Factors that modulate gastric ulcer healing.

摘要

Numerous factors influence gastric ulcer healing. The broad objective of the research described in this dissertation was to gain insight into the effects of new nonsteroidal anti-inflammatory drugs (NSAIDs), bacterial colonization and epidermal growth factor (EGF) on gastric ulcer healing.;Studies were performed to determine the effects of chronic administration of a nitric oxide (NO)-releasing NSAID (NO-NSAID) to rats with pre-existing gastric ulcers. Accelerated gastric ulcer healing was observed following treatment with nitrofenac, an NO-releasing derivative of diclofenac, despite the fact that it suppressed cyclooxygenase activity. Further, the accelerated ulcer healing appeared to be due to NO release, since administration of a nitric oxide donor also markedly accelerated ulcer healing.;Experiments were undertaken to examine the effect of treatment with the selective COX-2 inhibitor, celecoxib, on ulcer healing. Celecoxib exhibited anti-inflammatory activity in the carrageenan-airpouch model in the rat, reducing both leukocyte infiltration and prostaglandin E2 production. However, chronic administration of celecoxib to rats with gastric ulcers markedly impaired ulcer healing.;In the presence of a gastric ulcer in the rat, several different species of bacteria were found to colonize the ulcer site, resulting in delayed ulcer healing. Studies were conducted to characterize the time-course of colonization. Further, specific manipulation of the bacterial species colonizing the ulcers, through the administration of antibiotics or probiotics, influenced healing rates. Previous work had demonstrated that epidermal growth factor (EGF) could prevent bacterial colonization in the rabbit intestine. Taking into consideration the significant levels of bacteria colonizing a gastric ulcer site, EGF was administered to rats with ulcers to determine its ability to influence bacterial levels in the setting of pre-existing colonization. Chronic treatment with EGF markedly accelerated gastric ulcer healing. In association with this accelerated healing, a marked decrease in bacterial colonization of the ulcer site was observed.;Overall, these studies highlight the influence of NO, COX-2 inhibition and bacterial colonization on experimental gastric ulcer healing and provide clues to future development of agents that might be used clinically to treat ulcer disease.