misoprostol and Esophageal-Diseases

Clinical studies indicate that prostaglandins of E class (PGEs) may promote healing of tissue injury e.g., gastroduodenal and dermal ulcers. However, the precise roles of PGEs, their E-prostanoid (EP) receptors, signaling pathways including cAMP and cAMP response element-binding protein (CREB), and their relation to VEGF and angiogenesis in the tissue injury healing process remain unknown, forming the rationale for this study. Using an esophageal ulcer model in rats, we demonstrated that esophageal mucosa expresses predominantly EP2 receptors and that esophageal ulceration triggers an increase in expression of the EP2 receptor, activation of CREB (the downstream target of the cAMP signaling), and enhanced VEGF gene expression. Treatment of rats with misoprostol, a PGE1 analog capable of activating EP receptors, enhanced phosphorylation of CREB, stimulated VEGF expression and angiogenesis, and accelerated esophageal ulcer healing. In cultured human esophageal epithelial (HET-1A) cells, misoprostol increased intracellular cAMP levels (by 163-fold), induced phosphorylation of CREB, and stimulated VEGF expression. A cAMP analog (Sp-cAMP) mimicked, whereas an inhibitor of cAMP-dependent protein kinase A (Rp-cAMP) blocked, these effects of misoprostol. These results indicate that the EP2/cAMP/protein kinase A pathway mediates the stimulatory effect of PGEs on angiogenesis essential for tissue injury healing via the induction of CREB activity and VEGF expression.

Topics: Animals; Cell Line; CREB-Binding Protein; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Esophageal Diseases; Esophagus; Humans; Male; Misoprostol; Mucous Membrane; Neovascularization, Physiologic; Phosphorylation; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP2 Subtype; RNA, Messenger; Second Messenger Systems; Time Factors; Ulcer; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

Esophageal ulceration is a common and important cause of morbidity in patients with acquired immunodeficiency syndrome (AIDS). After known causes are excluded, a subgroup remains with unexplained esophageal ulceration, known as idiopathic esophageal ulceration (IEU). The current therapy of IEU includes corticosteroids or, less frequently, thalidomide, although no placebo-controlled trials have been reported. The aim of this retrospective study was to determine the outcome of treating IEU with misoprostol and viscous lidocaine.. A retrospective review of esophageal ulceration in AIDS identified seven subjects with IEU at our institution. IEU in these subjects was treated successfully with misoprostol, 200 microg, crushed and suspended in 2% viscous lidocaine, 15 ml, given orally a.c. and h.s. for 4 wk.. All patients reported symptomatic improvement within 2-3 days and complete resolution of their symptoms within 15 days. Healing of esophageal ulcerations was confirmed in five of seven subjects at a repeat endoscopy 8-12 wk later.. Misoprostol, an antiulcer drug, has GI cytoprotective properties, and viscous lidocaine, a topical anesthetic, coats mucosal surfaces. We speculate that misoprostol when delivered topically is 3-6 times more effective than when delivered systemically. Considering the rapid resolution of symptoms, healing of ulcers, and lack of side effects, we believe that misoprostol crushed and suspended in viscous lidocaine should be considered for further evaluation in prospective, placebo-controlled trials of IEU.

Topics: Acquired Immunodeficiency Syndrome; Administration, Topical; Adult; Anesthetics, Local; Anti-Ulcer Agents; Drug Combinations; Esophageal Diseases; Female; Humans; Lidocaine; Male; Middle Aged; Misoprostol; Retrospective Studies; Suspensions; Ulcer; Viscosity