Cyclopamine attenuates acute warm ischemia reperfusion injury in cholestatic rat liver: hope for marginal livers.
Cyclopamine attenuates acute warm ischemia reperfusion injury in cholestatic rat liver: hope for marginal livers.
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DOI：
10.1021/mp200115v
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发表时间：
2011-06-06
影响因子：
4.9
通讯作者：
Mahato RI
中科院分区：
文献类型：
--
作者：
Pratap A;Panakanti R;Yang N;Lakshmi R;Modanlou KA;Eason JD;Mahato RI
胆汁淤积是肝脏手术或移植患者因缺血再灌注（I/R）损伤导致即刻肝功能衰竭的重要危险因素。我们最近证明，在I/R之前用环巴胺（CYA）抑制Hedgehog（Hh）信号传导可预防肝损伤。在这项研究中，我们假设Hedgehog（Hh）信号可能调节胆汁淤积大鼠肝脏I/R损伤。通过胆管结扎（BDL）诱导胆汁淤积。BDL后7天，大鼠暴露于CYA或车辆7天，每天进行30分钟的缺血和4小时的再灌注前。测定Hh配体（音刺猬、Patched-1和胶质母细胞瘤-1）的表达、肝损伤评估、中性粒细胞浸润、细胞因子、脂质过氧化、细胞增殖和凋亡。在媒介物处理的BDL大鼠中观察到Hh配体的显著上调。I/R损伤叠加在这些动物上导致血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、总胆红素显著升高，伴有中性粒细胞募集和脂质过氧化增加。CYA预处理可降低组织学损伤和血清肝损伤标志物。CYA还减少中性粒细胞浸润、促炎细胞因子（例如α-平滑肌肌动蛋白和1型胶原蛋白的TNF-α和IL-1β表达），从而减少纤维化。此外，CYA治疗的动物显示减少的胆管细胞增殖和凋亡。CYA通过降低蛋白激酶B（Akt）和细胞外信号调节激酶（ERK）的活化来赋予肝脏保护作用。胆汁淤积中内源性Hh信号转导加重肝I/R期间的炎性损伤阻断Hh通路是限制胆汁淤积性边缘肝I/R损伤的一种临床相关的新方法。
Cholestasis is a significant risk factor for immediate hepatic failure due to ischemia reperfusion (I/R) injury in patients undergoing liver surgery or transplantation. We recently demonstrated that inhibition of Hedgehog (Hh) signaling with cyclopamine (CYA) before I/R prevents liver injury. In this study we hypothesized that Hedgehog (Hh) signaling may modulate I/R injury in cholestatic rat liver. Cholestasis was induced by bile duct ligation (BDL). Seven days after BDL, rats were exposed to either CYA or vehicle for 7 d daily before subjecting them to 30 min of ischemia and 4 h of reperfusion. Expression of Hh ligands (sonic hedgehog, Patched-1 and Glioblastoma-1), assessment of liver injury, neutrophil infiltration, cytokines, lipid peroxidation, cell proliferation and apoptosis were determined. Significant upregulation of Hh ligands was seen in vehicle treated BDL rats. I/R injury superimposed on these animals resulted in markedly elevated serum alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin accompanied with increased neutrophil recruitment and lipid peroxidation. Preconditioning with CYA reduced the histological damage and serum liver injury markers. CYA also reduced neutrophil infiltration, proinflammatory cytokines such as TNF-α and IL-1β expression of α-smooth muscle actin and Type 1 collagen resulting in reduced fibrosis. Furthermore CYA treated animals showed reduced cholangiocyte proliferation, and apoptosis. Hepatoprotection by CYA was conferred by reduced activation of protein kinase B (Akt) and extracellular signal regulated kinase (ERK). Endogenous Hh signaling in cholestasis exacerbates inflammatory injury during liver I/R. Blockade of Hh pathway represents a clinically relevant novel approach to limit I/R injury in cholestatic marginal liver.
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作者：
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通讯作者：
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10.1152/ajpgi.00318.2003
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