Hepatic expression of S32A/S36A IκBα does not reduce postischemic liver injury
Hepatic expression of S32A/S36A IκBα does not reduce postischemic liver injury
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DOI：
10.1016/j.jss.2004.10.023
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发表时间：
2005-04-01
影响因子：
2.2
通讯作者：
Lentsch, AB
中科院分区：
文献类型：
--
作者：
Okaya, T;Lentsch, AB
背景在肝缺血/再灌注损伤期间，转录因子NF-κ B的活化与促炎介质表达相关，并且被认为是再灌注后炎症反应的初始触发因素之一。在本研究中，我们试图确定体内腺病毒转染不能被丝氨酸磷酸化或降解的κ B-α（I κ B α）突变抑制剂（I κ B α SR）是否会抑制NF-κ B并改善肝脏对缺血/再灌注的炎症反应。对雄性C57 BL/6小鼠进行假手术或部分肝缺血（90分钟）和再灌注（长达8小时）。在诱导缺血前3天，用1 × 10（9）PFU含有β-半乳糖苷酶（LacZ）或I κ B α SR的腺病毒感染小鼠。在不同的时间点获得血清和组织用于分析。在未经处理的小鼠中，I κ B α的降解，发生在丝氨酸磷酸化后，在肝脏缺血结束时和早期再灌注过程中是明显的。转染I κ B α SR的小鼠表现出与LacZ转染小鼠相同程度的炎症和肝细胞损伤。LacZ和I kappa B alpha SR转染的肝脏在NF-κ B激活或促炎细胞因子产生方面没有差异。这些数据表明，涉及I κ B α丝氨酸磷酸化的NF-κ B活化途径不是诱导缺血/再灌注后肝脏炎症的主要机制，并表明替代途径，如I κ B α酪氨酸磷酸化，可能是肝脏缺血后反应所必需的。(C)2005年爱思唯尔公司All rights reserved.
Background. Activation of the transcription factor, NF-kappa B, during hepatic ischemia/reperfusion injury is associated with proinflammatory mediator expression and is thought to be one of the initial triggers for the inflammatory response after reperfusion. In the current study, we sought to determine whether in vivo adenoviral transfection of a mutant inhibitor of kappa B-alpha (I kappa B alpha), which cannot be serine phosphorylated or degraded (I kappa B alpha SR), would inhibit NF-kappa B and ameliorate the hepatic inflammatory response to ischemia/reperfusion.Materials and methods. Male C57BL/6 mice were subjected to sham surgery or partial hepatic ischemia (90 min) and reperfusion (up to 8 h). Mice were infected with 1 x 10(9) PFU of adenovirus containing either beta-galactosidase (LacZ) or I kappa B alpha SR 3 days prior to induction of ischemia. Serum and tissues were obtained at various times for analysis.Results. In unmanipulated mice, degradation of I kappa B alpha, as occurs after serine phosphorylation, was evident in liver by the end of ischemia and during early reperfusion. Mice transfected with I kappa B alpha SR displayed the same degree of inflammation and hepatocellular injury as LacZ-transfected mice. There was no difference between LacZ- and I kappa B alpha SR-transfected livers in terms of NF-kappa B activation or proinflammatory cytokine production.Conclusions. The data demonstrate that the pathway of NF-kappa B activation involving serine phosphorylation of I kappa B alpha is not the primary mechanism for induction of liver inflammation after ischemia/reperfusion and suggest that alternative pathways, such as tyrosine phosphorylation of I kappa B alpha, may be essential for the postischemic response in liver. (C) 2005 Elsevier Inc. All rights reserved.