This Independent Scientist Award will provide protected research time to enable the applicant to develop and apply new skills in the area of molecular biology as well as greatly expand his investigations into the mechanisms of hepatic ischemia/reperfusion-induced lung injury. Hepatic ischemia/reperfusion is a significant complication of liver resectional surgery, transplantation, trauma and hemorrhagic shock, and often results in acute lung injury. The precise mechanisms by which liver ischemia/reperfusion causes lung injury are currently unknown. Our preliminary data suggest that activation of the transcription factor, NF-kB, occurs in the lung prior to hepatic reperfusion and subsequent release of liver-derived proinflammatory cytokines into the circulation. We also provide evidence that serum levels of the neuropeptide, substance P, increase during hepatic ischemia, prior to reperfusion. Substance P is a potent activator of macrophages and we hypothesize that substance P release in response to hepatic ischemia stimulates alveolar macrophages and promotes the induction of lung inflammation. This proposal will address fundamental questions about the mechanisms by which ischemic liver injury induces acute lung inflammatory injury. We will determine the functional significance of the transcription factor, NF-kB in the lung inflammatory response induced by hepatic ischemia/reperfusion by generating cell-permeable fusion proteins containing a non-degradable form of the inhibitor of NF-kB, IkBa. Secondly, we will determine the role of alveolar macrophages in this lung inflammatory response using liposome-mediated depletion methods. Finally, we will determine the pathophysiological role of substance P in the induction of lung inflammation after hepatic ischemia/reperfusion using peptide antagonists and/or mutant mice lacking the receptor for substance P. The knowledge gained from these studies will provide mechanistic explanations for new therapeutic options for acute lung injury, and may be applicable to a number of other inflammatory lung diseases.
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