Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Transplantation. 2010 May 15;89(9):1050-6. doi: 10.1097/TP.0b013e3181d45a98.
BACKGROUND.: A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia/reperfusion injury, a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver ischemia/reperfusion injury. METHODS.: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 hr of reperfusion. The mice were given Sivelestat (100 mg/kg, subcutaneous) at 10 min before ischemia, 10 min before reperfusion, and at 1 and 3 hr of reperfusion thereafter. RESULTS.: Sivelestat treatment significantly reduced serum alanine aminotransferase levels and NE activity, when compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), chemokines (CXCL-1, CXCL-2, and CXCL-10), and toll-like receptor 4 was significantly reduced in the treatment group, along with diminished apoptosis through caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of proinflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate toll-like receptor 4 signaling. CONCLUSION.: Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.
中性粒细胞弹性蛋白酶（NE）抑制剂西维来司他已被批准用于治疗与全身炎症相关的急性肺损伤。一些报告还显示其在肝脏炎症状态下具有保护作用。我们最近记录了 NE 在肝缺血/再灌注损伤的病理生理学中的重要性，这是一种局部 Ag 非依赖性炎症反应。本研究旨在探讨临床可用的西维来司他在肝缺血/再灌注损伤中的潜在保护作用。
对 C57BL/6 小鼠的左叶和中叶进行部分热缺血 90 分钟，然后再灌注 6 或 24 小时。在缺血前 10 分钟、再灌注前 10 分钟以及再灌注后 1 小时和 3 小时，给予西维来司他（100mg/kg，皮下）。
与对照组相比，西维来司他治疗可显著降低血清丙氨酸氨基转移酶水平和 NE 活性。组织学肝脏检查显示，与对照组不同，西维来司他可改善肝细胞损伤并减少局部中性粒细胞活性和浸润。治疗组促炎细胞因子（肿瘤坏死因子-α和白细胞介素-6）、趋化因子（CXCL-1、CXCL-2 和 CXCL-10）和 Toll 样受体 4 的表达明显减少，通过 caspase-3 途径减少凋亡。此外，体外研究证实，在小鼠巨噬细胞培养物中，西维来司他可下调促炎细胞因子和趋化因子程序，并抑制先天 Toll 样受体 4 信号。
西维来司他介导的 NE 抑制可能代表肝移植和其他炎症疾病状态的有效治疗选择。
