Chemokine regulation of liver injury and recovery

描述(申请人提供)：肝脏在切除或大量损伤后再生的能力是独一无二的，以恢复原来的实质质量、结构和功能。肝切除或严重损伤后的再生依赖于高度调控的分子和细胞事件序列。细胞因子和生长因子被认为是控制肝细胞增殖和复制的启动和进展以及一旦肝质量恢复后这一过程的终止的重要信号。我们目前关于肝再生的大部分知识都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无价的，但该模型在临床上与严重损伤后的肝脏恢复/再生无关，例如发生在肝移植、切除手术或肝创伤导致的缺血/再灌注后。在临床上，缺血/再灌注是肝细胞缺血/再灌注损伤的重要来源。在肝切除模型中，已经证明这些相同的CXC趋化因子直接刺激肝细胞增殖，从而促进肝再生。相反，我们使用肝脏缺血/再灌注模型进行的初步研究表明，这些趋化因子对肝脏的恢复和再生是有害的。此外，利用培养的原代肝细胞，我们发现低浓度的CXC趋化因子可以防止细胞死亡，而高浓度的CXC趋化因子则促进细胞死亡。因此，本研究的总体假设是，CXC趋化因子在肝切除和缺血/再灌流期间对肝细胞增殖和再生的不同作用与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CXCR1和CXCR2的表达随着这些侮辱的反应而不同，这也有助于产生可能对许多肝病/紊乱的治疗产生重大和即时影响的治疗剂。公共卫生相关性：本提案中概述的研究与公共健康相关，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。通过这些研究获得的知识将为现有治疗剂的临床应用提供科学基础，这些治疗剂可能对一些肝脏疾病/紊乱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.