Mechanisms Of Ulcer Healing Research Articles

Su1750 Major Differences in the Mechanisms of Ulcer Healing in the Upper and Lower GI Tract, Despite Similar Morphologic Features: Novel Players are PLGF & Endoglin

Su1750 Major Differences in the Mechanisms of Ulcer Healing in the Upper and Lower GI Tract, Despite Similar Morphologic Features: Novel Players are PLGF & Endoglin

Effects of lansoprazole on the expression of VEGF and cellular proliferation in a rat model of acetic acid-induced gastric ulcer

A recent study reported that in addition to their inhibitory effect on gastric acid secretion, some proton pump inhibitors also exert a cytoprotective effect on the gastric mucosa. We investigated the effects of lansoprazole (LPZ) on the epithelial cell cycle, and on the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2). We examined the effects of 25 and 5 mg/kg LPZ on ulcer healing in an acetic acid-induced ulcer model in rats with and without indomethacin (IND) treatment. On days 14 and 28 after ulcer formation, we compared the ulcer diameter, bromodeoxyuridine (BrdU) uptake, apoptosis, vascular density, and the expressions of VEGF and MMP-2 in the different groups. LPZ administration increased the BrdU uptake that was reduced by IND administration. LPZ administration also increased VEGF expression at the ulcer margin in a dose-dependent manner. However, LPZ administration did not increase VEGF expression following IND pretreatment. Administration of IND alone significantly decreased MMP-2 expression at the ulcer margin; on the other hand, subsequent administration of LPZ increased the MMP-2 expression. One of the mechanisms of ulcer healing brought about by LPZ may be the involvement of endogenous prostaglandin (PG) secretion. The effect of endogenous PG secretion may be related to the induction of VEGF expression. On the other hand, LPZ administration increased MMP-2 expression, and this effect was not influenced by the inhibition of PG synthesis. The mechanisms of LPZ on ulcer healing may be involved by VEGF expression through endogenous PGs secretion. Additionally, the stimulated expression of MMP-2, which is not secreted by endogenous PGs, is another important factor for ulcer healing by LPZ.

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.

Current and Future Drugs for Acid-Peptic Disease: A Plethora of Opinions on Possible Mechanisms of Action

Sixty-seven invited participants involved in the development, evaluation, and use of therapies for acid-peptic disorders participated in a meeting to discuss the scientific basis for healing actions of ulcer drugs and the prospects for future developments ("Realities of Mucosal Protection in the Upper Gastrointestinal Tract," Lausanne, Switzerland, November 8-10, 1987). Eighty-one key statements were prepared and subsequently analyzed on the basis of a voting system. Of the 45 statements that dealt with existing therapies, only 3 statements showed positive consensus (agreement of two-thirds or more of voters) about mechanisms of ulcer healing. Participants agreed that both (1) hydrogen/potassium adenosine triphosphatase inhibitors and (2) histamine H2 antagonists healed ulcers solely by acid inhibition, and (3) that sucralfate works by topical action. Substantial uncertainty about the mechanisms by which bismuth compounds and antacids heal ulcers was noted as well as their wide range of effects. The mechanism of ulcer healing by prostaglandins and the clinical relevance of antiulcer effects of drugs demonstrated in acute studies with animals were also controversial. There was greater agreement among participants about unexplored drug effects that might produce ulcer healing. Of the 36 such mechanisms surveyed, the most support went to therapies aimed at enhancement of mucosal blood flow, epithelial restitution, and mucosal alkaline secretion or inhibition of luminal pepsin activity. The diversity of opinions among participants suggests a high level of empiricism in the development of ulcer healing drugs apart from those that inhibit acid secretion. This empiricism probably arises from inadequate understanding of processes of mucosal injury and repair.

Is reduced release of gastrin the mechanism of ulcer healing after gastroenterostomy?

Until recently in this unit gastroenterostomy was the operation of choice for patients with duodenal ulcer whose maximal acid output (MAO) is less than 30 mmol/hr. Ulceration (jejunal) has recurred in only 2.1%. Unlike partial gastrectomy, which has a peak incidence of ulcer recurrence in the first two years, the incidence of ulcer recurrence remains constant throughout the years after gastroenterostomy. In looking for the explanation of this low recurrence rate we have studied the effect of the operation upon serum gastrin responses to standardized test meals 3 weeks and 26 weeks after operation in 9 patients. Nine normal subjects acted as controls. Six months after operation the responses were significantly lowered, a fall in the serum levels of gastrin at 30, 45, 60 and 90 min after means suggesting that gastroenterostomy reduces both the gastric and intestinal phases of acid secretion. The mean integrated gastrin response (IGR) throughout the postprandial 90 min is also significantly lower 6 months after surgery. The overall mean reduction was 31.1%.