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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02HL072552-03
Application #
6768635
Study Section
Special Emphasis Panel (ZHL1-CSR-M (F2))
Program Officer
Colombini-Hatch, Sandra
Project Start
2002-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$107,244
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Kuboki, Satoshi; Sakai, Nozomu; Tschöp, Johannes et al. (2009) Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury. Am J Physiol Gastrointest Liver Physiol 296:G1054-9
Zahedi, Kamyar; Lentsch, Alex B; Okaya, Tomohisa et al. (2009) Spermidine/spermine-N1-acetyltransferase ablation protects against liver and kidney ischemia-reperfusion injury in mice. Am J Physiol Gastrointest Liver Physiol 296:G899-909
Kuboki, Satoshi; Shin, Thomas; Huber, Nadine et al. (2008) Peroxisome proliferator-activated receptor-gamma protects against hepatic ischemia/reperfusion injury in mice. Hepatology 47:215-24
Kuboki, Satoshi; Schuster, Rebecca; Blanchard, John et al. (2007) Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice. Am J Physiol Gastrointest Liver Physiol 292:G1141-9
Lentsch, Alex B; Pathrose, Peterson; Kader, Sarah et al. (2007) The Ron receptor tyrosine kinase regulates acute lung injury and suppresses nuclear factor kappaB activation. Shock 27:274-80
Solomkin, Joseph S; Robinson, Chad T; Cave, Cynthia M et al. (2007) Alterations in membrane cholesterol cause mobilization of lipid rafts from specific granules and prime human neutrophils for enhanced adherence-dependent oxidant production. Shock 28:334-8
Kuboki, Satoshi; Okaya, Tomohisa; Schuster, Rebecca et al. (2007) Hepatocyte NF-kappaB activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia. Am J Physiol Gastrointest Liver Physiol 292:G201-7
Husted, T L; Blanchard, J; Schuster, R et al. (2006) Potential role for IL-23 in hepatic ischemia/reperfusion injury. Inflamm Res 55:177-8
Barone, Sharon; Okaya, Tomohisa; Rudich, Steve et al. (2005) Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury. Am J Physiol Cell Physiol 289:C826-35
Okaya, Tomohisa; Lentsch, Alex B (2005) Hepatic expression of S32A/S36A IkappaBalpha does not reduce postischemic liver injury. J Surg Res 124:244-9

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