The liver is unique in its capacity to regenerate after resection or massive injury to restore original parenchymal mass, structure and function. Regeneration of the liver after resection or major injury is dependent upon a highly regulated sequence of molecular and cellular events. Cytokines and growth factors are known to serve as important signals controlling initiation and progression of hepatocyte proliferation and replication as well as termination of this process once liver mass has been restored. Much of our current knowledge regarding liver regeneration has been obtained using animal models of hepatectomy. While the information gained from these models has been invaluable, this model is not clinically relevant to liver recovery/regeneration after major injury, such as occurs after ischemia/reperfusion resulting from liver transplantation, resectional surgery or liver trauma. Ischemia/reperfusion represents a clinically relevant insultsignificant source of hepatocellular injury after ischemia/reperfusion. In models of hepatectomy, it has been shown that these same CXC chemokines directly stimulate hepatocytes to proliferate, thereby promoting liver regeneration. In contrast, our preliminary studies, using a model of hepatic ischemia/reperfusion, demonstrate that these chemokines are detrimental to liver recovery and regeneration. Furthermore, using cultured primary hepatocytes, we show that low concentrations of CXC chemokines prevent cell death whereas high concentrations promote cell death. Thus, the global hypothesis of this proposal is that the differential effects of CXC chemokines on hepatocyte proliferation and regeneration observed between hepatectomy and ischemia/reperfusion is directly related to the local concentration (expression) of CXC chemokines. In addition, we hypothesize that expression of the chemokine receptors, CXCR1 and CXCR2, differs in response to these insults and that this also contributeisting therapeutic agents that could have significant and immediate impact on the treatment of a number of liver diseases/disorders.

Public Health Relevance

The studies outlined in this proposal are relevant to public health because they will define the molecular events by which CXC chemokines regulate hepatocyte proliferation and regeneration. The knowledge gained by these studies will provide the scientific basis for the clinical application of existing therapeutic agents that could have significant and immediate impact on the treatment of a number of liver diseases/disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056029-14
Application #
8323573
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Sherker, Averell H
Project Start
2000-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$334,680
Indirect Cost
$121,508
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Wilson, Gregory C; Freeman, Christopher M; Kuethe, Joshua W et al. (2015) CXC chemokine receptor-4 signaling limits hepatocyte proliferation after hepatic ischemia-reperfusion in mice. Am J Physiol Gastrointest Liver Physiol 308:G702-9
Wilson, Gregory C; Kuboki, Satoshi; Freeman, Christopher M et al. (2015) CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration. PLoS One 10:e0120092
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Freeman, Christopher M; Quillin 3rd, Ralph C; Wilson, Gregory C et al. (2014) Characterization of microparticles after hepatic ischemia-reperfusion injury. PLoS One 9:e97945
Van Sweringen, Heather L; Sakai, Nozomu; Quillin, Ralph C et al. (2013) Roles of hepatocyte and myeloid CXC chemokine receptor-2 in liver recovery and regeneration after ischemia/reperfusion in mice. Hepatology 57:331-8
Sakai, Nozomu; Van Sweringen, Heather L; Schuster, Rebecca et al. (2012) Receptor activator of nuclear factor-ýýB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice. Hepatology 55:888-97
Sakai, Nozomu; Van Sweringen, Heather L; Quillin, R Cutler et al. (2012) Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice. Hepatology 56:1468-78
Zahedi, Kamyar; Barone, Sharon L; Xu, Jie et al. (2012) Hepatocyte-specific ablation of spermine/spermidine-N1-acetyltransferase gene reduces the severity of CCl4-induced acute liver injury. Am J Physiol Gastrointest Liver Physiol 303:G546-60
Sakai, Nozomu; Van Sweringen, Heather L; Belizaire, Ritha M et al. (2012) Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells. J Gastroenterol Hepatol 27:1609-16

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