POST BONE MARROW TRANSPLANTATION LUNG INJURY MECHANISMS

特发性肺炎综合征(LPS)是弥漫性肺损伤的一种形式 与可确定的传染病病原学有关，影响约六分之一 接受骨髓移植(BMT)的患者死亡率为 超过70%。这些患者经常被排除在其他 急性肺损伤的研究，最近没有受到 对器官衰竭和逆转的模式进行了前瞻性分析。 我们研究的基础将是开发一个大型临床 在接受骨髓移植的患者中建立数据库和样本库，以提高风险 对IPS和多器官衰竭的发展进行分层。 尽管这类患者的肺损伤机制很可能 异质性，我们提出了细胞激活/损伤的过程 以及在高强度条件反射过程中体内发生的脂质过氧化 骨髓移植前的治疗方案为患者的后续发展做好了准备 器官损伤。我们建议监测患者的这些过程 利用气相色谱/质谱仪进行骨髓移植 精确定量二十烷基类介体的酶代谢产物 血浆、尿液和支气管肺泡灌洗液作为体内细胞指标的研究 激活。我们将通过测量一种最近的氧化应激来评估体内的氧化应激 所描述的一类化合物，异前列烷，源于游离基 花生四烯酸膜的自由基介导的过氧化 磷脂。我们将通过以下方式同时评估抗氧化防御 测定还原和氧化的谷胱甘肽。大约一半的病人， 那些接受自体骨髓移植的人将获得药理剂量的 二甲基亚砜(DMSO)，一种充当自由基清除剂的试剂 并能抑制全血中细胞因子基因的表达。我们假设 DMSO，通过抑制供体细胞体外激活和减少 体内的氧化应激，为自体骨髓移植接受者提供保护。 生化数据，包括IL-8和肿瘤坏死因子-α的测量 将与接受同种异体移植的患者进行比较。 最后，我们建议研究条件化辐射和 化疗和骨髓移植对血管内皮细胞合成的调节 肺泡巨噬细胞趋化脂质和细胞因子的检测 它们的体外功能。这些研究结合了临床和生化 信息，将为指导发展提供科学数据 防治肺损伤的药理学策略 骨髓移植后。

The idiopathic pneumonia syndrome (LPs), a form of diffuse lung Injury not associated with a definable Infectious etiology, affects about one In six patients undergoing bone marrow transplantation (BMT) with a mortality in excess of 70%. These patients have frequently been excluded from other studies of acute lung injury and have not been subjected to recently developed prospective analyses of patterns of organ failure and reversal. The foundation of our studies will be the development of a large clinical database and specimen bank in patients undergoing BMT to allow better risk stratification for the development of IPS and multiple organ failure. Although the mechanisms of lung injury in such patients are likely heterogeneous, we propose that the processes of cellular activation/damage and in vivo lipid peroxidation occurring during the intense conditioning regimens prior to BMT predisposes patients for the subsequent development of organ injury. We propose to monitor these processes in patients undergoing BMT by employing gas chromatography/mass spectrometry to precisely quantify enzymatic metabolites of eicosanoid mediators In plasma, urine and bronchoalveolar lavage fluid as indices of in vivo cell activation. We will assess in vivo oxidant stress by measuring a recently described class of compounds, the isoprostanes, that derive from free radical-mediated peroxidation of arachidonic acid containing membrane phospholipids. We will concomitantly assess antioxidant defense by measuring reduced and oxidized glutathione. About half of the patients, those undergoing autologous BMT, will receive pharmacological doses of dimethylsulfoxide (DMSO), an agent that acts as a free radical scavenger and can suppress cytokine gene expression in whole blood. We hypothesize that DMSO, by suppressing donor cell activation ex vivo and decreasing oxidant stress in vivo, confers protection to autologous BMT recipients. Biochemical data, including measurement of IL-8 and TNF-alpha from these patients, will be compared with those undergoing allogeneic transplants. Finally, we propose to examine the effects of conditioning radiation and chemotherapy and marrow engraftment on the regulation of the synthesis of chemotactic lipids and cytokines in alveolar macrophages by examining their function ex vivo. These studies, combining clinical and biochemical information, will provide the scientific data to guide development of pharmacological strategies aimed at preventing and treating lung injury after bone marrow transplantation.