Post-irradiation modulation of GI injury

胃肠道是受辐射损伤的重要靶器官之一。腹部照射引起一系列的病理变化，分为1)前驱期，2)急性放射病，3)辐射的后期效应。恶心、呕吐、腹部痉挛和腹泻通常是辐射中毒的首发症状。这些效应是由神经变化介导的，并与小肠和大肠运动的改变有关。我们实验室的研究已经提供了与症状直接相关的小肠和大肠运动的戏剧性变化的证据。分泌性腹泻是早期放射性发病率和死亡率的重要组成部分，反映了血管内液体通过上皮向肠腔的转移。我们对肠道微血管的研究为放射性腹泻疾病的预测和改善提供了一种新的潜在方法。来自我们实验室的新证据表明，辐射在胃肠道的晚期损害效应是由神经和微血管变化介导的。这项拨款申请建议在两种动物模型(大鼠和狗)中确定低剂量率和高剂量率辐射暴露后的胃肠道影响，并制定缓解策略以减轻损害。此外，我们还将探索ACE抑制、NMDA受体抑制和超氧化物歧化酶类似物作为缓释剂。收缩记录将来自犬类和啮齿动物模型，并将与肌间神经丛的免疫组织化学研究以及 微血管研究。产品开发和积累临床前安全数据以便于向FDA提交是这项赠款申请的优先事项，我们的最终目标是提高人类对辐射暴露的耐受性。总而言之，实验研究表明，辐射导致的胃肠道损伤是可以治疗的。该项目的目标是将这些实验方法中的一种或多种应用于临床实践。

The gastrointestinal tract is one of the critical target organs afflicted by radiation injury. Abdominal irradiation causes an array of pathology which has been divided into 1) the prodromal phase, 2) acute radiation sickness, and 3) the late effects of radiation. Nausea, vomiting, abdominal cramping and diarrhea, often are the first manifestations of radiation toxicity. These effects are mediated by neural changes and associated with altered motility in the small and large intestine. Studies from our lab have provided evidence for dramatic changes in small and large intestinal motility with direct symptomatic relevance. Secretory diarrhea, a significant contribution to early radiation morbidity and mortality, reflects transfer of intravascular fluids to the intestinal lumen through the epithelium. Our studies of the intestinal microvasculature provide a novel potential method for the prediction and modification of radiation diarrheal illness. New evidence from our lab suggests that the late damaging effects of radiation in the gastrointestinal tract are mediated by both neural and microvascular changes. This grant application proposes to define gastrointestinal effects following both low and high dose rate radiation exposure in two animal models (rat and the dog), as well as developing mitigation strategies to ameliorate damage. In addition, we will explore ACE inhibition, NMDA receptor inhibition and SOD mimetics as a mitigating agents. Contractile recordings will be made from a canine and a rodent model and will be correlated with immunohistochemical studies of the myenteric plexus as well as microvascular studies. Product development and the accumulation of pre-clinical safety data to facilitate submission to the FDA is a priority of this grant application with our ultimate aim to improve human tolerance to radiation exposure. In summary, experimental studies suggest radiation-induced injury to the gastrointestinal tract can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.