Mechanisms of ulcer healing and effects of nonsteroidal anti-inflammatory drugs.

Ulceration of the gastroduodenal mucosa occurs frequently in humans, particularly in patients with a history of peptic ulcer disease. In order for healing to occur, mucosal damage stimulates secretion of growth factors in the adjacent mucosa and ulcer bed. Peptic ulcer healing is accomplished by the filling of the mucosal defect with cells that migrate from the ulcer margin and by connective tissue, including microvessels originating from granulation tissue. Peptic ulcer healing is accelerated both in humans and experimental models by gastric acid inhibition, which enhances cell migration and maturation of the granulation tissue. In experimental models, peptic ulcer healing can also be accelerated by oral administration of basic fibroblast growth factor, which increases angiogenesis in the ulcer bed, or by nitric oxide-releasing compounds, which improve gastric blood flow. Clinical and experimental data indicate that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) delay the healing of peptic ulcers by interfering with the action of growth factors, decreasing epithelial cell proliferation in the ulcer margin, decreasing angiogenesis in the ulcer bed, and slowing maturation of the granulation tissue. In order to reduce the gastroduodenal side-effects of NSAIDs, selective cyclo-oxygenase (COX)-2 inhibitors have been developed, which inhibit the inducible COX-2 isoform in inflammatory tissue but have only limited effect on the constitutive COX-1 isoform in the stomach. It has been reported that the selective COX-2 inhibitor L-745,337 has a reduced liability for gastrointestinal ulceration. In our chronic experimental gastric ulcer model in rats, however, delay of gastric ulcer healing with L-745,337 was comparable to that with ordinary NSAIDs. It has also been reported that nitric oxide-releasing NSAIDs have a low relative risk of gastrointestinal ulceration but, again, in our chronic gastric ulcer model, nitric oxide did not reverse NSAID-induced deleterious effects on ulcer healing. In contrast, the proton pump inhibitor omeprazole has been shown to reverse NSAID-induced deleterious effects on gastric ulcer healing in our model. Comparable results have also been reported in humans. Histologic analysis has shown that omeprazole reverses the effects of NSAIDs on cell proliferation, angiogenesis, and maturation of the granulation tissue. In conclusion, only highly effective gastric acid inhibition reliably reverses NSAID-induced delay of gastric ulcer healing.