Department of Surgery, Section of Abdominal Transplantation, Washington University School of Medicine, St. Louis, MO, USA.
Transpl Immunol. 2012 Jun;26(4):201-6. doi: 10.1016/j.trim.2012.01.001. Epub 2012 Jan 21.
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 (0.1mg/kg) resulted in significant reduction in levels of activated NF-κB (0.58±0.18 vs. 1.37±0.06O.D./min/10 μg 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/2 μg protein, p=0.003) and IL-1β (6.0±0.91 vs. 19.8±5.2 vs. 5±1.7 pg/10 μg 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.
脂肪肝供肝对缺血再灌注（I/R）损伤的耐受性较差，这导致移植后原发性移植物无功能增加。I/R 损伤后核因子 kappa-B（NFκB）的激活在激活促炎反应导致损伤中起着至关重要的作用。
我们通过在 Zucker 大鼠（瘦鼠到瘦鼠或肥胖鼠到瘦鼠）的原位肝移植（OLT）模型中评估 NFκB 在脂肪肝损伤中的作用，以确定脂肪肝损伤的机制。肥胖供体接受硼替佐米治疗，以评估 NF-κB 在脂肪肝 I/R 损伤中的作用。通过 ELISA 分析肝组织中 NFκB 和促炎细胞因子的水平。通过血清转氨酶水平和组织病理学分析评估相关的移植物损伤。
脂肪肝供肝的 I/R 损伤导致 NF-κB（40%，p<0.003），特别是移植后 p65 亚基的激活显著增加。亲脂性供体预处理蛋白酶体抑制剂硼替佐米（0.1mg/kg）可显著降低激活的 NF-κB 水平（0.58±0.18 与 1.37±0.06O.D./min/10 μg 蛋白，p<0.003）。与对照治疗的脂肪肝和瘦鼠肝移植相比，硼替佐米治疗还降低了促炎细胞因子 MIP-2 的表达（106±17.5 与 443.3±49.9 与 176±10.6 pg/mL，p=0.02）、TNF-α（223.8±29.9 与 518.5±66.5 与 264.5±30.1 pg/2 μg 蛋白，p=0.003）和 IL-1β（6.0±0.91 与 19.8±5.2 与 5±1.7 pg/10 μg 蛋白，p=0.02），同时 ALT 水平也显著降低（715±71 与 3712.5±437.5 与 606±286 U/L，p=0.01）。
这些结果表明，脂肪肝肝移植的 I/R 损伤与 NFκB 亚基 p65 的过度激活有关，导致再灌注损伤和坏死的炎症机制。亲脂性供体的蛋白酶体抑制可减少 NFκB p65 的激活和炎症 I/R 损伤，改善大鼠模型中脂肪肝移植物的移植结果。
