Pathogenesis of Liver-Dependent Acute Lung Injury

肝依赖性急性肺损伤的发病机制

• 批准号: 7805421
• 负责人: KENNETH L BRIGHAM
• 金额: $ 38.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-18 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805421
• 关键词: Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biochemical; Bleomycin; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Cells; Clinical; Data; Doctor of Medicine; Endotoxemia; Endotoxins; Family suidae; Fibrosis; Functional disorder; Gene Expression; Hematopoietic; Hepatic; Hour; Hypoxemia; In Situ; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Interleukin-6; Ischemia; Laboratories; Leukocytes; Liver; Liver Circulation; Liver Failure; Lung; Lung Inflammation; Marrow; Measurement; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Mus; Myelosuppression; Organ; Oxidative Stress; Pathogenesis; Patients; Physiological; Plasma; Plastics; Population; Preparation; Proteins; Pulmonary Edema; Reaction; Recruitment Activity; Regional Perfusion; Regulation; Reporting; Research Personnel; Respiratory distress; Role; Sepsis; Stem cells; Structure of parenchyma of lung; Testing; Time; cell type; cytokine; in vivo; injured; insight; lung injury; novel; oxidant stress; prevent; programs; research study; response; transcription factor; vasoconstriction

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.

描述（由申请人提供）：肝功能与急性肺损伤之间存在联系：a）在肝衰竭的情况下，ARDS几乎是致命的； b）肝功能障碍在ARDS患者中很常见； c）动物研究表明，响应内毒素血症或肝缺血，从肝脏中释放了促炎性细胞因子。在原位灌注猪的准备中，我们发现内毒素诱导的肺损伤只有在循环中包括肝脏时才发生。我们得出的结论是，内毒素不会直接损伤肺部，而是“刺激性”肺部受伤，该肺部由内毒素诱导的介质从肝脏释放出来。我们假设：a）内毒素素肺部受伤的直接作用，但受伤需要从肝脏释放的介质； b）内毒素血症诱导编码蛋白质的基因的肝表达增加，该基因被分泌到循环系统中，即介导肝脏依赖性肺损伤，c）骨髓衍生的干细胞是对肝脏和肺部和肺部和肺内内毒素血症的急性炎症反应的关键调节剂； d）抑制内毒素诱导的急性炎症和骨髓细胞肺损伤主要是非杂质，间充质样干细胞子集的作用。我们将通过：1）确定肺内毒素“启动”是否为受伤的内毒素“启动”是由于内毒素引起的介质从肝脏中释放而引起的损伤，确定对肺和肝脏中内毒素诱导的介导者的分子反应，并识别出在肝脏中产生的内毒素介导者，并释放出了循环症状的疾病。 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间充质状； 3）确定体内的骨髓细胞扩展池对内毒素诱导的炎症和肺损伤的影响，并表征在寄生虫小鼠制备中内毒素后，在内毒素后，在体内募集到肺和肝脏的细胞种群。这些研究将阐明急性肺部炎症和损伤的机制，并确定治疗的新型潜力。