Department of Surgery, Royal Free Hospital and University College London, London, UK.
J Gastroenterol Hepatol. 2010 Dec;25(12):1891-9. doi: 10.1111/j.1440-1746.2010.06312.x.
Liver transplantation and resection surgery involve a period of ischemia and reperfusion to the liver, which initiates an inflammatory cascade resulting in liver and remote organ injury. Bucillamine is a low molecular weight thiol antioxidant that is capable of rapidly entering cells. We hypothesized that bucillamine acts by replenishing glutathione levels, thus reducing neutrophil activation, modulating Bax/Bcl-2 expression, and subsequently, attenuating the effects of warm ischemia-reperfusion injury (IRI) in the liver.
The effect of bucillamine was studied in a rat model of liver IRI with 45 min of partial (70%) liver ischemia and 3 h of reperfusion. Liver injury was assessed by measuring serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and liver histology. Oxidative stress was quantified by measuring F(2) isoprostane and glutathione levels. Leukocyte adhesion was assessed by intravital microscopy, and inflammatory cytokine response was assessed by measuring serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels. Bax and Bcl-2 expression was measured by reverse transcription-polymerase chain reaction.
The model produced significant liver injury with elevated transaminases and an acute inflammatory response. Bucillamine reduced the liver injury, as indicated by reduced AST (932 ± 200.8 vs 2072.5 ± 511.79, P < 0.05). Bucillamine reduced Bax expression, serum CINC-1 levels, and neutrophil adhesion, and upregulated Bcl-2. However, bucillamine did not affect tissue glutathione levels nor the levels of oxidative stress, as measured by plasma and hepatic F(2) isoprostane levels.
Bucillamine reduces warm ischemia-reperfusion in the liver by inhibiting neutrophil activation and modulating Bax/Bcl-2 expression.
肝移植和切除术涉及肝脏的缺血再灌注期，这会引发炎症级联反应，导致肝脏和远处器官损伤。丁硫氨酸氨苯砜是一种低分子量硫醇抗氧化剂，能够快速进入细胞。我们假设丁硫氨酸氨苯砜通过补充谷胱甘肽水平来发挥作用，从而减少中性粒细胞的激活，调节 Bax/Bcl-2 的表达，从而减轻肝脏的热缺血再灌注损伤 (IRI) 的影响。
我们在大鼠肝脏 IRI 模型中研究了丁硫氨酸氨苯砜的作用，该模型采用 45 分钟部分（70%）肝缺血和 3 小时再灌注。通过测量血清转氨酶（天冬氨酸氨基转移酶 [AST] 和丙氨酸氨基转移酶 [ALT]）和肝脏组织学来评估肝损伤。通过测量 F(2) 异前列烷和谷胱甘肽水平来量化氧化应激。通过活体显微镜评估白细胞黏附，通过测量血清细胞因子诱导的中性粒细胞趋化因子-1 (CINC-1) 水平来评估炎症细胞因子反应。通过逆转录-聚合酶链反应测量 Bax 和 Bcl-2 的表达。
该模型产生了显著的肝损伤，伴有转氨酶升高和急性炎症反应。丁硫氨酸氨苯砜减少了肝损伤，AST 降低（932±200.8 与 2072.5±511.79，P<0.05）。丁硫氨酸氨苯砜降低了 Bax 表达、血清 CINC-1 水平和中性粒细胞黏附，并上调了 Bcl-2。然而，丁硫氨酸氨苯砜并未影响组织谷胱甘肽水平，也未影响血浆和肝 F(2) 异前列烷水平所测量的氧化应激水平。
丁硫氨酸氨苯砜通过抑制中性粒细胞激活和调节 Bax/Bcl-2 的表达来减少肝脏的热缺血再灌注。
