MODULATION OF POST BMT LUNG INJURY BY CAPTOPRIL

申请人的描述（Applicant's Description） 本提案的目的是了解，在临床实验室中， 翻译试验，肺损伤的病理生理学与 大剂量放化疗后进行骨髓移植 的观察结果 间质性肺炎综合征（IPS）与自体和 同种异体移植表明多个过程协同作用， 启动导致IPS的过程。 我们观察到一个惊人的， 血清铁水平和转铁蛋白饱和度持续升高， 接受BMT的患者。 这些数据表明， 铁超载发生，这是伴随着产生的 铁催化活性氧（ROS）。 我们假设这些活性氧 通过直接损伤肺细胞， 或者通过激活导致肺损伤的炎症级联反应。 为了验证这一假设，我们提出了以下具体目标：（1） 在临床试验中，确定巯基抗氧化剂/铁螯合剂 卡托普利可预防大剂量化疗/放疗后肺损伤 或单纯化疗， （BMT）。 肺损伤的测量包括（a）高分辨率CT扫描，（B） 肺功能指标（FEV、FVC、DLCO、脉搏血氧饱和度）。 (2)到 建立血清和DNA中氧化剂介导肺损伤替代标志物 从接受BMT的患者的外周血白色细胞中。 我们将 测量（a）氧化剂介导的损伤对（1）细胞DNA的足迹 （2）细胞膜和细胞质（a） 醛、脂质过氧化氢和硫代巴比妥酸反应物质 （TBARS）和（B）炎性介质和生长因子，包括TGF-β。 铁的测量将包括a）血清游离铁，（B）血清铁，（c） 转铁蛋白和（d）铁蛋白样本将在不同时间采集 在BMT期间和之后。 为了实现这些目标，我们组建了一个多学科团队， 具有临床BMT肺损伤评估经验的研究者， 炎症生物学和自由基生物学 获得的结果 这些研究将为IPS的机制提供新的信息， BMT和应该有重要意义的病人，谁接受BMT。

DESCRIPTION (Applicant's Description) The objective of this proposal is to understand, in a clinical laboratory translational trial, the pathophysiology of lung injury associated with high-dose chemoradiotherapy followed by BMT. The observation that interstitial pneumonia syndrome (IPS) is associated with autologous and allogeneic transplantation suggests that multiple processes act in concert to initiate the process that leads to IPS. We have observed a striking and consistent elevation in serum iron levels and saturation of transferrin in patients undergoing BMT. These data suggest that a temporary state of iron-overload occurs, and that this is accompanied by the generation of iron-catalyzed reactive oxygen species (ROS). We hypothesize that these ROS cause lung damage after BMT either by causing direct damage to lung cells, or by activating an inflammatory cascade that contributes to lung injury. In order to test the hypothesis we propose the following specific aims: (1) To determine, in a clinical trial, if the thiol anti-oxidant/iron chelator captopril can prevent lung injury after high-dose chemotherapy/radiotherapy or chemotherapy alone in patients undergoing bone marrow transplantation (BMT). Measures of lung injury include (a) high-resolution CT-scans, (b) measures of lung function (FEV, FVC, DLCO, pulse oximetry). (2) To establish surrogate markers of oxidant-mediated lung injury in serum and DNA from peripheral blood white cells in patients undergoing BMT. We will measure (a) footprints of oxidant-mediated injury to (1) cellular DNA (8-hydroxyguanosine (8-OHDGI), and (2) cellular membranes and cytoplasm (a) aldehydes, lipid hydroperioxides and thiobarbituric acid reactive substances (TBARS) and (b) inflammatory mediators and growth factors, including TGF-P. Measures of iron will include a)serum free iron, (b) serum iron, (c) transferrin and (d) ferritin samples will be collected at various times during and after BMT. To accomplish these aims we have assembled a multidisciplinary team of investigators with experience in clinical BMT assessment of lung injury, the biology of inflammation and free radical biology. The results obtained from these studies will provide new information on the mechanisms of IPS after BMT and should have important implications for patient, who undergo BMT.