Nuclear factor {kappa}B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury.
Nuclear factor {kappa}B inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury.
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DOI：
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发表时间：
2005
期刊：
影响因子：
24.5
通讯作者：
H. Suetsugu;Y. Iimuro;T. Uehara;T. Nishio;N. Harada;M. Yoshida;E. Hatano;G. Son;J. Fujimoto
中科院分区：
文献类型：
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作者：
H. Suetsugu;Y. Iimuro;T. Uehara;T. Nishio;N. Harada;M. Yoshida;E. Hatano;G. Son;J. Fujimoto
背景在肝脏缺血/再灌注损伤中，活化的肝巨噬细胞(Kupffer细胞)主要受转录因子核因子kappaB(NFkappaB)的调控，涉及炎性细胞因子、急性时相反应蛋白和细胞黏附分子的表达。目的研究肝组织中NFkappaB的失活能否减轻全肝热缺血再灌注损伤。方法用腺病毒载体导入转基因大鼠，造成大鼠肝脏过度表达抑制因子kappaBalpha超抑制因子(IkappaBalpha SR)。在温热条件下，完全阻断肝十二指肠韧带结构20min，然后再灌流，造成肝脏缺血再灌注损伤。对照组包括未感染和对照病毒(AdLacZ)感染的大鼠。结果IkappaBalpha SR在Kupffer细胞和肝细胞中高表达，阻断再灌注后NFkappaB(P65)的核转位。IkappaBalpha SR基因转染组可显著减轻缺血再灌注损伤，抑制诱导型一氧化氮合酶和硝基酪氨酸的表达。此外，IkappaBalpha SR过表达未检测到明显的肝细胞凋亡。结论腺病毒转导IkappaBalpha SR基因可减轻肝脏短期热缺血再灌注损伤，其机制可能与抑制肝巨噬细胞活化有关。
BACKGROUND In hepatic ischaemia/reperfusion injury, activated liver macrophages (Kupffer cells) are dominantly regulated by a transcription factor, nuclear factor kappaB (NFkappaB), with respect to expression of inflammatory cytokines, acute phase response proteins, and cell adhesion molecules. AIMS We assessed whether inactivation of NFkappaB in the liver could attenuate total hepatic warm ischaemia/reperfusion injury. METHODS We studied rats with hepatic overexpression of inhibitor kappaBalpha super-repressor (IkappaBalpha SR) caused by a transgene introduced using an adenoviral vector. Hepatic ischaemia/reperfusion injury was induced under warm conditions by total occlusion of hepatoduodenal ligament structures for 20 minutes, followed by reperfusion. Controls included uninfected and control virus (AdLacZ) infected rats. RESULTS IkappaBalpha SR was overexpressed in Kupffer cells as well as in hepatocytes, blocking nuclear translocation of NFkappaB (p65) into the nucleus after reperfusion. Gene transfection with IkappaBalpha SR, but not with LacZ, markedly attenuated ischaemia/reperfusion injury, suppressing inducible nitric oxide synthase and nitrotyrosine expression in the liver. Moreover, no remarkable hepatocyte apoptosis was detected under IkappaBalpha SR overexpression. CONCLUSIONS Adenoviral transfer of the IkappaBalpha SR gene in the liver ameliorates short term warm ischaemia/reperfusion injury, possibly through attenuation of hepatic macrophage activation.