Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
J Surg Res. 2010 Aug;162(2):184-92. doi: 10.1016/j.jss.2009.03.057. Epub 2009 May 3.
Hepatic resection may be curative in patients with hepatobiliary malignancies but excessive loss of liver volume may cause hepatic dysfunction and increase susceptibility to subsequent postoperative infections and sepsis. Herein, we hypothesized that pretreatment with simvastatin may protect against lipopolysaccharide (LPS)-induced liver damage after partial hepatectomy.
Male C57Bl/6 mice underwent 68% hepatectomy and exposed to LPS after 24h. Animals were pretreated with simvastatin (0.02 and 0.2mg/kg). Serum alanine aminotransferase (ALT) and tumor necrosis factor-alpha (TNF-alpha) as well as leukocyte infiltration and hepatocyte apoptosis were examined 6h after LPS challenge. An in vitro endothelial cell adhesion assay was used to study the mechanisms of simvastatin on leukocyte adhesion and the role of P-selectin and lymphocyte function antigen-1 (LFA-1).
Partial hepatectomy increased the sensitivity of the remnant liver tissue to LPS-provoked tissue injury. Simvastatin pretreatment reduced the LPS-induced increase in serum levels of ALT by 65% in hepatectomized animals. Moreover, simvastatin decreased leukocyte infiltration and hepatocyte apoptosis in the liver remnant of endotoxemic mice. LPS-provoked serum levels of TNF-alpha were decreased by 83% in hepatectomized animals treated with simvastatin. TNF-alpha-induced leukocyte adhesion as well as P-selectin expression in endothelial cells and LFA-1 function were inhibited by simvastatin in vitro.
These novels findings demonstrate that simvastatin protects the remnant liver against endotoxemic injury following major hepatectomy. Thus, simvastatin reduced LPS-induced leukocyte recruitment and hepatocyte apoptosis in the liver remnant. One key mechanism appears to be related to the inhibition of TNF-alpha formation and function (P-selectin expression) as well as to direct actions on LFA-1 function. Thus, simvastatin may represent a novel therapeutic approach to prevent septic liver damage after partial liver resection.
肝切除术可能对肝胆恶性肿瘤患者具有治愈作用，但过度的肝体积损失可能导致肝功能障碍，并增加术后感染和脓毒症的易感性。在此，我们假设在部分肝切除术前应用辛伐他汀可能预防脂多糖（LPS）诱导的肝损伤。
雄性 C57Bl/6 小鼠行 68%肝切除术，术后 24 小时给予 LPS。动物预先用辛伐他汀（0.02 和 0.2mg/kg）处理。在 LPS 攻击后 6 小时，检测血清丙氨酸氨基转移酶（ALT）和肿瘤坏死因子-α（TNF-α）以及白细胞浸润和肝细胞凋亡。体外内皮细胞黏附实验用于研究辛伐他汀对白细胞黏附的作用机制以及 P-选择素和淋巴细胞功能相关抗原-1（LFA-1）的作用。
部分肝切除增加了剩余肝组织对 LPS 引起的组织损伤的敏感性。辛伐他汀预处理使肝切除动物的 LPS 诱导的血清 ALT 水平升高降低了 65%。此外，辛伐他汀降低了内毒素血症小鼠剩余肝脏中的白细胞浸润和肝细胞凋亡。辛伐他汀处理的肝切除动物的 LPS 诱导的血清 TNF-α水平降低了 83%。TNF-α诱导的白细胞黏附和内皮细胞 P-选择素表达以及 LFA-1 功能在体外被辛伐他汀抑制。
这些新发现表明，辛伐他汀可保护剩余肝脏免受大肝切除术后内毒素血症损伤。因此，辛伐他汀减少了 LPS 诱导的剩余肝脏中白细胞募集和肝细胞凋亡。一个关键机制似乎与抑制 TNF-α形成和功能（P-选择素表达）以及直接作用于 LFA-1 功能有关。因此，辛伐他汀可能代表预防部分肝切除术后脓毒症性肝损伤的一种新的治疗方法。
