Liver Lung Interactions in Lung Inflammation

从实验观察和临床经验来看，非常清楚的是，肝脏和肺之间的相互作用可以在肺部炎症的开始和转归中发挥关键作用。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和肺之间的相互作用机制。每个项目以不同的方式阐述的基本主题是，肝脏损伤，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，最终可能导致急性肺损伤，而二十烷类化合物在调节这一过程中发挥关键作用。肝脏产生的促炎细胞因子，包括肿瘤坏死因子α，构成了肝脏炎症信号。核因子kappaB(NFkB)和CCAAT增强子结合蛋白β(C/EBPbeta)这两个转录因子的激活。IL-6)在肺和肝的反应中起关键作用，肺对肝损伤的反应过程由这两种因子的激活模式决定。氧化应激是许多肝损伤的常见原因，肝脏尿素循环功能的异常会放大氧化应激，导致转录因子的激活，从而细胞因子的释放，放大肺的炎症信号。该计划为加强来自肺部医学、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奠定了结构基础。作为一个整体，该计划将把肺损伤的病理生理学与促进或缓和炎症反应的肝肺关系的生化、细胞和分子机制结合起来。实验方法包括整个动物的生理准备，以及大量的转基因小鼠模型，以及作为实验工具的骨髓和肝细胞移植技术。该提案承诺通过提供新的预防或治疗策略的理论基础以及识别高危个体的能力，获得与肺损伤机制有关的新信息。该提案是因为相关研究人员确信，将共同主题、互补专业知识和独特技术整合到一个协调计划中将更具创造性、更有成效，更有可能促进对炎症性肺部疾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.