Gu Xiao-Ping, Xu Fu-Tao, Jiang Yong, Qiu Yu-Dong, Ding Yi-Tao
Department of Anesthesiology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, People's Republic of China.
Ann Clin Lab Sci. 2004 Spring;34(2):187-94.
This study investigated the effects of pyrrolidine dithiocarbamate (PDTC), a novel NF-kappaB inhibitor, on the expression of multiple inflammatory mediators and on neutrophilic inflammation of the graft in rats following liver transplantation. Orthotopic liver transplantation (OLT) was performed after 24 hr of cold storage using University of Wisconsin (UW) solution that contained various concentrations of PDTC. We determined the time course of NF-kappaB activation and of the expression of multiple inflammatory signals: tumor necrosis factor-alpha (TNF-alpha), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM)-1. Serum alanine aminotransferase (ALT), intrahepatic myeloperoxidase (MPO/WBC ratio, a measure of neutrophil accumulation), and Mac-1 expression (CD11b/CD18, a measure of circulating neutrophil activity) were also evaluated. The results showed that PDTC decreased OLT-induced NF-kappaB activation in a dose-dependent manner (from 20 mmol/L to 60 mmol/L), diminished TNF-alpha, CINC, and ICAM-1 protein levels in the graft, and reduced the OLT-induced increase of serum TNF-alpha level. Pretreatment with PDTC significantly suppressed OLT-induced neutrophilic inflammation of the graft. The PDTC-exposed livers (PDTC, 40 mmol/L), in comparison with the control livers, had a significant reduction of MPO/WBC ratio (7.04+/-0.97 vs 14.07+/-1.31) and Mac-1 expression (181+/-11.3% vs 281+/-13.2%) at 6 hr after reperfusion. Furthermore, PDTC inhibited the increase of serum ALT levels after liver transplantation. In conclusion, PDTC inhibited NF-kappaB activation and the expression of the inflammatory mediators. These effects were associated with improved graft viability through inhibited intrahepatic neutrophilic inflammation. A therapeutic strategy directed at inhibition of NF-kappaB activation within the transplanted liver might be effective in reducing intrahepatic neutrophilic inflammation, and be beneficial to prolonged graft storage.
本研究调查了新型核因子-κB（NF-κB）抑制剂吡咯烷二硫代氨基甲酸盐（PDTC）对肝移植大鼠移植物中多种炎症介质表达及中性粒细胞炎症的影响。采用含不同浓度PDTC的威斯康星大学（UW）溶液冷保存24小时后进行原位肝移植（OLT）。我们测定了NF-κB激活的时间进程以及多种炎症信号的表达：肿瘤坏死因子-α（TNF-α）、细胞因子诱导的中性粒细胞趋化因子（CINC）和细胞间黏附分子-1（ICAM）-1。还评估了血清丙氨酸氨基转移酶（ALT）、肝内髓过氧化物酶（MPO/白细胞比值，中性粒细胞积聚的指标）以及Mac-1表达（CD11b/CD18，循环中性粒细胞活性的指标）。结果显示，PDTC以剂量依赖性方式（从20 mmol/L至60 mmol/L）降低OLT诱导的NF-κB激活，减少移植物中TNF-α、CINC和ICAM-1蛋白水平，并降低OLT诱导的血清TNF-α水平升高。PDTC预处理显著抑制OLT诱导的移植物中性粒细胞炎症。与对照肝脏相比，在再灌注6小时时，暴露于PDTC的肝脏（PDTC，40 mmol/L）的MPO/白细胞比值（7.04±0.97对14.07±1.31）和Mac-1表达（181±11.3%对281±13.2%）显著降低。此外，PDTC抑制肝移植后血清ALT水平升高。总之，PDTC抑制NF-κB激活和炎症介质表达。这些作用与通过抑制肝内中性粒细胞炎症改善移植物活力相关。针对抑制移植肝内NF-κB激活的治疗策略可能有效减少肝内中性粒细胞炎症，并有利于延长移植物保存时间。
