Liver Lung Interactions in Lung Inflammation

从实验观察和临床经验都非常清楚，肝和肺之间的相互作用在肺部炎症的发生和结局中起着关键作用。我们提出了一个由四个相互关联的项目和三个核心领域组成的计划项目，研究急性肺损伤综合征中肝与肺相互作用的机制。每个项目都以不同的方式解决了潜在的主题，即肝损伤，无论是由内毒素血症，直接创伤还是药物损伤引起的，都可以在肺部发出炎症反应的信号，这些炎症反应可能最终导致急性肺损伤，而二十烷酸在调节这一过程中起着关键作用。肝脏中产生的促炎细胞因子，包括肿瘤坏死因子α，构成肝脏炎症信号。核因子κ B （NFkB）和CCAAT增强子结合蛋白β （C/EBPbeta，又称NF-IL6）这两种转录因子的激活对肺和肝脏的反应至关重要，肺对肝损伤的反应过程取决于这两种因子的激活模式。氧化应激是许多肝损伤的常见原因，肝尿素循环功能异常会加重氧化应激，导致转录因子的激活增强，从而导致细胞因子的释放，放大肺的炎症信号。该项目为加强肺部医学、外科、儿科、药理学、生物化学、微生物学和免疫学、分子生理学和生物物理学等研究人员以前和现在的合作奠定了基础。该计划作为一个整体将整合肺损伤的病理生理学与肝-肺关系的生化细胞和分子机制，这些机制有助于或调节炎症反应。实验方法包括全动物生理制备以及许多转基因小鼠模型和骨髓和肝细胞移植技术作为实验工具。该提案承诺获得与肺损伤机制相关的新信息，这些信息将通过为新的预防或治疗策略以及识别风险个体的能力提供基本原理而具有临床相关性。该提案的结果来自参与研究人员的信念，即共同的主题，互补的专业知识和独特的技术组合成一个协调的项目将更具创造性。更有成效，更有可能推进对炎症性肺病的发病机制和潜在治疗的理解。

It is abundantly clear from both experimental observations and clinical experience, that interactions between the liver and the lungs can play a critical role in the initiation and outcome of lung inflammation. We propose a Program Project consisting of four inter-related projects and three core areas to investigate mechanisms of interactions between the liver and the lungs in acute lung injury syndromes. The underlying theme, addressed in different by each of the projects, is that hepatic injury, whether resulting from endotoxemia, direct trauma or drug injury, can signal an inflammatory response in the lungs that may eventuate in acute lung injury and that eicosanoids play a critical role in modulating that process. Pro-inflammatory cytokines, including tumor necrosis factor alpha, produced in the liver, comprise the liver inflammatory signal. Activation of two transcription factors, nuclear factor kappa B (NFkB) and CCAAT enhancer binding protein beta (C/EBPbeta a.k.a. NF-IL6) is critical to the response in the lungs and in the liver and the course of the response of the lungs to liver injury is determined by the pattern of activation of these two factors. Oxidant stress is common to many causes of hepatic injury and abnormalities in function of the hepatic urea cycle exaggerate oxidant stress resulting in enhanced activation of transcription factors and thus cytokine release, amplifying the inflammatory signal to the lungs. The program forms a structural basis for enhancing previous and existing collaborations among investigators from Pulmonary Medicine, Surgery, Pediatrics, Pharmacology, Biochemistry, Microbiology and Immunology and Molecular Physiology and Biophysics. The program as a whole will integrate the pathophysiology of lung injury with biochemical cellular and molecular mechanisms of liver-lung relationships that contribute to or moderate the inflammatory response. Experimental approaches include whole animal physiologic preparations as well as numerous genetically altered mouse models and bone marrow and hepatocyte transplantation technology as experimental tools. The proposal promises to obtain new information related to mechanisms of lung injury which will be clinically relevant by providing rationales for new preventive or therapeutic strategies as well as the ability to identity at risk individuals The proposal results from the conviction by the involved investigators that the common themes, complementary expertise and unique technologies assembled into a coordinated program will be more creative, more productive and more likely ti advance understanding of the pathogenesis and potential therapy of inflammatory lung disease.