Liver Lung Interactions in Lung Inflammation

从实验观察和临床经验中非常清楚的是，肝脏和肺部之间的相互作用可以在肺部炎症的发生和结果中发挥关键作用。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，以研究急性肺损伤综合征中肝脏和肺之间的相互作用机制。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，都可以发出肺部炎症反应的信号，这可能导致急性肺损伤，而类花生酸在调节这一过程中起着关键作用。在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。两种转录因子的激活，即核因子kappa B（NFk B）和CCAAT增强子结合蛋白β（C/EBP β，又名NF-IL 6）对于肺和肝中的应答是关键的，并且肺对肝损伤的应答过程由这两种因子的激活模式决定。氧化应激是肝损伤的许多原因所共有的，并且肝尿素循环功能的异常加剧氧化应激，导致转录因子的活化增强，从而导致细胞因子释放，放大对肺的炎症信号。该计划形成了一个结构性的基础，以加强来自肺医学，外科，儿科，药理学，生物化学，微生物学和免疫学以及分子生理学和生物物理学的研究人员之间以前和现有的合作。该计划作为一个整体将肺损伤的病理生理学与肝-肺关系的生化细胞和分子机制相结合，这些机制有助于或缓和炎症反应。实验方法包括整个动物的生理制剂以及许多遗传改变的小鼠模型和骨髓和肝细胞移植技术作为实验工具。该提案承诺通过提供新的预防或治疗策略以及识别风险个体的能力来获得与肺损伤机制相关的新信息，这些信息将与临床相关。该提案源于相关研究人员的信念，即共同的主题，互补的专业知识和独特的技术组装成一个协调的计划将更具创造性，更有成效，更有可能促进对炎症性肺病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.