CYTOKINES AND LIVER GROWTH BY PEROXISOME PROLIFERATORS

肝细胞保留响应于肝损伤或由于病毒感染、药物肝毒性、缺血性损伤、代谢性疾病和肝移植导致的质量损失而增殖的能力。虽然许多事件是重要的肝细胞增殖的代偿性肝生长模型，包括啮齿动物部分肝切除模型已被广泛的特点，肝细胞增殖的分子基础，在直接有丝分裂刺激过氧化物酶体增殖物（Pps）的反应还没有很好地理解。大鼠单次给予PP导致肝细胞DNA合成的初级促有丝分裂刺激，需要核激素受体蛋白PPARalpha的表达，并且在幅度上与代偿性肝生长模型中观察到的相当。单次给药PP-肝脏生长模型已适用于小鼠，以检查遗传靶向菌株的生长反应差异。在单剂量PP处理的小鼠中观察到的肝脏质量和NP细胞活化的显著变化已经确立了该实验用于检查信号传导途径的实用性，这些信号传导途径对于这些化合物刺激肝细胞生长是重要的。以前的研究人员对TNF-α的重要性得出了相互矛盾的结论。PP诱导的肝脏生长刺激的IL-6细胞因子活化途径。将通过以下特定目的来解决细胞因子信号传导途径对PP刺激的肝脏生长的贡献：（1）表征小鼠模型中PP单次给药后观察到的肝脏质量增加的基础。(2)检查IL-6信号通路对PP刺激的肝脏生长的潜在贡献。（3）通过检查不表达PPARalpha基因的小鼠对部分肝切除术的再生反应，评估PPARalpha功能对肝生长的重要性。通过过氧化物酶体增殖物激活途径对肝细胞增殖的基础的详细理解可能对未来开发在各种临床情况下增强肝脏再生能力的疗法有用。

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.