CYTOKINES AND LIVER GROWTH BY PEROXISOME PROLIFERATORS

肝细胞在病毒感染、药物肝毒性、缺血性损伤、代谢性疾病和肝移植后引起的肝损伤或质量损失时仍具有增殖能力。虽然在包括啮齿动物肝部分切除模型在内的代偿性肝生长模型中，许多对肝细胞增殖具有重要作用的事件已经被广泛地描述，但对过氧化体增殖物(PPS)直接促有丝分裂刺激的肝细胞增殖的分子基础还不是很清楚。在大鼠中，单次给药PP导致对肝细胞DNA合成的初级有丝分裂刺激，这需要核激素受体蛋白PPARpha的表达，并且在大小上与肝脏代偿性生长模型中看到的类似。单剂量PP-肝脏生长模型已经被适应于小鼠，以检查遗传靶标菌株的生长反应的差异。在单剂量PP处理的小鼠中观察到的肝脏质量和NP细胞激活的显著变化，为研究这些化合物刺激肝细胞生长的重要信号通路奠定了基础。之前的研究人员对肿瘤坏死因子-α的重要性得出了相互矛盾的结论。IL-6细胞因子激活途径在PP诱导的肝脏生长刺激中的作用。细胞因子信号通路在PP刺激的肝脏生长中的作用将通过以下特定目的来解决：(1)在小鼠模型中确定单剂量PP后观察到的肝脏质量增加的基础。(2)探讨IL-6信号通路在PP刺激的肝脏生长中的作用。(3)通过检测不表达PPARpha基因的小鼠肝部分切除后的再生反应，评估PPARpha功能对肝脏生长的重要性。详细了解过氧化体增殖物激活途径对肝细胞增殖的基础，可能有助于未来开发在各种临床情况下增强肝脏再生能力的治疗方法。

Liver cells retain the capacity to proliferate in response to hepatic injury or loss of mass as a result of viral infection, drug hepatotoxicity, ischemic injury, metabolic diseases and following liver transplantation. Although many of the events that are important for liver cell proliferation in compensatory liver growth models including the rodent partial hepatectomy model have been extensively characterized, the molecular basis for liver cell proliferation in response to direct mitogenic stimulation by peroxisome proliferators (Pps) is not well understood. Single dose PP-administration in the rat results in primary mitogenic stimulation of hepatocyte DNA synthesis that requires the expression of the nuclear hormone receptor protein PPARalpha, and is comparable in magnitude to that seen in compensatory hepatic growth models. A single dose PP-hepatic growth model has been adapted to the mouse in order to examine differences in the growth response in genetically targeted strains. The significant changes in liver mass and NP cell activation observed in single dose PP-treated mice have established the utility of this experimental for the examination of signaling pathways that are important for stimulating liver cell growth by these compounds. Previous investigators have arrived at conflicting conclusions regarding the importance of the TNF-alpha. IL-6 cytokine activation pathway for PP-induced liver growth stimulation. The contribution of cytokine signaling pathways to PP-stimulated hepatic growth will be addressed through the following specific aims: (1) Characterize the basis for the observed increase in liver mass following single dose PP- administration in the mouse model. (2) Examine the potential contributions of IL-6 signaling pathways to PP-stimulated hepatic growth. (3)Assess the importance of PPARalpha function for hepatic growth by examining the regenerative response to partial hepatectomy in mice that do not express the PPARalpha gene. A detailed understanding of the basis for liver cell proliferation by peroxisome proliferator activation pathways may be useful for future development of therapies that will augment the regenerative capacity of the liver in a variety of clinical situations.