Post-irradiation modulation of Gastrointestinal (GI) injury

胃肠道是辐射损伤的重要靶器官之一。腹部辐射引起一系列病理，可分为1)前驱期，2)急性辐射病，以及3)辐射的晚期效应。恶心、呕吐、腹部绞痛和腹泻，往往是辐射中毒的首要表现。这些影响是由神经变化介导的，并与小肠和大肠的运动性改变有关。我们实验室的研究提供了小肠和大肠运动剧烈变化与直接症状相关的证据。分泌性腹泻是早期辐射发病率和死亡率的重要原因，反映了血管内液体通过上皮转移到肠腔。我们对肠道微血管系统的研究为放射性腹泻疾病的预测和治疗提供了一种新的潜在方法。我们实验室的新证据表明，辐射在胃肠道中的晚期破坏性影响是由神经和微血管变化介导的。本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效应，并制定缓解策略以改善损害。此外，我们将探索ACE抑制，NMDA受体抑制和SOD模拟物作为缓解剂。收缩记录将从犬和啮齿动物模型中进行，并将与肌肠丛的免疫组织化学研究相关联

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.