Inflammation and Signal Transduction in Esophagitis

描述（由申请人提供）：胃食管反流病（GERD）是迄今为止最常见的食管疾病，影响超过十分之一的40岁以上成人和四分之一的60岁以上成人。GERD可能导致严重并发症的发生，包括溃疡、狭窄、出血、柱状化生（Barretts食管）和最终的食管腺癌。初步数据表明，酸诱导的食管炎症始于粘膜中酸敏感香草酸受体（TRPV 1）的激活和粘膜层中血小板聚集因子（PAF）的合成。PAF扩散出粘膜层，引起白细胞中过氧化氢的产生和环行肌中IL-6的产生，其中IL-6引起额外的过氧化氢的产生。我们建议将重点放在食管腔内酸引起的炎症反应上，即，负责粘膜层中酸诱导的PAF形成的机制，以及负责环形肌中PAF/IL-6诱导的过氧化氢产生的机制。我们将检验以下假设：A）食管腔中的酸与粘膜层中存在的TRPV 1受体相互作用，导致粘膜层中PAF的形成。B）PAF由粘膜层释放并与白细胞和环行肌相互作用，通过激活白细胞中的NADPH氧化酶诱导H2 O2的产生，并诱导环行肌中IL-6的产生，其中IL-6激活吞噬样NADPH氧化酶，产生H2 O2。C）H2 O2在诱导实验性食管炎后存在于粘膜层中，但在短期暴露于酸后不存在。为了解释这一变化，我们提出，PAF是在粘膜中产生的酸的初始反应。PAF从粘膜释放，诱导肌肉和白色血细胞产生H2 O2。反过来，H2 O2可以上调粘膜NADPH氧化酶，导致粘膜中H2 O2的延迟产生。我们已经证明，清除H2 O2逆转了在食管炎中观察到的一些运动变化，指出ROS是运动障碍的重要介质。了解H2 O2过量产生的机制可能有助于设计新的治疗方法，重点是恢复正常的食管和LES功能，并不总是通过抑酸治疗得到改善。

DESCRIPTION (provided by applicant): Gastro-esophageal reflux disease (GERD) is by far the most common esophageal disorder, affecting more than one in ten adults over 40 years of age and one in four adults over 60. GERD may lead to the development of serious complications including ulcers, strictures, bleeding, columnar metaplasia (Barretts esophagus), and eventually adenocarcinoma of the esophagus. Preliminary data demonstrate that acid-induced inflammation of the esophagus begins with activation of acid sensitive vanilloid receptors (TRPV1) in the mucosa and synthesis of platelet aggregating factor (PAF) in the mucosal layer. PAF diffuses out of the mucosal layer causing production of hydrogen peroxide in leukocytes and production of IL-6 in circular muscle, where IL-6 causes production of additional hydrogen peroxide. We propose to focus on the onset of inflammation in response to acid in the esophageal lumen, i.e., on mechanisms responsible for acid-induced formation of PAF in the mucosal layer, and on mechanisms responsible for PAF/lL-6 -induced production of hydrogen peroxide in the circular muscle. We will test the hypothesis that: A) Acid in the esophageal lumen interacts with TRPV1 receptors present in the mucosal layer, leading to formation of PAF in the mucosal layer. B) PAF is released by the mucosal layer and interacts with leukocytes and with circular muscle, inducing production of H2O2 by activation of NADPH oxidase in leukocytes, and inducing production of IL-6 in circular muscle, where IL-6 activates a phagocytic-like NADPH oxidase, producing H2O2. C) H2O2 is present in the the mucosal layer after induction of experimental esophagitis, but not after short-term exposure to acid. To explain this change we propose that PAF is produced in the mucosa in the initial response to acid. PAF is released from the mucosa inducing production of H2O2 by muscle and white blood cells. H2O2 in turn, may upregulate mucosa NADPH oxidase, causing delayed production of H2O2 in the mucosa. We have demonstrated that scavenging H202 reverses some of the motor changes observed in esophagitis, pointing to ROS as an important mediator of dysmotility. Understanding the mechanisms responsible for overproduction of H2O2 may help in devising novel therapeutic approaches focused on restoring normal esophageal and LES function that are not always improved by acid suppression therapy.