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道疾病，影响超过十分之一的40岁以上成年人和四分之一的60岁以上成年人。反流胃食管反流可导致严重并发症的发展，包括溃疡、狭窄、出血、柱状化生（巴雷特食管），并最终导致食道腺癌。初步数据表明，酸致食管炎症始于粘膜中酸敏感香草样受体（TRPV1）的激活和粘膜层血小板聚集因子（PAF）的合成。PAF扩散出粘膜层，导致白细胞产生过氧化氢，并在圆形肌肉中产生IL-6，其中IL-6导致产生额外的过氧化氢。我们建议将重点放在食管腔内酸反应引起的炎症上，即酸诱导粘膜层中PAF形成的机制，以及PAF/lL-6诱导环状肌肉中过氧化氢产生的机制。我们将验证以下假设：A)食管腔内的酸与存在于粘膜层的TRPV1受体相互作用，导致粘膜层形成PAF。B) PAF由粘膜层释放，与白细胞和圆形肌肉相互作用，通过激活白细胞中的NADPH氧化酶诱导H2O2的产生，并诱导圆形肌肉中IL-6的产生，其中IL-6激活吞噬细胞样NADPH氧化酶，产生H2O2。C)实验性食管炎诱导后粘膜层中存在H2O2，但短期酸暴露后不存在H2O2。为了解释这种变化，我们提出PAF是在粘膜对酸的初始反应中产生的。PAF从粘膜释放，诱导肌肉和白细胞产生H2O2。H2O2反过来可能上调粘膜NADPH氧化酶，导致粘膜中H2O2的产生延迟。我们已经证明清除H202逆转了食道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H2O2过量产生的机制可能有助于设计新的治疗方法，专注于恢复正常的食管和LES功能，这些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.