Menegazzi M, Carcereri-De Prati A, Suzuki H, Shinozuka H, Pibiri M, Piga R, Columbano A, Ledda-Columbano G M
Dipartimento di Biochimica, Università di Verona, Italy.
Hepatology. 1997 Mar;25(3):585-92. doi: 10.1002/hep.510250316.
Our previous studies have shown a different pattern of immediate early gene and growth factor gene expression between compensatory liver regeneration occurring after cell loss/death and direct hyperplasia induced by primary mitogens. In the present study, modifications in the activation of two transcription factors, NF-kappaB and AP-1; steady-state levels of tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA); and induction of the inducible nitric oxide synthase (iNOS) were examined in rat liver during different types of cell proliferation. Compensatory regeneration was induced in male Wistar rats by partial hepatectomy of two thirds (PH) or a necrogenic dose of CCl4 (2 mL/kg), whereas direct hyperplasia was induced by a single administration of the primary mitogens lead nitrate (LN, 100 micromol/kg), cyproterone acetate (CPA, 60 mg/kg), or nafenopin (NAF, 200 mg/kg). Liver regeneration after treatment with CCl4 was associated with an increase in steady-state levels of TNF-alpha mRNA, activation of NF-kappaB and AP-1, and induction of iNOS. A strong and prolonged activation of NF-kappaB but not of AP-1 was observed in LN-induced hyperplasia. LN also induced an increase in hepatic levels of TNF-alpha and iNOS mRNA. On the other hand, direct hyperplasia induced by two other primary mitogens, NAF and CPA, occurred in the complete absence of modifications in the hepatic levels of TNF-alpha mRNA, activation of NF-kappaB and AP-1, or induction of iNOS, although the number of hepatocytes entering S phase 18 to 24 hours after NAF was similar to that seen after PH. These results add further support to the hypothesis that cell proliferation occurring in the absence of cell loss/death may be triggered by unknown signaling pathways different from those responsible for the transition of hepatocytes from G0 to G1 after PH or cell necrosis.
我们之前的研究表明，细胞丢失/死亡后发生的代偿性肝再生与原发性促细胞分裂剂诱导的直接增生之间，即时早期基因和生长因子基因的表达模式有所不同。在本研究中，我们检测了大鼠肝脏在不同类型细胞增殖过程中，两种转录因子NF-κB和AP-1的激活变化；肿瘤坏死因子α（TNF-α）信使核糖核酸（mRNA）的稳态水平；以及诱导型一氧化氮合酶（iNOS）的诱导情况。通过对雄性Wistar大鼠进行三分之二肝部分切除术（PH）或给予致死剂量的四氯化碳（CCl4，2 mL/kg）来诱导代偿性再生，而通过单次给予原发性促细胞分裂剂硝酸铅（LN，100 μmol/kg）、醋酸环丙孕酮（CPA，60 mg/kg）或萘酚平（NAF，200 mg/kg）来诱导直接增生。用CCl4处理后的肝再生与TNF-α mRNA稳态水平的升高、NF-κB和AP-1的激活以及iNOS的诱导有关。在LN诱导的增生中观察到NF-κB的强烈且持续激活，但未观察到AP-1的激活。LN还诱导肝脏中TNF-α和iNOS mRNA水平升高。另一方面，由另外两种原发性促细胞分裂剂NAF和CPA诱导的直接增生，在TNF-α mRNA的肝脏水平、NF-κB和AP-1的激活或iNOS的诱导方面完全没有变化，尽管NAF处理后18至24小时进入S期的肝细胞数量与PH处理后相似。这些结果进一步支持了以下假说：在没有细胞丢失/死亡的情况下发生的细胞增殖可能由未知的信号通路触发，这些信号通路不同于PH或细胞坏死后负责肝细胞从G0期转变为G1期的信号通路。
