CXC chemokines and liver regeneration

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DESCRIPTION (provided by applicant): 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.