Pathogenesis of Liver-Dependent Acute Lung Injury

描述（由申请人提供）：肝功能与急性肺损伤之间存在联系：a)在肝功能衰竭的情况下，ARDS几乎都是致命的；b)肝功能障碍常见于ARDS患者；c)动物研究表明，在内毒素血症或肝脏缺血的情况下，肝脏会释放促炎细胞因子。在原位灌注猪制剂中，我们发现内毒素诱导的肺损伤仅发生在肝脏被纳入循环时。我们得出的结论是，内毒素不会直接损伤肺，而是通过内毒素诱导的肝脏释放介质介导的肺损伤。我们假设：a)内毒素的直接作用使肺为损伤做好准备，但损伤需要肝脏释放的介质；b)内毒素血症诱导肝脏中编码蛋白质的基因表达增加，这些蛋白质分泌到循环中，介导肝依赖性肺损伤；c)骨髓来源的干细胞是肝脏和肺部内毒素血症急性炎症反应的关键调节剂；d)骨髓细胞对内毒素诱导的急性炎症和肺损伤的抑制主要是一种非造血间充质样干细胞的作用。我们将通过以下方法来验证这些假设：1)确定内毒素“启动”肺部损伤是否对内毒素诱导的介质从肝脏释放造成的损伤是必要的，确定肺和肝脏对内毒素血症的分子反应，并确定内毒素诱导的介质在肝脏产生并释放到循环中介导肺损伤；2)确定骨髓来源细胞对内毒素诱导的炎症（肺和肝）和肝脏释放介质的作用，表征这些细胞对内毒素诱导的分子反应的作用，确定是否必须将骨髓细胞递送到肺和肝脏以防止肺损伤，确定有效的骨髓来源细胞群是否为非造血细胞和间充质细胞样；3)在体内确定获得扩大的骨髓细胞池对内毒素诱导的炎症和肺损伤的影响，并描述在异种小鼠制备中内毒素血症后向肺和肝脏募集的细胞群。这些研究将阐明急性肺部炎症和损伤的机制，并确定新的治疗潜力。

DESCRIPTION (provided by applicant): There are connections between hepatic function and acute lung injury: a) ARDS in the setting of hepatic failure is almost uniformly fatal; b) hepatic dysfunction is common in patients with ARDS; and c) animal studies demonstrate release of pro-inflammatory cytokines from the liver in response to endotoxemia or hepatic ischemia. In an in situ perfused swine preparation we find that endotoxin induced lung injury only occurs when the liver is included in the circulation. We conclude that endotoxin does not injure the lung directly, but "primes" the lung for injury that is mediated by endotoxin induced release of mediators from the liver. We hypothesize that: a) Direct effects of endotoxin prime the lung for injury, but injury requires mediators released from the liver; b) Endotoxemia induces increased hepatic expression of gene(s) encoding protein(s) secreted into the circulation that mediate liver dependent lung injury, c) Bone marrow derived stem cells are critical modulators of the acute inflammatory response to endotoxemia in both the liver and the lungs and; d) Suppression of endotoxin induced acute inflammation and lung injury by bone marrow cells is primarily an effect of a subset of non-hematopoietic, mesenchymal-like stem cells. We will test these hypotheses by: 1) Determining whether endotoxin "priming" of the lung for injury is necessary for injury caused by endotoxin induced release of mediators from the liver, determining molecular responses to endotoxemia in both the lungs and liver and identifying endotoxin induced mediators produced in the liver and released into the circulation that mediate lung injury; 2) Determining effects of bone marrow derived cells on endotoxin induced inflammation (lung and liver) and release of mediators by the liver, characterizing effects of these cells on endotoxin induced molecular responses, determining whether bone marrow cells must be delivered to both the lungs and the liver to prevent lung injury, and determining whether the population of effective marrow derived cells is non-hematopoietic and mesenchymal-like; and 3) Determining in vivo the effects of access to an expanded pool of bone marrow cells on endotoxin-induced inflammation and lung injury and characterizing the populations of cells recruited to the lungs and the liver in vivo following endotoxemia in a parabiotic mouse preparation. These studies will elucidate mechanisms of acute lung inflammation and injury and identify novel potentials for therapy.