BIOPHYSICAL PRINCIPLES OF PERISTALTIC PHENOMENA

食道返流是一种常见的疾病，影响儿童和儿童中的一种。 10名成人，如果不治疗可能会导致慢性食管炎、误吸 肺炎、食道狭窄和Barretts食道，癌前病变 条件。尽管食管炎是一种多因素疾病，但 依赖不适当的下食道括约肌(LES)松弛、速度 对食道清除、粘膜阻力等因素的损害 LES压力是主诉慢性阻塞性肺疾病患者的常见发现 胃灼热。 初步数据显示，食道和LES环行肌利用 不同的钙离子来源、磷脂库和信号转导途径 对乙酰胆碱(ACh)的反应而收缩。A)在食道肌肉中 ACh诱导的收缩需要细胞外钙离子内流，并可能是 与磷脂酰胆碱代谢、二酰甘油的产生有关 (DAG)和花生四烯酸，以及蛋白激酶C(PKC)的激活 依赖途径。B)在LES肌肉中，ACh诱导的收缩利用 磷脂酰肌醇代谢引起的细胞内钙离子释放 (PI)，以及钙调蛋白-肌球蛋白轻链激酶依赖的途径。 另一方面，静息LES音调可能是由于基础PI相对较低 水解导致IP3诱导的钙释放低于最大水平 与二酰甘油相互作用激活PKC。C)在诱导后 实验性食管炎基础水平的PI水解度几乎 废止了，语气也大幅降低。信号转导 LES收缩反应ACh变化的途径 依赖于IP3的产生、钙释放和钙调蛋白 激活依赖于细胞外钙的内流和 激活PKC。 因此，在下一个资助期，我们建议调查：a) 依赖于磷脂酰胆碱的水解的一系列事件， 二酰甘油和花生四烯酸的产生，PKC的激活，以及 食管肌收缩。B)负责的事件 LES音调的维护和负责切换的机制 蛋白激酶C依赖的通路负责维持钙调蛋白的紧张度 ACh反应中使用的依赖途径。C)这些方面的变化 在急性实验性食管炎模型中发生的通路，以及在 慢性食管炎模型。 这些数据将有助于理解细胞内信号转导途径。 正常的食道和LES，并定义了一些信号的变化 转导与食管炎相关。这些数据可能会提供一些 对酸致损伤和酸中毒之间关系的洞察 LES和食道功能的改变，并最终可能提供 为制定有效的临床策略提供合理依据。

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.