Esophageal reflux is a common condition that affects children and one in ten adults, and if untreated may result in chronic esophagitis, aspiration pneumonia, esophageal strictures, and Barretts esophagus, a premalignant condition. Although esophagitis is a multifactorial disease that may depend on inappropriate Lower Esophageal Sphincter (LES) relaxation, speed of esophageal clearance, mucosal resistance and other factors, impairment of LES pressure is a common finding in patients complaining of chronic heartburn. Preliminary data suggest that esophageal and LES circular muscle utilize distinct Ca++ sources, phospholipid pools and signal transduction pathways to contract in response to acetylcholine (ACh). A) In esophageal muscle ACh-induced contraction requires influx of extracellular Ca++ and may be linked to phosphatidylcholine metabolism, production of diacylglycerol (DAG) and arachidonic acid, and activation of a protein kinase C (PKC) dependent pathway. B) In LES muscle ACh-induced contraction utilizes intracellular Ca++ release arising from metabolism of phosphatidilinositol (PI), and a calmodulin-myosin light chain kinase-dependent pathway. Resting LES tone on the other hand may be due to relatively low basal PI hydrolysis resulting in submaximal levels of IP3-induced calcium release and interaction with diacylglycerol to activate PKC. C) After induction of experimental esophagitis basal levels of PI hydrolysis are almost abolished and tone is substantially reduced. The signal transduction pathway responsible for LES contraction in response to ACh changes from one which depends on IP3 production, calcium release and calmodulin activation to one which relies on influx of extracellular calcium and activation of PKC. In the next funding period we therefore propose to investigate: A) The cascade of events which depend upon the hydrolysis of phosphatidylcholine, production of diacylglycerol and arachidonic acid, activation of PKC, and contraction of esophageal muscle. B) The events responsible for maintenance of LES tone and the mechanism responsible for a switch from a PKC dependent pathways responsible for maintenance of tone to a calmodulin dependent pathway utilized in response to ACh. C) The changes in these pathways occurring in a model of acute experimental esophagitis, and in a model of chronic esophagitis. These data will help in understanding the signal transduction pathways in the normal esophagus and LES, and define some of the changes in signal transduction associated with esophagitis. The data may provide some insights into the relationships between acid induced damage and alterations in LES and esophageal function, and may eventually provide a rational basis for devising effective clinical strategies.
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