MODULATION OF POST BMT LUNG INJURY BY CAPTOPRIL

描述(申请人的描述) 这项建议的目标是理解，在临床实验室中 转译试验，肺损伤的病理生理学与 大剂量放化疗后进行骨髓移植。观察到的是 间质性肺炎综合征(IPS)与自体和 同种异体移植提示多个过程协同作用 启动通向IPS的流程。我们观察到了一场引人注目的 血清铁水平和转铁蛋白饱和度的持续升高 接受骨髓移植的患者。这些数据表明，一种暂时的 铁超载会发生，而这是伴随着产生的 铁催化的活性氧物种(ROS)。我们假设这些RO 在骨髓移植后造成肺损伤，或者通过对肺细胞造成直接损害， 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，确定硫醇抗氧化剂/铁络合剂 卡托普利对大剂量放化疗后肺损伤的预防作用 或在接受骨髓移植的患者中仅接受化疗 (BMT)。肺损伤的测量包括(A)高分辨率CT扫描，(B) 测量肺功能(FEV、FVC、DLCO、脉搏血氧饱和度)。(2)至 建立血清和DNA中氧化性肺损伤的替代标记物 从接受骨髓移植的患者的外周血白细胞中分离出来。我们会 测量(A)氧化剂对(1)细胞DNA的损伤足迹 (8-羟基鸟苷(8-OHDGI))和(2)细胞膜和细胞质(A) 醛、脂质过氧化氢和硫代巴比妥酸活性物质 (B)炎症介质和生长因子，包括转化生长因子-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的时间收集 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， 具有肺损伤临床骨髓移植评估经验的研究人员， 炎症生物学和自由基生物学。从以下方面获得的结果： 这些研究将为IPS的发病机制提供新的信息 骨髓移植，对接受骨髓移植的患者有重要意义。

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.