Liver injury can be due to infection, toxic or traumatic insults, or the hepatic inflammatory response and can cause significant health problems. The liver's regenerative and reparative mechanisms are critically important for hepatic recovery after an insult, and if functioning adequately, allow patients to avoid long term liver dysfunction or death. A common liver injury is partial hepatectomy to treat benign or malignant liver tumors. In this case, hepatic mass typically restores itself within weeks to months, with continued health of the host. Occasionally, for unclear reasons or due to underlying liver disease, the liver's regenerative response is insufficient and it is unable to compensate for its decreased mass, resulting in patient death from liver failure. Aside from supportive care and hepatic transplantation, we have few therapeutic modalities to treat the failing liver. The liver's repair mechanisms are complex and likely involve immune, inflammatory, and regenerative factors. Inflammation is a critical part of the host response to injury and infection and is intimately tied to tissue repair and wound healing. Inflammatory mediators, such as the CXC chemokines, are essential for the liver's response to injury. The CXC chemokines are involved in hepatic inflammation; recent data suggests that they also play an important role in hepatic regeneration following liver injury. Following hepatectomy, MIP-2 is important for initiating liver regeneration, and may function by altering the balance between hepatocyte proliferation and apoptosis. Similarly, while IP-10 does not appear to have direct hepatoproliferative effects, it indirectly augments hepatocyte proliferation in vivo, likely by upregulation of the CXCR2 receptor, which is important for MIP-2's cellular effects. We hypothesize that MIP-2 functions by two mechanisms, enhancing hepatocyte proliferation, as well as having anti-apoptotic protective effects. To investigate this hypothesis, we will examine specific MIP-2-related mechanisms of hepatocyte proliferation and apoptosis following 70% hepatectomy, as well as IP-10's modulating effects in this system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK053224-06A2
Application #
6862507
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Serrano, Jose
Project Start
1998-05-01
Project End
2010-04-30
Budget Start
2005-06-01
Budget End
2006-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$317,944
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Ren, Xiaodan; Hu, Bin; Colletti, Lisa M (2010) IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol 298:G74-80
Hu, Bin; Colletti, Lisa M (2010) CXC receptor-2 knockout genotype increases X-linked inhibitor of apoptosis protein and protects mice from acetaminophen hepatotoxicity. Hepatology 52:691-702
Hu, Bin; Colletti, Lisa M (2008) Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice. Am J Physiol Gastrointest Liver Physiol 295:G45-G53
Ren, Xiaodan; Hu, Bin; Colletti, Lisa (2008) Stem cell factor and its receptor, c-kit, are important for hepatocyte proliferation in wild-type and tumor necrosis factor receptor-1 knockout mice after 70% hepatectomy. Surgery 143:790-802
Ren, Xiaodan; Hogaboam, Cory; Carpenter, Audra et al. (2003) Stem cell factor restores hepatocyte proliferation in IL-6 knockout mice following 70% hepatectomy. J Clin Invest 112:1407-18
Ren, Xiaodan; Carpenter, Audra; Hogaboam, Cory et al. (2003) Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse. Am J Pathol 163:563-70