Kidney Response to Radiation and Chemotherapy

描述(申请人提供)：该项目基于这样的假设，即晚期辐射引起的正常组织损伤可以通过辐射后的药物干预来预防和/或治疗。利用大鼠放射性肾病模型研究晚期放射性正常组织损伤的病理生理机制(S)，并将这些机制的认识用于开发预防和治疗这些损伤的方法。放射性肾病是骨髓移植(BMT)条件调节的主要并发症，而大鼠是这种肾病的优秀模型，这一发现为该项目增加了一个临床前组成部分。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：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，即使治疗是在照射后几周开始和/或不是无限期持续的。这些发现对晚期辐射损伤的标准机制解释提出了相当大的怀疑，并表明辐射治疗、辐射事故或核恐怖主义造成的损伤可以通过辐射后药物干预来治疗或预防。这项建议的具体目标分为四个相关类别： 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的近端机制的假说。 2)证实血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体阻滞剂防治放射性肾病作用机制不同的假说。 3)明确ACE抑制剂和AII受体阻滞剂预防放射性肾病的作用机制。 4)完成使用血管紧张素转换酶抑制剂预防骨髓移植患者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.