leukotriene-b4 and Peptic-Ulcer

Chronic non-specific pulmonary diseases are frequently followed by the development of inflammatory-degenerative and erosive-ulcerative processes in the mucous membrane of the stomach and duodenum. The literature date are presented on the frequency of combination of these conditions, the attempt is made to assess their link from the viewpoint of pathogenesis. Disturbances of respiratory lung function and hypoxia as well as non-respiratory metabolic functions of the pulmonary tissue are regarded as etiological factors of pathological processes in the gastro-duodenal area.

Topics: Adult; Angiotensins; Arachidonic Acid; Arachidonic Acids; Chronic Disease; Duodenal Diseases; Duodenitis; Female; Gastritis; Histamine; Humans; Hypoxia; Leukotriene B4; Lung; Lung Diseases; Male; Middle Aged; Peptic Ulcer; Prostaglandins; SRS-A; Stomach Diseases; Thromboxane A2

The leukotrienes, platelet activating factor and intracellular calcium have been implicated in the development of gastro-intestinal lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) but the relative significance of these inflammatory mediators in lesion formation has not been established in sensitive and specific models of gastro-intestinal ulceration. In the present study the effects of drugs affecting 5-lipoxygenase activity, the actions of platelet activating factor and intracellular calcium on the development of gastric and intestinal ulceration induced by NSAIDs were investigated in highly sensitive models of ulcerogenicity induced by treatment with either the cholinomimetic, acetyl-beta-methyl choline chloride, in mice (gastric mucosal lesions) or adjuvant-induced polyarthritis in rats (gastric and intestinal mucosal lesions) as well as in normal mice (intestinal mucosal lesions). The 5-lipoxygenase inhibitors, such as MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-+ ++dimethylpropanoic acid), given at doses shown to reduce the indomethacin-induced increase in mucosal leukotriene B4 concentrations were found to partially prevent the development of gastric and intestinal lesion induced by indomethacin and gastric lesions from aspirin, but the same doses of MK-886 did not affect gastric lesions from diclofenac. Pretreatment with these inhibitors at both 3-5 h and 0-0.25 h was required to achieve protection against gastric mucosal damage from indomethacin. Immediate prior administration of platelet activating factor antagonists (e.g. WEB-2086) with the 5-lipoxygenase inhibitors did not affect gastric or intestinal lesions induced by indomethacin. The calcium antagonist, verapamil, was slightly protective against gastric and intestinal lesions induced by indomethacin. Gastric lesions were further prevented by combinations of a single dose of verapamil with a platelet activating factor antagonist but not combined with a 5-lipoxygenase inhibitor; other combinations of verapamil with lipoxygenase inhibitors or platelet-activating factor antagonists being without inhibitory effects on gastric or intestinal lesions compared with the drugs alone. These results show that 5-lipoxygenase products and intracellular calcium play a major role in acute gastric and intestinal damage by the NSAIDs, but platelet-activating factor has little or no appreciable involvement.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Arthritis; Arthritis, Experimental; Calcium; Cholinergic Agents; Female; Leukotriene Antagonists; Leukotriene B4; Male; Mice; Peptic Ulcer; Platelet Activating Factor; Rats; Thiocholine

The cyclo-oxygenase inhibitor indomethacin induces a pattern of gastrointestinal injury in the rat that is site-dependent. This study compared the extent of injury to different regions of the rat intestine (small intestine, caecum and colon) with the corresponding changes in arachidonic acid metabolism in these areas, following long-term, low-dose indomethachin.. Rats (eight per group) received either indomethacin (3 mg.kg/day) or control diet for either 6 or 12 weeks. At termination animals were bled, examined both macroscopically and microscopically for ulcers, and assayed for blood thromboxane B2, intestinal tissue prostaglandin E2 content and production of leukotriene B4. In a further eight animals luminal indomethacin concentrations from the small intestine, caecum and colon were measured following 6 weeks of chronic drug ingestion.. At 6 weeks, macroscopic ulcers were observed in 2/8 (small intestine), 3/8 (caecum) and 1/8 (colon) animals. The corresponding ratios at 12 weeks were 5/8, 8/8 and 0/8. In control animals, a site-dependent gradient of the prostaglandin E2 concentration was found. In indomethacin-dosed animals the intestinal prostaglandin E2 content was reduced significantly in the caecum at 6 weeks, and in all tissues at 12 weeks. An increased leukotriene B4 production was observed in the caecum only, at 12 weeks (P < 0.01), and the blood thromboxane B2 was reduced at both time points (P < 0.05).. There is a site-dependent gradient of the prostaglandin E2 concentration in the rat intestine. The rat caecum is particularly sensitive to long-term low-dose indomethacin, both in terms of chronic intestinal inflammation and changes in prostanoid metabolism. This site-dependent degree of injury may be associated with a local cyclo-oxygenase inhibition.

Topics: Animals; Colon; Digestive System; Dinoprostone; Gastric Mucosa; Indomethacin; Leukotriene B4; Male; Peptic Ulcer; Rats; Rats, Sprague-Dawley; Time Factors

Forty patients suffering from peptic ulcer were examined for concentrations of leukotrienes B4 and C4 as compared to the activity of myeloperoxidase in the periulcerous zone of the gastric mucosa. 20 healthy persons made up the control. It is assumed that the rise of leukotrienes B4 and C4 concentrations as well as myeloperoxidase activation contribute to chronic inflammation in the periulcerous zone. Chronic inflammation of the gastric mucosa is regarded as an important pathogenetic factor of ulcerogenesis.

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Female; Gastric Mucosa; Gastritis; Histamine H2 Antagonists; Humans; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Peptic Ulcer; Peroxidase; SRS-A

Topics: Diarrhea; Gastric Mucosa; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Intestinal Mucosa; Leukotriene B4; Lipoxygenase; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins E, Synthetic; SRS-A; Thromboxane A2