The Role of Arachidonic Acid Metabolites in Gastrointestinal Homeostasis

Abstract

Metabolites of arachidonic acid have a broad range of physiological functions in the gastrointestinal tract, and seem to be involved in certain disturbances of gastrointestinal integrity and function. Prostaglandins inhibit gastric acid secretion, apparently via an adenylate cyclaselinked receptor, and also stimulate bicarbonate and mucus production by alternative mechanisms. These are all beneficial in treating gastroduodenal ulceration. Moreover, clinical studies have revealed deficient prostaglandin synthesis in the gastric and duodenal mucosa of patients with gastrointestinal ulcers, which suggests that endogenous prostaglandins have a protective role in the gastrointestinal tract. In animal studies, prostaglandin analogues have been shown to protect the gastric mucosa from damage induced by various potent irritants, and this protection seems to involve the deeper layers of the mucosa as well as the epithelium. Indeed, misoprostol and other prostaglandin analogues have proved therapeutically effective in treating gastroduodenal ulceration. Prostaglandins also influence intestinal motility and fluid movement. Prostaglandin E derivatives generally relax circular smooth muscle, contract longitudinal smooth muscle and increase fluid secretion into the intestinal lumen. As a result of these effects, prostaglandins may cause diarrhoea. There is also evidence that prostaglandin synthesis is increased in patients with diarrhoea. Finally, it has been reported that tissue concentrations of prostaglandins are increased in patients with ulcerative colitis, but it is unclear if this is a primary cause, or secondary event. Significantly greater conversion of arachidonic acid to its metabolites was recorded in the mucosa of patients with inflammatory bowel disease compared with the mucosa of healthy subjects. This included a substantial increase in the concentration of leukotriene B₄. Moreover, the drugs sulphasalazine and 5-amino-salicylic acid, which are used for the treatment of ulcerative colitis, markedly decreased the synthesis of leukotriene B₄ and other products of arachidonic acid metabolism. Thus, prostaglandins, in particular, have important effects on gastrointestinal function. They may have a beneficial effect in the treatment of gastric or duodenal ulcers. However, they can cause intestinal secretion and diarrhoea, and may play a pathogenetic role in ulcerative colitis.