Ischemia-reperfusion injury in rat steatotic liver is dependent on NF魏B P65 activation

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• 作者：Sabarinathan Ramachandran^a ; ¹ ; Jane M. Liaw^a ; ¹ ; Jianluo Jia^a ; Sean C. Glasgow^a ; Wei Liu^a ; Krista Csontos^a ; G.A. Upadhya^a ; T. Mohanakumar^a ; ^b ; William C. Chapman^a ; ^{chapmanwi@wudosis.wustl.edu}
• 关键词：IL-1尾 ; interleukin-1 beta ; I/R ; ischemia&ndash ; reperfusion ; Ln ; lean ; MIP-2 ; macrophage inflammatory protein-2 ; NF魏B ; nuclear factor kappa-B ; PS-341 ; bortezomib ; Ob ; obese ; OLT ; orthotopic liver transplant ; TNF-伪 ; tumor necrosis factor alpha
• 刊名：Transplant Immunology
• 出版年：2012
• 期刊代码：251_09663274
• 类别：med
• 出版时间：June, 2012
• 卷：26
• 期：4
• 页码：201-206
• 文件大小：746 K

摘要

Background

Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to increased primary graft nonfunction following transplantation. Activation of nuclear factor kappa-B (NF魏B) following I/R injury plays a crucial role in activation of pro-inflammatory responses leading to injury.

Methods

We evaluated the role of NF魏B 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-魏B in steatotic liver I/R injury. Hepatic levels of NF-魏B and pro-inflammatory cytokines were analyzed by ELISA. Serum transaminase levels and histopathological analysis were performed to assess associated graft injury.

Results

I/R injury in steatotic liver results in significant increases in activation of NF-魏B (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-魏B (0.58 卤 0.18 vs. 1.37 卤 0.06 O.D./min/10 渭g 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 卤 17.5 vs. 443.3 卤 49.9 vs. 176 卤 10.6 pg/mL, p = 0.02), TNF-伪 (223.8 卤 29.9 vs. 518.5 卤 66.5 vs. 264.5 卤 30.1 pg/2 渭g protein, p = 0.003) and IL-1尾 (6.0 卤 0.91 vs. 19.8 卤 5.2 vs. 5 卤 1.7 pg/10 渭g protein, p = 0.02) along with a significant reduction in ALT levels (715 卤 71 vs. 3712.5 卤 437.5 vs. 606 卤 286 U/L, p = 0.01).

Conclusion

These results suggest that I/R injury in steatotic liver transplantation are associated with exaggerated activation of NF魏B subunit p65, leading to an inflammatory mechanism of reperfusion injury and necrosis. Proteasome inhibition in steatotic liver donor reduces NF魏B p65 activation and inflammatory I/R injury, improving transplant outcomes of steatotic grafts in a rat model.