Neutrophils can cause impaired liver function, parenchymal injury and even liver failure during a number of important clinical situations including hepatic ischemia-reperfusion, hemorrhagic shock and resuscitation, endotoxemia and sepsis, remote traumas, well as alcoholic hepatitis. Although neutrophils can accumulate rapidly in hepatic sinusoids and post-sinusoidal venules, migration into the extravascular space and direct attack on parenchymal cells leads to the most serious and irreversible injury. Our previous work defined the unique behavior of neutrophils in the liver vasculature and the conditions necessary for injury to occur. Although we clearly established the importance of cytokines, adhesion molecules and neutrophil activation in vivo, our data strongly suggest that a chemotactic signal must be generated to trigger neutrophil transmigration. Preliminary data showed a protective effect of an antiserum against MIP-2 after galactosamine/endotoxin treatment. Therefore, we hypothesize that members of the CXC chemokine family, KC and MIP-2 are involved in neutrophil activation and sequestration in the liver vasculature. In addition, CXC chemokines are responsible for extravasation into the parenchyma and are a key signal for the attack on individual hepatocytes. Moreover, parenchymal cell apoptosis can be a proinflammatory event by modulating the transcriptional regulation of CXC chemokines. To test these hypotheses, we will address the following specific aims: 1) Define the relevance of CXC chemokines in comparison to other inflammatory mediators in the activation and recruitment of neutrophils into the liver vasculature during endotoxemia in vivo. 2) Determine if CXC chemokines are a relevant signal for transmigration of neutrophils in the liver during endotoxemia in vivo. 3) Determine if CXC chemokine formation and neutrophil transmigration can be modulated by apoptotic cell death in hepatocytes during endotoxemia or Fas receptor ligation in vitro and in vivo. 4) Determine CXC chemokine formation in hepatocytes and/or neutrophils and their pathophysiological importance in the adherence-dependent killing of hepatocytes by neutrophils in vitro. We will perform these studies in well-defined models of inflammatory liver injury in vivo and in vitro using C3HebIFeJ mice. In addition, a number of gene knock-out mice with deletions of specific receptors, e.g. CXC chemokine receptor 2, TNF receptor 1, IL-i receptor 1 and antioxidant enzymes, e.g. glutathione peroxidase, will be used. This investigation will provide important new insights into the molecular mechanisms of neutrophil- induced liver injury and will help to identify potentially selective therapeutic intervention strategies that can be used to prevent neutrophil cytotoxicity without affecting vital host-defense functions.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Russo, Denise A
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University of Arizona
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Woolbright, Benjamin L; Jaeschke, Hartmut (2018) Is Keratin-18 only a Marker of Cell Death in Acute-On-Chronic Liver Failure? J Lab Precis Med 3:
Woolbright, Benjamin L; Jaeschke, Hartmut (2018) Alcoholic Hepatitis: Lost in Translation. J Clin Transl Hepatol 6:89-96
Woolbright, Benjamin L; Jaeschke, Hartmut (2018) Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity. Curr Pharmacol Rep 4:346-357
Ramachandran, Anup; Jaeschke, Hartmut (2018) Acetaminophen Toxicity: Novel Insights Into Mechanisms and Future Perspectives. Gene Expr 18:19-30
Ramachandran, Anup; Jaeschke, Hartmut (2018) Oxidative Stress and Acute Hepatic Injury. Curr Opin Toxicol 7:17-21
Woolbright, Benjamin L; Williams, C David; Ni, Hongmin et al. (2017) Microcystin-LR induced liver injury in mice and in primary human hepatocytes is caused by oncotic necrosis. Toxicon 125:99-109
Woolbright, Benjamin L; Bridges, Brian W; Dunn, Winston et al. (2017) Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18. Gene Expr 17:301-312
Woolbright, Benjamin L; Jaeschke, Hartmut (2017) Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. J Hepatol 66:836-848
Woolbright, Benjamin L; Ding, Wen-Xing; Jaeschke, Hartmut (2017) Caspase inhibitors for the treatment of liver disease: friend or foe? Expert Rev Gastroenterol Hepatol 11:397-399
Weemhoff, James L; Woolbright, Benjamin L; Jenkins, Rosalind E et al. (2017) Plasma biomarkers to study mechanisms of liver injury in patients with hypoxic hepatitis. Liver Int 37:377-384

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