Protective role of bortezomib in steatotic liver ischemia/reperfusion injury through abrogation of MMP activation and YKL-40 expression.
Protective role of bortezomib in steatotic liver ischemia/reperfusion injury through abrogation of MMP activation and YKL-40 expression.
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DOI：
10.1016/j.trim.2013.12.003
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发表时间：
2014-03
影响因子：
1.5
通讯作者：
Chapman WC
中科院分区：
文献类型：
--
作者：
Tiriveedhi V;Upadhya GA;Busch RA;Gunter KL;Dines JN;Knolhoff BL;Jia J;Sarma NJ;Ramachandran S;Anderson CD;Mohanakumar T;Chapman WC
脂肪变性肝移植耐受缺血再灌注（I/R）损伤差，导致移植后存活率低。然而，导致I/R损伤的分子机制仍有待确定。我们先前报道硼替佐米对肥胖大鼠肝移植模型中冷诱导的I/R损伤的保护作用是通过下调NF-κB。在本报告中，使用Zucker大鼠（从肥胖、瘦素缺乏供体到瘦受体）的原位肝移植（奥尔特）模型，我们定义了脂肪性肝损伤的机制，并表征了硼替佐米在抑制MMP活化和YKL-40中的作用，MMP活化和YKL-40均参与细胞外基质沉积和纤维化，这是肝移植失败的关键病理特征。用硼替佐米（i. v.，0.1 mg/kg）以评估MMP和YKL-40在脂肪变性肝I/R损伤中的作用。脂肪变性肝脏中的I/R损伤导致YKL-40表达显著增加（9倍），MMP-2活化（15倍）/MMP-9活化（12倍）。硼替佐米治疗将YKL-40和MMP的表达降低至基础水平。与未处理的I/R损伤动物相比，硼替佐米还显著抑制促纤维化（VEGF、HGF、bFGF、TGF-β）和促炎性（IL-1β、TNF-α和IFN-γ）细胞因子。这些结果表明，移植后脂肪变性肝脏中的I/R损伤与MMP活化和YKL-40上调相关，导致促纤维化和促炎细胞因子释放。蛋白酶体抑制剂硼替佐米的给药通过抑制MMP和YKL-40的表达有效地减轻了I/R损伤，因此支持该药物在供体管理中预防I/R损伤及其后遗症的临床效用。
Steatotic liver grafts tolerate ischemia–reperfusion (I/R) injury poorly, contributing to poor survival following transplantation. However the molecular mechanisms leading to I/R injury still remain to be defined. We have previously reported that the protective effect of bortezomib towards inhibiting cold induced I/R injury in obese rat liver transplant model is through NF-κB down modulation. In this report using an orthotopic liver transplant (OLT) model in Zucker rats (from obese, leptin deficient donor, to lean recipient) we defined the mechanisms of steatotic liver injury, and characterized the role of bortezomib in inhibiting MMP activation and YKL-40, both of which are involved in extracellular matrix deposition and fibrosis, the key pathological features of liver allograft failure. Obese donor rats were treated with bortezomib (i.v., 0.1 mg/kg immediately prior to liver procurement) to assess the role of MMP and YKL-40 in steatotic liver I/R injury. I/R injury in steatotic livers resulted in significant increases in expression of YKL-40 (9 fold), and activation of MMP-2 (15 fold)/MMP-9 (12 fold). Bortezomib treatment reduced the expression of YKL-40 and MMP to basal levels. Bortezomib also inhibited the pro-fibrotic (VEGF, HGF, bFGF, TGF-β) and pro-inflammatory (IL-1β, TNF-α and IFN-γ) cytokines significantly in comparison to untreated animals with I/R injury. These results demonstrate that I/R injury in steatotic livers following transplantation are associated with MMP activation and YKL-40 upregulation resulting in pro-fibrotic and pro-inflammatory cytokine release. Administration of the proteosomal inhibitor, bortezomib, effectively attenuated the I/R injury by inhibiting MMP and YKL-40 expression and therefore support the clinical utility of this drug in donor management for preventing I/R injury and its sequelae.
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影响因子：
37.8
作者：
Cheung, PY;Sawicki, G;Schulz, R
通讯作者：
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影响因子：
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Ramachandran S;Liaw JM;Jia J;Glasgow SC;Liu W;Csontos K;Upadhya GA;Mohanakumar T;Chapman WC
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