Department of Experimental Surgery, Academic Medical Center, Amsterdam, The Netherlands.
Antioxid Redox Signal. 2012 Oct 15;17(8):1109-23. doi: 10.1089/ars.2011.4291. Epub 2012 Jun 7.
The aim was to investigate the impact of ischemia-reperfusion (I/R) on intrahepatic oxidative stress, oxidative phosphorylation, and nucleotide metabolism in relation to liver damage and inflammation in cholestatic rats to elucidate the molecular mechanisms responsible for post-I/R pathogenesis during cholestasis.
Pre-I/R cholestatic livers exhibited mild hepatopathology in the form of oxidative/nitrosative stress, perfusion defects, necrosis and apoptosis, inflammation, and fibrosis. Plasma bilirubin concentration in cholestatic livers was 190 μM. I/R in cholestatic livers exacerbated hepatocellular damage and leukocyte infiltration. However, myeloperoxidase activity in neutrophils at 6 h reperfusion was not elevated in cholestatic livers compared to pre-I/R levels and to control (Ctrl) livers. At 6 h reperfusion, cholestatic livers exhibited severe histological damage, which was absent in Ctrl livers. Despite a lower antioxidative capacity after I/R, no cardiolipin peroxidation and equivalent reduced glutathione/oxidized glutathione ratios and Hsp70 levels were found in cholestatic livers versus Ctrls. Bilirubin acted as a potent and protective antioxidant. Postischemic resumption of oxidative phosphorylation in Ctrl livers proceeded rapidly and encompassed reactive hyperemia, which was significantly impaired in cholestatic livers owing to extensive vasoconstriction and perfusion defects. Normalization of intrahepatic energy status and nucleotide-based metabolic cofactors was delayed in cholestatic livers during reperfusion. Innovation and
Cholestatic livers possess sufficient antioxidative capacity to ameliorate radical-mediated damage during I/R. I/R-induced damage in cholestatic livers is predominantly caused by microvascular perfusion defects rather than exuberant oxidative/nitrosative stress. The forestalled rate of oxidative phophorylation and recovery of bioenergetic and possibly metabolic parameters during the early reperfusion phase are responsible for extensive liver damage.
本研究旨在探讨缺血再灌注（I/R）对胆汁淤积大鼠肝内氧化应激、氧化磷酸化和核苷酸代谢的影响，以及与肝损伤和炎症的关系，以阐明在胆汁淤积时导致 I/R 后发病机制的分子机制。
I/R 前胆汁淤积的肝脏表现出轻微的肝病理改变，包括氧化/硝化应激、灌注缺陷、坏死和凋亡、炎症和纤维化。胆汁淤积肝脏的血浆胆红素浓度为 190μM。I/R 在胆汁淤积的肝脏中加重了肝细胞损伤和白细胞浸润。然而，与 I/R 前水平和对照（Ctrl）肝脏相比，中性粒细胞的髓过氧化物酶活性在胆汁淤积的肝脏中在再灌注 6 小时时并未升高。再灌注 6 小时时，胆汁淤积的肝脏表现出严重的组织学损伤，而对照肝脏则没有。尽管 I/R 后抗氧化能力降低，但在胆汁淤积的肝脏中未发现心磷脂过氧化，且还原型谷胱甘肽/氧化型谷胱甘肽比值和 Hsp70 水平与对照肝脏相当。胆红素是一种有效的保护抗氧化剂。Ctrl 肝脏在再灌注后氧化磷酸化的恢复迅速进行，包括反应性充血，而由于广泛的血管收缩和灌注缺陷，胆汁淤积的肝脏中这种充血显著受损。在再灌注期间，胆汁淤积的肝脏中肝内能量状态和核苷酸代谢辅助因子的正常化被延迟。
胆汁淤积的肝脏具有足够的抗氧化能力，可以减轻 I/R 期间自由基介导的损伤。胆汁淤积肝脏的 I/R 损伤主要是由微血管灌注缺陷引起的，而不是过度的氧化/硝化应激。在早期再灌注阶段，氧化磷酸化的恢复速度和生物能量学以及可能的代谢参数的恢复延迟是导致广泛肝损伤的原因。
