Ischemia-reperfusion injury in rat steatotic liver is dependent on NFκB P65 activation.
Ischemia-reperfusion injury in rat steatotic liver is dependent on NFκB P65 activation.
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DOI：
10.1016/j.trim.2012.01.001
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发表时间：
2012-06
影响因子：
1.5
通讯作者：
Chapman WC
中科院分区：
文献类型：
--
作者：
Ramachandran S;Liaw JM;Jia J;Glasgow SC;Liu W;Csontos K;Upadhya GA;Mohanakumar T;Chapman WC
脂肪变性肝移植耐受缺血再灌注（I/R）损伤较差，导致移植后原发性移植物无功能增加。I/R损伤后核因子κ B（NFκB）的活化在导致损伤的促炎反应活化中起关键作用。我们通过Zucker大鼠原位肝移植（奥尔特）模型（瘦变瘦或肥胖变瘦）来评估NFκB在脂肪性肝损伤中的作用，以确定脂肪性肝损伤的机制。用硼替佐米治疗肥胖供体以评估NF-κB在脂肪肝I/R损伤中的作用。ELISA法检测肝脏NF-κB和促炎细胞因子水平。进行血清转氨酶水平和组织病理学分析以评估相关的移植物损伤。脂肪变性肝的I/R损伤导致NF-κB活化显著增加（40%，p<0.003），特别是移植后p65亚基。用蛋白酶体抑制剂硼替佐米（0.1 mg/kg）预处理脂肪变性供体导致活化的NF-κB水平显著降低（0.58±0.18 vs. 1.37±0.06 O.D./ min/10μg蛋白，p<0.003）。与对照组相比，硼替佐米治疗还分别降低了促炎细胞因子MIP-2的表达（106±17.5 vs. 443.3±49.9 vs. 176±10.6 pg/mL，p=0.02），TNF-α（223.8±29.9 vs. 518.5±66.5 vs 264.5±30.1 pg/2μg蛋白，p=0.003）和IL-1β（6.0±0.91 vs. 19.8±5.2 vs. 5±1.7 pg/10μg蛋白，p= 0.02），沿着ALT水平显著降低（715±71 vs. 3712.5±437.5 vs. 606±286 U/L，p=0.01）。这些结果提示脂肪变性肝移植中I/R损伤与NFκB B亚单位p65过度活化有关，导致再灌注损伤和坏死的炎症机制。脂肪变性肝供体中蛋白酶体抑制减少NFκB p65活化和炎性I/R损伤，改善大鼠模型中脂肪变性移植物的移植结果
Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to increased primary graft nonfunction following transplantation. Activation of nuclear factor kappa-B (NFκB) following I/R injury plays a crucial role in activation of pro-inflammatory responses leading to injury. We evaluated the role of NFκB in steatotic liver injury by using an orthotopic liver transplant (OLT) model in Zucker rats (lean to lean or obese to lean) to define the mechanisms of steatotic liver injury. Obese donors were treated with bortezomib to assess the role of NF-κB in steatotic liver I/R injury. Hepatic levels of NF-κB and pro-inflammatory cytokines were analyzed by ELISA. Serum transaminase levels and histopathological analysis were performed to assess associated graft injury. I/R injury in steatotic liver results in significant increases in activation of NF-κB (40%, p<0.003), specifically the p65 subunit following transplantation. Steatotic donor pretreatment with proteasome inhibitor bortezomib (0.1 mg/kg) resulted in significant reduction in levels of activated NF-κB (0.58±0.18 vs. 1.37±0.06 O.D./min/10μg protein, p<0.003). Bortezomib treatment also reduced expression of pro-inflammatory cytokines MIP-2 compared with control treated steatotic and lean liver transplants respectively (106±17.5 vs. 443.3±49.9 vs. 176±10.6 pg/mL, p=0.02), TNF-α (223.8±29.9 vs. 518.5±66.5 vs 264.5±30.1 pg/2μg protein, p=0.003) and IL-1β (6.0±0.91 vs. 19.8±5.2 vs 5±1.7 pg/10μg protein, p= 0.02) along with a significant reduction in ALT levels (715±71 vs 3712.5±437.5 vs 606±286 U/L, p=0.01). These results suggest that I/R injury in steatotic liver transplantation are associated with exaggerated activation of NFκB subunit p65, leading to an inflammatory mechanism of reperfusion injury and necrosis. Proteasome inhibition in steatotic liver donor reduces NFκB p65 activation and inflammatory I/R injury, improving transplant outcomes of steatotic grafts in a rat model.
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