阿那白滞素对缺血再灌注小鼠结肠癌肝脏微转移灶生长抑制机制探讨  

Anakinra inhibits the outgrowth of colorectal micrometastases in the ischemia-reperfusion treated mouse livers

作　　者：夏涛[1] 李威[1] 罗运生[1] 陈远健[1] 杨颢[1] 甘涛[1] 

机构地区：[1]柳州市人民医院胃肠外科,广西柳州545006

出　　处：《中华肿瘤防治杂志》2015年第14期1090-1095,共6页Chinese Journal of Cancer Prevention and Treatment

摘　　要：目的探讨白介素1(IL-1)受体拮抗剂阿那白滞素对缺血再灌注(ischemia-reperfusion,I/R)小鼠肝脏中结肠癌微转移灶生长影响及其机制。方法利用小鼠肝脏I/R模型和小鼠结肠癌CT26细胞肝转移模型,验证I/R对小鼠结肠癌肝脏微转移灶的促进作用,并观察阿那白滞素预处理对其的影响。以酶联免疫吸附测定(enzyme-linked immuno sorbent assay,ELISA)法检测血清及肝脏中白介素1α(IL-1α)、白介素1β(IL-1β)和肿瘤坏死因子α(tumor necrosis factorα,TNF-α),全自动干式生化分析仪检测血清中的丙氨酸氨基转移酶(alanine aminotransferase,ALT)和天冬氨酸氨基转移酶(aspartate transaminase,AST),采用比色法检测肝脏中髓过氧化物酶(myeloperoxidase,MPO),荧光实时定量PCR法(quantitative real-time PCR,qPCR)检测肝脏中白介素6(IL-6)、血管内皮生长因子(vascular endothelial growth factor,VEGF)、基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)和E选择素的mRNA表达。结果缺血再灌注后,血清及肝脏中IL-1α和IL-1β的含量显著上升。I/R小鼠肝脏结肠癌最大肿瘤体积、肿瘤总体积以及可见肿瘤数量分别为(43.3±18.4)cm3、(85.4±46.2)cm3和(9.0±5.1)个,而阿那白滞素预处理则对此具有显著的抑制作用,分别为(18.1±7.3)cm3、(35.0±10.0)cm3和(3.7±1.9)个,P值分别为0.000 4、0.008 5和0.013 1。与单独的肝脏I/R小鼠相比,阿那白滞素预处理后I/R组小鼠的肝脏炎症坏死,以及ALT、AST、MPO的相对活性和TNF-α均被显著抑制,而IL-6、VEGF、MMP-9和E选择素的mRNA表达也明显下降。结论肝脏I/R显著促进了结肠癌肝脏微转移灶的生长,而阿那白滞素预处理能够通过抑制I/R诱导的炎症损伤及促肿瘤生长细胞因子的表达抑制这种促生长作用。OBJECTIVE To investigate whether IL-1receptor antagonist Anakinra could impact on the outgrowth of colorectal micrometastases accelerated by liver ischemia-reperfusion（I/R）in the liver and its mechanism.METHODSWe used mice liver I/R model and mice colon cells CT26 liver metastasis model to examine the influence of anakinra on the growth of colon tumor in the I/R treated mouse livers.We detected the concentrations of IL-1α,IL-1βand TNF-αof serum and liver by ELSIA,serum ALT and AST by automatic biochemical analyzer,relative activity of MPO by colorimetry,and mRNA expressions of IL-6,VEGF,MMP-9and E-selectin of livers by quantitative real-time PCR.RESULTSThe results showed that I/R promoted the upregulation of IL-1αand IL-1βin the serum and liver in the mice.Pretreatment of anakinra inhibited the promotion of liver I/R treatment on the growth of colon tumor in the mouse livers.（Max tumor volume,（18.1±7.3）cm^3 vs.（43.3±18.4）cm^3（P=0.000 4）;total tumor volume,（35.0±10.0）cm^3 vs（85.4±46.2）cm^3,P=0.008 5;No.tumor per liver,（3.7±1.9）vs.（9.0±5.1）（P= 0.013 1）.Compared with the mice of CT26＋I/R group,those of CT26＋I/R＋Anakinra group had the lower inflammation necrosis,ALT,AST,MPO and TNF-α,and mRNA expressions of IL-6,VEGF,MMP-9and E-selectin in the livers.CONCLUSIONS Liver I/R significantly promoted the outgrowth of colorectal micrometastases in the mice liver.And anakinra pretreatment suppresses this promotive effect by inhibiting I/R-induced inflammation injury and the increase of tumor-promoted factors.

关 键 词：结直肠肿瘤 转移灶 缺血再灌注 阿那白滞素 白介素1 

分 类 号：R735.35[医药卫生—肿瘤]