Liver Lung Interactions in Lung Inflammation

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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.