Chemokine regulation of liver injury and recovery

描述（由申请人提供）：肝脏在切除或大面积损伤后再生以恢复原始实质质量、结构和功能的能力是独特的。切除或严重损伤后肝脏的再生依赖于高度调节的分子和细胞事件序列。已知细胞因子和生长因子充当控制肝细胞增殖和复制的起始和进展以及一旦肝质量已经恢复就终止该过程的重要信号。我们目前关于肝再生的知识大部分是通过肝切除的动物模型获得的。虽然从这些模型中获得的信息是非常宝贵的，但该模型与严重损伤后的肝脏恢复/再生没有临床相关性，例如由肝移植、切除手术或肝创伤引起的缺血/再灌注后发生的情况。缺血/再灌注是缺血/再灌注后肝细胞损伤的一个临床相关的重要来源。在肝切除模型中，已经显示这些相同的CXC趋化因子直接刺激肝细胞增殖，从而促进肝再生。相反，我们的初步研究，使用肝缺血/再灌注模型，表明这些趋化因子对肝脏恢复和再生是有害的。此外，使用培养的原代肝细胞，我们表明，低浓度的CXC趋化因子防止细胞死亡，而高浓度促进细胞死亡。因此，该提议的总体假设是，在肝切除术和缺血/再灌注之间观察到的CXC趋化因子对肝细胞增殖和再生的差异作用与CXC趋化因子的局部浓度（表达）直接相关。此外，我们假设趋化因子受体CXCR 1和CXCR 2的表达在对这些损伤的反应中不同，并且这也有助于对许多肝脏疾病/病症的治疗产生显著和直接影响的治疗剂。公共卫生相关性：本提案中概述的研究与公共卫生相关，因为它们将定义CXC趋化因子调节肝细胞增殖和再生的分子事件。这些研究获得的知识将为现有治疗药物的临床应用提供科学依据，这些药物可能对许多肝脏疾病/病症的治疗产生重大和直接的影响。

DESCRIPTION (provided by applicant): 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.