for synthesis of prostaglandins, exists in two isoforms (COX-1 and COX-2). COX-1 is constitutively expressed in the gastrointestinal tract in large quantities and has been suggested to maintain mucosal integrity through continuous generation of prostaglandins. COX-2 is induced predominantly during inflammation. On this premise selective COX-2 inhibitors not affecting COX-1 in the gastrointestinal tract mucosa have been developed as gastrointestinal sparing anti-inflammatory drugs. They appear to be well tolerated by experimental animals and humans following acute and chronic (three or more months) administration. However, there is increasing evidence that COX-2 has a greater physiological role than merely mediating pain and inflammation. Thus gastric and intestinal lesions do not develop when COX-1 is inhibited but only when the activity of both COX-1 and COX-2 is suppressed. Selective COX-2 inhibitors delay the healing of experimental gastric ulcers to the same extent as non-COX-2 specific non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, when given chronically to experimental animals, they can activate experimental colitis and cause intestinal perforation. The direct involvement of COX-2 in ulcer healing has been supported by observations that expression of COX-2 mRNA and protein is upregulated at the ulcer margin in a temporal and spatial relation to enhanced epithelial cell proliferation and increased expression of growth factors. Moreover, there is increasing evidence that upregulation of COX-2 mRNA and protein occurs during exposure of the gastric mucosa to noxious agents or to ischaemia-reperfusion. These observations support the concept that COX-2 represents (in addition to COX-1) a further line of defence for the gastrointestinal mucosa necessary for maintenance of mucosal integrity and ulcer healing.

Figure 1

Diagrammatic presentation of the mechanisms of non-steroidal anti-inflammatory drug (NSAID) injury to the gastrointestinal tract.

Figure 2

(A) Ulcer healing curve assessed by video endoscopy. The data indicate mean (SEM) percentage residual ulcer size over the observation time points. Compared with placebo, omeprazole (omepr) and basic fibroblast growth factor (bFGF) treated rats showed significant reductions in ulcer diameter over days 6-15. Indomethacin (Indom) treated rats showed significantly increased ulcer diameters over days 8-22. Co-treatment with bFGF had no effect on the indomethacin induced increase in ulcer diameter. In contrast, omeprazole co-treatment reversed the deleterious effects of indomethacin. (B) Data from the same study, expressed as residual ulcer size on day 15 as a percentage of the initial ulcer size on day 1. Indomethacin plus omeprazole treated rats showed comparable ulcer diameters to placebo treated rats. *p<0.02,**p<0.005 versus placebo (from Schmassmann and colleagues⁴⁵ with permission).

Figure 3

Diagrammatic presentation of ulcer healing and factors affecting ulcer healing. Healing of the ulcer is accomplished by filling the mucosal defect with cells migrating from the ulcer margin and by connective tissue, including microvessels originating from granulation tissue. Speed and quality of ulcer healing depend, among other factors, on (1) epithelial cell migration and proliferation in the mucosal ulcer margin, (2) angiogenesis in the ulcer bed, (3) maturation and contraction of the granulation tissue in the ulcer bed, and (4) quality of remodelling of epithelial and mesenchymal structures in the late healing phase. In the intact mucosa, cyclooxygenase 1 (COX-1) is the predominant COX isoform in the gastrointestinal tract. In contrast, during wound healing, expression of cyclooxygenase 2 (COX-2), but not COX-1, is strongly increased in the repair zone of ulcer healing (from Schmassmann and colleagues^46 76 with permission).

Figure 4

(A) Time sequence of immunoreactivity of cyclooxygenase (COX)-1, COX-2, and cell proliferation (as measured by bromodeoxyuridine (BrdU) incorporation) at the ulcer margin over 21 days. (B) Ulcer healing curve assessed by video endoscopy. The data indicate mean (SEM) percentage residual ulcer size over the observation period. The specific COX-2 inhibitor L-744,337 delayed ulcer healing to the same extent as diclofenac or indomethacin when administered at doses of similar anti-inflammatory potency (as tested in the carrageenan paw model) (from Schmassmann and colleagues⁷⁶ with permission).