Pim-3 protects against hepatic failure in D-galactosamine (D-GalN)-sensitized rats
Pim-3 protects against hepatic failure in D-galactosamine (D-GalN)-sensitized rats
复制标题
Pim-3 可预防 D-半乳糖胺 (D-GalN) 致敏大鼠的肝衰竭
DOI：
10.1111/j.1365-2362.2009.02235.x
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发表时间：
2010-02-01
影响因子：
5.5
通讯作者：
Luo, J.
中科院分区：
文献类型：
--
作者：
Liu, L. -M.;Zhang, J. -X.;Luo, J.
背景暴发性肝衰竭（FHF）由于大量肝细胞凋亡和出血坏死而导致死亡率高，需要开发针对肝细胞保护和再生的有效治疗方法。Pim-3是一种肝生长刺激因子，属于丝氨酸/苏氨酸激酶Pim-家族，其参与gp 130介导的细胞增殖诱导、信号转导和转录激活因子3（STAT 3）下游的细胞凋亡保护以及血管内皮生长因子-A依赖性血管发生和血管生成，材料与方法雄性Wistar大鼠同时腹腔注射脂多糖（LPS），（100 μ g kg（-1））和D-半乳糖胺（D-GalN）（600 mg kg（-1））。结果外源性Pim-3基因可保护LPS/D-GalN诱导的小鼠肝损伤，存活率达80%以上，并改善肝脏病理形态。Pim-3预处理组大鼠肝细胞凋亡阳性细胞比例和caspase-3活性水平明显降低。此外，外源性Pim-3显著抑制肝脏中肿瘤坏死因子-α和白细胞介素-1 β的表达，降低p53和诱导型一氧化氮合酶mRNA水平，但升高肝脏中Bcl-2家族的抗凋亡成员Bcl-2蛋白的水平。结论外源性Pim-3基因可通过抑制肝细胞凋亡，改善肝组织炎症反应，对大鼠FHF具有保护作用，其机制可能与抑制炎症介质的表达，促进抗凋亡蛋白Bcl-2的表达有关。
Background Fulminant hepatic failure (FHF) has a high mortality resulted from massive hepatic apoptosis and haemorrhage necrosis; it is required to develop a valid therapy directed towards hepatocyte protection and regeneration. Pim-3, a hepatic growth stimulator, belongs to the serine/threonine kinase Pim-family that has been implicated in gp130-mediated induction of cell proliferation, protection from apoptosis downstream of Signal transducer and activator of transcription 3 (STAT3) and vascular endothelial growth factor-A-dependent vasculogenesis and angiogenesis, thus is suggested to possibly play a role in the tissue repair of FHF.Materials and methods Male Wistar rats received simultaneous intraperitoneal injections of lipopolysaccharide (LPS) (100 mu g kg(-1)) and D-galactosamine (D-GalN) (600 mg kg(-1)). One day prior to LPS/D-GalN administration, naked plasmid or Ringer's solution was injected via tail vein by hydrodynamics-based procedure.Results Exogenous Pim-3 gene protected against LPS/D-GalN-induced lethality with survival rate of more than 80% and improved the hepatic pathomorphism. The fractions of hepatic apoptotic-positive cells and the levels of caspase-3 activity were markedly lower in Pim-3-pretreated rats. Furthermore, exogenous Pim-3 significantly inhibited expression of tumour necrosis factor-alpha and interleukin-1 beta in the liver, declined p53 and inducible nitric oxide synthase mRNAs levels, but elevated levels of Bcl-2 protein, an anti-apoptosis member of Bcl-2 family, in the liver. Exogenous Pim-3, however, showed little effect on expression of Bax, a pro-apoptosis member of Bcl-2 family.Conclusions Pim-3 gene could protect rats from FHF by inhibiting liver apoptosis and improving inflammatory response of liver tissues, which could be associated with inhibiting expression of inflammatory mediators and promoting expression of anti-apoptosis protein Bcl-2.