Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection
Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection
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DOI：
10.1053/jhep.2003.50066
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发表时间：
2003-02-01
期刊：
影响因子：
13.5
通讯作者：
Kupiec-Weglinski, JW
中科院分区：
文献类型：
--
作者：
Shen, XD;Ke, BB;Kupiec-Weglinski, JW
缺血/再灌注（I/R）损伤是临床器官移植中的重要问题。越来越多的证据表明，T淋巴细胞，特别是活化的CD 4 + T细胞，在肝脏I/R损伤中起关键作用。本研究分析了信号转导子和转录激活子4（Stat 4）和Stat 6信号转导在肝I/R损伤中的作用。使用部分肺叶热缺血模型，评估野生型（WT）、T细胞缺陷、Stat 4-/Stat 6-缺陷敲除（KO）小鼠组的I/R损伤的程度/严重性。通过肝细胞损伤（血清丙氨酸氨基转移酶[SALT]水平）、中性粒细胞蓄积（髓过氧化物酶[MPO]活性）和组织学（Suzuki评分）评估，90分钟热缺血后6小时再灌注诱导WT和Stat 6 KO小鼠暴发性肝功能衰竭。相反，T细胞缺陷（nu/nu小鼠）或Stat 4信号传导的破坏（Stat 4 KO小鼠）减少了I/R损伤。与WT或Stat 6缺陷型T细胞的过继转移不同，输注Stat 4缺陷型T细胞未能恢复nu/nu小鼠的肝I/R损伤并阻止肿瘤坏死因子α（TNF-α）的产生。在Stat 4 KO受体中，TNF-α/Th 1型细胞因子信使RNA（mRNA）/蛋白质表达模式减少，沿着血红素加氧酶-1（HO-1）过表达伴随肝细胞保护作用。相比之下，HO-1抑制恢复了其他I/R抵抗性Stat 4科斯的肝损伤。总之，Stat 4信号传导是必需的，而Stat 4中断保护免受小鼠热肝I/R损伤。由Stat 4破坏提供的细胞保护仍然是HO-1依赖性的。
Ischemia/reperfusion (I/R) injury remains an important problem in clinical organ transplantation. There is growing evidence that T lymphocytes, and activated CD4+ T cells in particular, play a key role in hepatic I/R injury. This study analyzes the role of signal transducer and activator of transcription 4 (Stat4) and Stat6 signaling in liver I/R injury. Using a partial lobar warm ischemia model, groups of wild-type (WT), T cell-deficient, Stat4-/Stat6-deficient knockout (KO) mice were assessed for the extent/severity of I/R injury. Ninety minutes of warm ischemia followed by 6 hours of reperfusion induced a fulminant liver failure in WT and Stat6 KO mice, as assessed by hepatocellular damage (serum alanine aminotransferase [SALT] levels), neutrophil accumulation (myeloperoxidase [MPO] activity) and histology (Suzuki scores). In contrast, T cell deficiency (nu/nu mice) or disruption of Stat4 signaling (Stat4 KO mice) reduced I/R insult. Unlike adoptive transfer of WT or Stat6-deficient T cells, infusion of Stat4-deficient T cells failed to restore hepatic I/R injury and prevented tumor necrosis factor alpha (TNF-alpha) production in nu/nu mice. Diminished TNF-alpha/Th1-type cytokine messenger RNA (mRNA)/ protein elaborations patterns, along with overexpression of heme oxygenase-1 (HO-1)-accompanied hepatic cytoprotection in Stat4 KO recipients. In contrast, HO-1 depression restored hepatic injury in otherwise I/R resistant Stat4 KOs. In conclusion, Stat4 signaling is required for, whereas Stat4 disruption protects against, warm hepatic I/R injury in mice. The cytoprotection rendered by Stat4 disruption remains HO-1-dependent.