15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Body-Weight

Human esophageal adenocarcinoma (EAC) develops in a sequence from gastroesophageal reflux disease (GERD), columnar-lined esophagus (CLE), dysplasia, and eventually to EAC. We established a rat surgical EAC model with esophagogastroduodenal anastomosis (EGDA) to mimic the staged process of esophageal adenocarcinogenesis. Profiling of the AA metabolites with mass spectrometry showed that prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 15-hydroeicosatetraenoic acid (HETE), 12-HETE, 8-HETE and 5-HETE all increased at the esophagoduodenal junction after EGDA as compared with the proximal esophagus, with PGE2 as the major metabolite. Consistent with this profile, cyclooxygenase 2 (Cox2) was overexpressed in the basal cell layer of esophageal squamous epithelium, CLE cells and EAC tumor cells of the EGDA rats, as compared with the normal esophageal epithelium. Sulindac (a Cox inhibitor), nordihydroguaiaretic acid (NDGA, a lipoxygenase inhibitor) and alpha-difluoromethylornithine (DFMO, an ornithine decarboxylase inhibitor) were tested for their possible inhibitory actions against the formation of EAC in the rat EGDA model. In a short-term study (for 4 weeks after surgery), dietary administration of both sulindac (300 and 600 p.p.m.) and NDGA (100 p.p.m.) effectively reduced the EGDA-induced inflammation. In a long-term chemoprevention study (for 40 weeks after surgery), 300 p.p.m. sulindac, alone or in combination with 100 p.p.m. NDGA or 0.5% DFMO, decreased the tumor incidence from 57.7 to 26.9%, or 16.7 or 20%, respectively (P < 0.05). NDGA alone (100 and 200 p.p.m.) slightly decreased the tumor incidence to 52.4 and 37%, respectively, although the difference was not statistically significant. DFMO alone did not show significant effects on tumor incidence. Inhibition of tumor formation by sulindac was correlated with lowered levels of PGE2. In conclusion, sulindac exerted its chemopreventive effect against the formation of EAC in the rat EGDA model possibly through its inhibition of Cox.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Animals; Arachidonic Acid; Body Weight; Cyclooxygenase 2; Dinoprostone; Eflornithine; Esophageal Neoplasms; Esophagus; Gas Chromatography-Mass Spectrometry; Hydroxyeicosatetraenoic Acids; Immunoenzyme Techniques; In Situ Hybridization; Inflammation; Isoenzymes; Leukotriene B4; Male; Masoprocol; Mass Spectrometry; Neoplasms; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Sulindac; Time Factors

In isolated canine saphenous veins, the contractions elicited by the 15-lipoxygenase metabolites 15-HETE and 15-HPETE were augmented by 5-hydroxytryptamine (5-HT) in a concentration-dependent way. This potentiation was not mediated by the endothelium nor was it influenced by the 5-HT2-antagonist ketanserin. Phentolamine, however, reduced both the contractions and the potentiation by 5-HT. These data provide evidence for a receptor-mediated potentiation by 5-HT which occurs independently of 5-HT2-receptors. The interaction between 5-HT or aggregating platelets and 15-HPETE was studied in isolated rabbit brachiocephalic arteries. Threshold concentrations of 5-HT and platelets markedly potentiated the contractions elicited by 15-HPETE. In brachiocephalic arteries obtained from cholesterol-fed rabbits, 15-HPETE, 5-HT and platelets caused contractions similar to those obtained in control rabbits. The potentiating effect of 5-HT and platelets on the 15-HPETE-induced contractions was also comparable to that observed in control rabbits. Moreover, no difference was found between control platelets and platelets obtained from hypercholesterolemic rabbits. Our findings demonstrate a positive interaction between 5-HT and 15-lipoxygenase metabolites of arachidonic acid in arteries and veins. This interaction persists in atherosclerotic arteries and could indicate that this mechanism is involved in the genesis of vasospasm.

Topics: Animals; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Body Weight; Dogs; Female; Hydroxyeicosatetraenoic Acids; Hypercholesterolemia; In Vitro Techniques; Ketanserin; Leukotrienes; Lipid Peroxides; Male; Muscle Contraction; Muscle, Smooth, Vascular; Phentolamine; Rabbits; Saphenous Vein; Serotonin; Vasoconstrictor Agents