Kidney Response to Radiation and Chemotherapy

描述（由申请人提供）：本项目基于以下假设：晚期辐射诱导的正常组织损伤可以通过辐射后药理学干预进行预防和/或治疗。 大鼠放射性肾病模型用于研究晚期放射诱导的正常组织损伤的病理生理学机制，这些机制的理解用于开发预防和治疗这些损伤的方法。 发现放射性肾病是骨髓移植（BMT）预处理的主要并发症，并且大鼠是这种肾病的极好模型，为该项目增加了临床前成分。 血管紧张素转换酶（ACE）抑制剂和血管紧张素II（AII）阻滞剂可用于预防和治疗BMT肾病的发现直接导致了临床研究。 这些研究受到以下发现的强烈影响，即阻断肾素-血管紧张素系统可以永久性地干扰放射性肾病的发展，即使在照射后数周开始治疗和/或不无限期地持续治疗。 后者的研究结果提出了相当大的疑问，对标准的机械解释，晚期辐射损伤，并建议辐射治疗，辐射事故或核恐怖主义造成的伤害，可以治疗或预防与辐照后的药理干预。 这项建议的具体目标分为四个相关的类别： 1)驳斥放射诱导的肾素-血管紧张素系统激活是放射性肾病近端机制原因的假设。 2)证实ACE抑制剂和AII阻断剂预防和治疗放射性肾病的机制不同的假设。 3)确定ACE抑制剂和AII受体阻断剂预防放射性肾病疗效的机制基础。 4)完成使用ACE抑制剂预防BMT患者发生放射性肾病的随机、前瞻性试验。

DESCRIPTION (provided by applicant): This project is based on the hypothesis that late radiation-induced normal tissue injuries can be prevented and/or treated with post-irradiation pharmacologic intervention. The rat radiation nephropathy model is used to study the pathophysiological mechanism(s) of late radiation-induced normal tissue injuries, and these mechanistic understandings are used in the development of methods for prophylaxis and treatment of these injuries. The discovery that radiation nephropathy is a major complication of bone marrow transplantation (BMT) conditioning, and that the rat was an excellent model for this nephropathy, added a preclinical component to the project. The discovery that angiotensin converting enzyme (ACE) inhibitors and an angiotensin II (AII) blockers could be used for the prophylaxis and treatment of BMT nephropathy led directly to clinical studies. The studies are strongly influenced by the finding that blocking the renin-angiotensin system can permanently interfere with the development of radiation nephropathy even when treatment is started weeks after irradiation and/or is not continued indefinitely. These latter findings cast considerable doubt on the standard mechanistic explanations for late radiation injuries, and suggest that injuries caused by radiation therapy, radiation accidents or nuclear terrorism could be treated or prevented with post-irradiation pharmacological interventions. The specific aims of this proposal fall into four related groups: 1) Refute the hypothesis that radiation-induced activation of the renin-angiotensin system is the proximal mechanistic cause of radiation nephropathy. 2) Confirm the hypothesis that prophylaxis and treatment of radiation nephropathy with ACE inhibitors and AII blockers operate by different mechanisms. 3) Determine the mechanistic basis for the efficacy of ACE inhibitors and AII receptor blockers in the prophylaxis of radiation nephropathy. 4) Complete the randomized, prospective, trial of the use of ACE inhibitors to prevent the development of radiation nephropathy in BMT patients.