Liver Lung Interactions in Lung Inflammation

肺部炎症中肝肺的相互作用

• 批准号: 6838687
• 负责人: BRIAN W CHRISTMAN
• 金额: $ 189.46万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838687
• 关键词: cytokine; inflammation; liver disorder; lung injury; oxidative stress

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.

从实验观察和临床经验中可以清楚地看出，肝脏和肺部之间的相互作用在肺部炎症的发生和结果中发挥着关键作用。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项目，以研究急性肺损伤综合征中肝脏和肺部之间相互作用的机制。每个项目以不同方式解决的基本主题是，肝损伤，无论是由内毒素血症、直接创伤还是药物损伤引起，都可能发出肺部炎症反应的信号，最终可能导致急性肺损伤，而类二十烷酸在其中发挥着关键作用。调节该过程的作用。肝脏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 kappa B (NFkB) 和 CCAAT 增强子结合蛋白 β（C/EBPbeta 又名 NF-IL6）这两种转录因子的激活对于肺部和肝脏的反应以及肺部对病毒的反应过程至关重要。肝损伤是由这两个因素的激活模式决定的。氧化应激是导致肝损伤的许多原因的常见原因，肝脏尿素循环功能异常会加剧氧化应激，导致转录因子激活增强，从而导致细胞因子释放，从而放大向肺部发出的炎症信号。该计划为加强肺科、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研究人员之间先前和现有的合作奠定了结构基础。该项目作为一个整体将把肺损伤的病理生理学与促进或调节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生理制剂以及大量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，通过为新的预防或治疗策略提供基本原理以及识别高危个体的能力，这些信息将具有临床相关性。将主题、互补的专业知识和独特的技术整合到一个协调的计划中将更具创造性、更有成效，并且更有可能促进对炎症性肺病的发病机制和潜在治疗的理解。