MECHANISMS OF POST BONE MARROW TRANSPLANTATION LUNG INJ

特发性肺炎综合征（LPs）是一种弥漫性肺损伤， 与可确定的感染性病因相关，约六分之一的患者 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种大型临床 接受BMT的患者的数据库和标本库， 对IPS和多器官衰竭的发展进行分层。 尽管这些患者的肺损伤机制可能 异质性，我们提出，细胞活化/损伤的过程 和体内脂质过氧化反应发生在强烈的条件反射 BMT前的治疗方案使患者易于发生后续发展 器官损伤。我们建议监测患者的这些过程 采用气相色谱/质谱法进行BMT， 精确定量类二十烷酸介质的酶代谢产物， 血浆、尿液和支气管肺泡灌洗液作为体内细胞指标 activation.我们将评估在体内氧化应激通过测量最近 所描述的一类化合物，异前列烷，衍生自游离的 自由基介导的花生四烯酸膜过氧化 磷脂我们将同时评估抗氧化防御， 测量还原型和氧化型谷胱甘肽。大约一半的病人， 接受自体骨髓移植的患者，将接受药理剂量的 二甲基亚砜（DMSO），一种作为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通过抑制供体细胞的体外活化， 体内氧化应激对自体BMT受体具有保护作用。 生物化学数据，包括来自这些细胞的IL-8和TNF-α的测量。 将与接受同种异体移植的患者进行比较。 最后，我们建议检查条件辐射的影响， 化疗和骨髓移植对调节 肺泡巨噬细胞趋化性脂质和细胞因子 它们的体外功能。这些研究结合了临床和生化 信息，将提供科学数据，以指导发展 旨在预防和治疗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.