CXC chemokines and liver regeneration

描述（由申请人提供）：肝损伤可能是由于感染，毒性或创伤性损伤，或肝脏炎症反应，并可能导致严重的健康问题。肝脏的再生和修复机制对肝脏损伤后的恢复至关重要，如果功能充分，可以使患者避免长期肝功能障碍或死亡。一种常见的肝损伤是部分肝切除术来治疗良性或恶性肝肿瘤。在这种情况下，肝脏肿块通常会在几周到几个月内自行恢复，并保持宿主的健康。偶尔，由于不明原因或由于潜在的肝脏疾病，肝脏的再生反应不足，无法补偿其减少的质量，导致患者因肝功能衰竭而死亡。除了支持性护理和肝移植，我们几乎没有治疗肝衰竭的方法。肝脏的修复机制很复杂，可能涉及免疫、炎症和再生因素。炎症是宿主对损伤和感染反应的关键部分，与组织修复和伤口愈合密切相关。炎症介质，如CXC趋化因子，对肝脏对损伤的反应至关重要。CXC趋化因子参与肝脏炎症；最近的数据表明，它们在肝损伤后的肝再生中也起重要作用。肝切除术后，MIP-2对启动肝再生很重要，可能通过改变肝细胞增殖和凋亡之间的平衡发挥作用。同样，虽然IP-10似乎没有直接的肝细胞增殖作用，但它可能通过上调CXCR2受体间接增强肝细胞增殖，这对MIP-2的细胞作用很重要。我们假设MIP-2通过两种机制起作用，促进肝细胞增殖，并具有抗凋亡保护作用。为了验证这一假设，我们将研究70%肝切除术后肝细胞增殖和凋亡的特异性mip -2相关机制，以及IP-10在该系统中的调节作用。

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.