IL-18Ab拮抗BCG+LPS诱导的小鼠急性免疫性肝坏死的实验研究
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摘要
病毒性肝炎的发病机理与免疫功能紊乱有关，从目前资料来看，它与Th1细胞因子介导的细胞毒性作用密切相关，常与一系列细胞因子组成的反应链有关，其中IL-18是最嘱目的一种，由这种前卫因子诱发的一系列细胞因子级联反应，导致组织凋亡、炎症、坏死，因此造成严重肝组织严重损伤，甚至导致肝功能衰竭，危及生命。本实验通过建立BCG+LPS诱导的小鼠急性肝坏死模型，在此基础上，早期使用IL-18抗体阻断IL-18的作用，从而阻断了介导肝脏凋亡、炎症、坏死的反应链，保护肝组织免受损伤。通过动物实验，初步探讨IL-18在急性免疫性肝损伤中的意义，及早期使用IL-18抗体及时阻断细胞因子级联反应对保护肝组织的重要性。
在小鼠IL-18人工合成的基础上，实验又分成二个步骤：首先用小鼠IL-18(10uS／次／只)分别与等体积福氏完全或不完全佐剂混合，按免疫程序制备小鼠抗IL-18抗血清，用ELISA法检测血清抗体效价，抗体效价为等体积50％抑制的IL-18浓度为400pg／ml。第二步，在拮抗小鼠免疫性肝坏死实验中，每只小鼠腹腔注射卡介苗(BCG)100mg／kg，十天后再腹腔注射内毒素(LPS)1 mg／kg来诱导小鼠的急性免疫性肝坏死，在设立BCG免疫激活对照组的基础上，按注射LPS前半小时的处理条件不同，即是否施予抗Il-18血清(0.2ml／只)，设立抗IL-18抗体治疗组、模型组，注射小剂量LPS(1mg／kg)24小时后观察各组小鼠肝组织的病理改变，并测定其血清IL-18的水平及肝组织表达的IL-18、IFN-γ、TNF-α mRNA的水平的差异。结果显示：在模型组中，小鼠肝组织病变明显，可见大片肝脏组织坏死，其炎症活动度计分显著高于治疗组及对照组(P＜0.01)，其血清IL-18的水平及肝组织表达的IL-18、IFN-γ、TNF-α mRNA的水
1L一1 SAb拮抗BC份LPS诱导的小眼急性免疫性肝坏死的实验研究
中文摘要
平也明显高于其它两组(P<0 .01)。通过相关分析发现，肝组织的炎症活动
度与血清IL一18的水平及肝组织表达的IL一18、IFN一Y、INF一a mRNA的
水平均呈明显的正相关关系，其r值，p值在统计学上均有显著差异。
实验提示:IL一18在急性免疫性肝损伤中起到重要作用，有明显的致
凋亡、致炎及致组织细胞坏死的作用，IL一18处于THI细胞因子级联反
应的前面，能自我正反馈调节促进炎症损伤的发展。通过中和 IL一18的
生物活性，能阻断肝组织的凋亡、炎症、坏死的进一步发展，对肝组织
有良好的保护作用。为治疗急性及重型肝炎提供了一个新的思路和方法。
Mechanism of viral hepatitis is intimately correlation with disorder of immune system mediated by cytotoxicity of Thl cell. It is usually correlation with reaction chain induced by a series of cytokines, and IL-18 is the notablest one in series of cytokines which constituted cascade reaction chain. It may induce tissue apoptosis, inflammation, necrosis, and led to serious injury in liver, even to acute liver function failure and endanger the suffering life. By setting up hepatic necrosis model induced with BCG+LPS, we investigated the effect of IL-18 antibody to counteract action of IL-18, so as to block the reaction chain leading to hepatic apoptosis, inflammation, necrosis and kept hepatic tissue away from damage in earlier period. To study rudimentarily the role of IL-18 in acute immunity hepatic injury, and the important of blocking cascade reaction of cytokines by exerting IL-18 antibody in early stage.
Based on the artificial Synthesis of mouse IL-18, experiment devide into two procedur: the first step, immunised mice used mixture of mouse IL-18 (10ug/time/each) added equal volume FCA or FIA, got the anti-IL-18 serum of mice according to immune procedure , detected the value of anti-IL-18 serum with ELISA: the concentration of the equal volum IL-18 50% Inhibited is 400pg/ml. The secondary step, in the experiment of counteracting acute immunity hepatic necrosis of mice induced by BCG+LPS. the models of acute immunity hepatic necrosis were induced by BCG 100 mg/kg via abdominal cavity injection and LPS 1 mg/kg was added after 10 days. Based on setting up BCG matched control, mice were divide
into two groups, anti-IL-18 antibody treatment group and model group, according to the different of disposal condition, exerting anti-IL-18 serum on mice (each 0.2ml) or not before the injection of LPS (lmg/kg) and then observed mice liver inflammation activity, detected serum IL-18 level and the expression level of IL-18 mRNA, TNF-alpha mRNA, IFN-gamma mRNA of the Liver tissue in each groups 24 hours later. The results displayed that mice's liver inflammation was notable, mass necrosis was observed in the model group and the count scores of inflammation activity was marked higher than the other two groups (P<0.01), so did the serum IL-18 level and the expression level of IL-18 mRNA, TNF- alpha mRNA, IFN-gamma mRNA of the Liver tissue(P<0.01). Correlation analysis suggested that inflammation activity was positive correlation with serum IL-18 level, the expression level of IL-18 mRNA, TNF-alpha mRNA and IFN-gamma mRNA of the Liver tissue. Their r value and p value have all significant differences in statistic
s.
This experiment indicated that IL-18 played an important role in acute immunity hepatic injury before the cascade reaction of Thl cytokine which can accelerate markedly apoptosis and inflammation, and development of inflammation by self-positive feedback. By the neutralization of IL-18, IL-18 antibody can block the development of hepatic apoptosis, inflammation, necrosis and protect markedly the liver tissue from damage. It offered a new idea and method on treatment of acute and fulminate hepatitis.
在小鼠IL-18人工合成的基础上，实验又分成二个步骤：首先用小鼠IL-18(10uS／次／只)分别与等体积福氏完全或不完全佐剂混合，按免疫程序制备小鼠抗IL-18抗血清，用ELISA法检测血清抗体效价，抗体效价为等体积50％抑制的IL-18浓度为400pg／ml。第二步，在拮抗小鼠免疫性肝坏死实验中，每只小鼠腹腔注射卡介苗(BCG)100mg／kg，十天后再腹腔注射内毒素(LPS)1 mg／kg来诱导小鼠的急性免疫性肝坏死，在设立BCG免疫激活对照组的基础上，按注射LPS前半小时的处理条件不同，即是否施予抗Il-18血清(0.2ml／只)，设立抗IL-18抗体治疗组、模型组，注射小剂量LPS(1mg／kg)24小时后观察各组小鼠肝组织的病理改变，并测定其血清IL-18的水平及肝组织表达的IL-18、IFN-γ、TNF-α mRNA的水平的差异。结果显示：在模型组中，小鼠肝组织病变明显，可见大片肝脏组织坏死，其炎症活动度计分显著高于治疗组及对照组(P＜0.01)，其血清IL-18的水平及肝组织表达的IL-18、IFN-γ、TNF-α mRNA的水
1L一1 SAb拮抗BC份LPS诱导的小眼急性免疫性肝坏死的实验研究
中文摘要
平也明显高于其它两组(P<0 .01)。通过相关分析发现，肝组织的炎症活动
度与血清IL一18的水平及肝组织表达的IL一18、IFN一Y、INF一a mRNA的
水平均呈明显的正相关关系，其r值，p值在统计学上均有显著差异。
实验提示:IL一18在急性免疫性肝损伤中起到重要作用，有明显的致
凋亡、致炎及致组织细胞坏死的作用，IL一18处于THI细胞因子级联反
应的前面，能自我正反馈调节促进炎症损伤的发展。通过中和 IL一18的
生物活性，能阻断肝组织的凋亡、炎症、坏死的进一步发展，对肝组织
有良好的保护作用。为治疗急性及重型肝炎提供了一个新的思路和方法。
Mechanism of viral hepatitis is intimately correlation with disorder of immune system mediated by cytotoxicity of Thl cell. It is usually correlation with reaction chain induced by a series of cytokines, and IL-18 is the notablest one in series of cytokines which constituted cascade reaction chain. It may induce tissue apoptosis, inflammation, necrosis, and led to serious injury in liver, even to acute liver function failure and endanger the suffering life. By setting up hepatic necrosis model induced with BCG+LPS, we investigated the effect of IL-18 antibody to counteract action of IL-18, so as to block the reaction chain leading to hepatic apoptosis, inflammation, necrosis and kept hepatic tissue away from damage in earlier period. To study rudimentarily the role of IL-18 in acute immunity hepatic injury, and the important of blocking cascade reaction of cytokines by exerting IL-18 antibody in early stage.
Based on the artificial Synthesis of mouse IL-18, experiment devide into two procedur: the first step, immunised mice used mixture of mouse IL-18 (10ug/time/each) added equal volume FCA or FIA, got the anti-IL-18 serum of mice according to immune procedure , detected the value of anti-IL-18 serum with ELISA: the concentration of the equal volum IL-18 50% Inhibited is 400pg/ml. The secondary step, in the experiment of counteracting acute immunity hepatic necrosis of mice induced by BCG+LPS. the models of acute immunity hepatic necrosis were induced by BCG 100 mg/kg via abdominal cavity injection and LPS 1 mg/kg was added after 10 days. Based on setting up BCG matched control, mice were divide
into two groups, anti-IL-18 antibody treatment group and model group, according to the different of disposal condition, exerting anti-IL-18 serum on mice (each 0.2ml) or not before the injection of LPS (lmg/kg) and then observed mice liver inflammation activity, detected serum IL-18 level and the expression level of IL-18 mRNA, TNF-alpha mRNA, IFN-gamma mRNA of the Liver tissue in each groups 24 hours later. The results displayed that mice's liver inflammation was notable, mass necrosis was observed in the model group and the count scores of inflammation activity was marked higher than the other two groups (P<0.01), so did the serum IL-18 level and the expression level of IL-18 mRNA, TNF- alpha mRNA, IFN-gamma mRNA of the Liver tissue(P<0.01). Correlation analysis suggested that inflammation activity was positive correlation with serum IL-18 level, the expression level of IL-18 mRNA, TNF-alpha mRNA and IFN-gamma mRNA of the Liver tissue. Their r value and p value have all significant differences in statistic
s.
This experiment indicated that IL-18 played an important role in acute immunity hepatic injury before the cascade reaction of Thl cytokine which can accelerate markedly apoptosis and inflammation, and development of inflammation by self-positive feedback. By the neutralization of IL-18, IL-18 antibody can block the development of hepatic apoptosis, inflammation, necrosis and protect markedly the liver tissue from damage. It offered a new idea and method on treatment of acute and fulminate hepatitis.
引文
1 王泰龄，刘霞，周元平，等。炎症活动度及纤维化程度计分方案中华肝脏病杂志1998，6(4)：195-497
2 Salgame P, Abrams JS, Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11; 254(5029):279-282
3 Bertoletti A, D'Elios MM, Boni C, et al.Different cytokine profiles of intrahepatic T cell in chronic hepatitis B and hepatitis C virus infection J.gastroenterology, 1997 Jan, 112(1):193-199
4 Vingerhoets J, Michielsen P, Vanham G , et al. HBV-specific lymphoprofilerative and cytokine respones in patients with hepatitis B.J.Hepatology, 1998, 28:8-16.
5 姜荣龙，卢桥生，郭亚兵，等。Th1／Th2细胞在慢性乙型肝炎病毒感染中的作用 第一军医大学学报2000：20(2)：103-110
6 文维群，章廉，肖红，等。IL_18表达水平与HBC感染相关性的临床研究中华医学杂志2001，81(11)：655-658
7 王静艳，刘沛，孙金良，等。乙型病毒性肝炎患者血清，TNF-α、IFN-γ、IL-6和IL-8的检测意义 中国公共卫生1998，14(5)：262-263
8 张萍，吴文漪，魏来。乙型病毒性肝炎患者外周血T辅助细胞1、2型细胞因子含量的测定及临床意义 徐州医学院学报2001，21(4)：304-306
9 Yokochi S, Ishiwata Y, Hashimoto H, et al.Hepatoprective effect of propageermanium on Corynebacterium parvum and lipopolysaccharide-induced liver injury in mice. Scand J Immunol 1998 Aug,48(2):182-191
10 Yang TJ, Wei HL, Liu GT.Effects of 16 drugs on immunological liver injury induced by BCG+ lipopolysaccharide in mice. J. Zhongguo Yao Li Xue Bao 1997 Mar;18(2):185-188
11 Tsuji H, Mukaida N, Kaneko S, et al. Alleviation of lipopolysaccharide-induced IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12, and IL-18 production. J Immunol 1999 Jan 15;162(2):1049-1055
12 Hase K, Kadota S, Basnet P, et al. Protective effect of celosian, an acidic polysarride, on chemically and immunologically liver injuries. Biol Pham Bull 1996 Apr, 19(4):567-572
13 Santucci L, Fiorucci S, Cammilleri F , et al.Galeectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. Hepatology 2000 Feb;31(3):399-406
14 Matsui K, Yoshimoto T, Tsutsui H, et al. Propionibacterium acnes treatment dimishes CD4+NK1.1T cells but induces type-1 T cells in the liver by induction of IL-12 and IL-18 prouduction from Kuffer cells. J Immunol. 1997 Jul 1;159(1):97-106
15 Chang JT, Segal BM, Nakanishi K, et al.The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of
IL-12 receptor beta2 subnit. Eur J Immunol.2000Apr;30(4):1113-1119
16 Mishima S, Xu D, Lu Q.acterial translocation is inhibited in inducible nitric oxide sythase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth.Arch surg 1997 Nov;132(11):1190-1195
17 Roulston A, Lin R, Beauparlant P, et al. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors regulation of HIV-I and cytokin expression by NF-κB. Mcrobiol Rev,1995;59:481-505
18 Baeuerle PA.The inducible transerption activator NF-κB regulation by distinct protein subunits. Biochmica et Biophysica Acta.1991;1072(1):63—80
19 Grove M,Plumb M. C / EBP, NF-κB and c-Ets faimily memhers and transcrptional regulation of the cellspecific and iducible macrophage inflammatory protein-1 immediate-early gene. Mol CellBiol,1993,13:5276—5289
20 Dinarello CA.Interleukin-18, a proinflammatory cytokine.Eur Cytokine Netw 2000, sep,1(3):483-486
21 顾大勇，曾祥元。内毒素诱导肺血管内皮细胞ICAM-1的表达及NP-κ作用。中国微循环2002；2(6)：25-28
22 Schutt C. Fighting infection:the role of lipopolysaccharide binding proteins CD14 and LBP. Pathobiology,1999, 67(5-6):227-229
23 Su GL, Klein RD, Aminlari A, et al. kupffer cell activation by Lipopolysaccharide in rats:role for LBP and toil-like receptor 4.
Hepatology,2000, 31(4):932-936
24 Schumann RR, Zweigner J. A novel acute-phase maker:LPB. Clin Chem LAb Med, 1999, 37(3):271-274
25 Tsutsui H, Martsui K, Kawada N, et al. IL-18 accont for both TNF-alpha and Fasligand-mediated hepatotoxic phthways inendotoxin-induced liver injury in mice. J. Immonp;1997 Oct 15;159(8):3961-3967
26 袁建成，周立新，秦孝健，等。内毒素诱导的肝细胞及枯否细胞凋亡与肝脏损伤的关系。中华医学杂志，1998，78(6)：423-425。
27 Myers ML, Schook LB. immunotoxicity of nitrosamines. Experimental immunotoxicology.1996, pp.351-366
28 Leist M, Gantner F, Bohlinger L, et al.TNF-induced hepatocyapoptosis precedes liver failure in experiment murine shock models.Am J Path,1995,146:1220-1234
29 Tsutsui H, Martsui K, Okamara H, et al. Pathophysiological roles of interleukin-18 in inflammatory liver disease. Immunoiogical Reviews,2000,174:192-209
30 Luster MI, Simeonova PP,Gallucci RM,et al.Role of inflammation in chemical-induced hepatotoxity.Toxicology,2001,120:317-321
31 Ashkenazi A, Dixit VM. Death receptors:signaling and modulation.Scince,1998 Aug 28;281(5381):1305-1308
32 Ockner RK. Apoptosis and liver disease:Recent concepts of mechanism and significance. J Gastroenterol Hepatol 2001 Mar;16(3):248-260
33 Li Xk, Fujino M, Sugioka A, et al. Fulminant hepatitis by Fas-ligand
expression in MRL-lpr/lpr mice grafted with Fas-positive livers and wild-type mice with Fas-mutant livers.Transplantation.2001 Feb 27;71(4):503-508
34 Puren AJ, Fantozzi G; Dinarello CA. Gene expression, synthesis, and sercretion of interleukin-18 and interleukin-1 beta are differentially regulated in homan blood mononuclear cells and mouse spleen cells.Proc. Natl. Acod Sci. USA, 1999, 96:2256-2261
35 Lebel-Binay S, Berger A, Zinzindohoue F, et al. Interleukin-18:biological properties and clinical implications. Eur Cytokine Netw 2000 Mar;11(1):15-26
36 Hiroko T,Kiyoshi M, Haroki O. Pathophysiological roles of Interleukin-18 in inflammatory liver disease. Immunologyical Review,2000, 174:192-209
37 Fraser A, Evan G. A license to kill. Cell. 1996 Jun 14; 85(6):781-784.Review
38 Arnott ID, Drummond HE, Ghosh S. Gut luminal neutrophil migration is influenced by the anatomical site of Crohn's disease. Eur J Gastroenterol Hepatol. 2001 Mar;13(3):239-243
39 XQ,Leung BP,Arthur HM, et al. Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 2001 Jan 1;166(1):517-521
40 Kawaguchi Y, Terajima H, Harigai M.Interleukin-18 as a novel diagnostic marker and indicator of disease severity in adult-onset Still's
disease. Arthritis Rheum. 2001 Jul;44(7):1716-1717.
41 Kawashima M, Yamamura M, Taniai M, et al. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease. Arthritis Rheum 2001 Mar;44(3):550-560
42 El-Mezzein RE, Matsumoto T, Nomiyama H, et al. Increased secretion of IL-18 in vitro by peripheral blood mononuclear cells of patients with bronchial asthma and atopic dermatitis. Clin Exp Immunol 2001 Nov;126(2):193-8
43 Docke WD,Randow F,Syrbe U, et al. Monocyte deactivation in septic patients:restoration by IFN-gamma treatment.Nat Med.1997 Jun;3(6):678-681
44 Muhl H, Kampfer H, Bosmann M, et al. Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells.Biochem Biophys Res Commun.2000 Jan 27;267(3):960-963
45 Yamamaka K,Tanaka M,Kayagaki N, et al.Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level oflL-18.J Immunol.2000 Jul 15;165(2):997-1003.
2 Salgame P, Abrams JS, Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11; 254(5029):279-282
3 Bertoletti A, D'Elios MM, Boni C, et al.Different cytokine profiles of intrahepatic T cell in chronic hepatitis B and hepatitis C virus infection J.gastroenterology, 1997 Jan, 112(1):193-199
4 Vingerhoets J, Michielsen P, Vanham G , et al. HBV-specific lymphoprofilerative and cytokine respones in patients with hepatitis B.J.Hepatology, 1998, 28:8-16.
5 姜荣龙，卢桥生，郭亚兵，等。Th1／Th2细胞在慢性乙型肝炎病毒感染中的作用 第一军医大学学报2000：20(2)：103-110
6 文维群，章廉，肖红，等。IL_18表达水平与HBC感染相关性的临床研究中华医学杂志2001，81(11)：655-658
7 王静艳，刘沛，孙金良，等。乙型病毒性肝炎患者血清，TNF-α、IFN-γ、IL-6和IL-8的检测意义 中国公共卫生1998，14(5)：262-263
8 张萍，吴文漪，魏来。乙型病毒性肝炎患者外周血T辅助细胞1、2型细胞因子含量的测定及临床意义 徐州医学院学报2001，21(4)：304-306
9 Yokochi S, Ishiwata Y, Hashimoto H, et al.Hepatoprective effect of propageermanium on Corynebacterium parvum and lipopolysaccharide-induced liver injury in mice. Scand J Immunol 1998 Aug,48(2):182-191
10 Yang TJ, Wei HL, Liu GT.Effects of 16 drugs on immunological liver injury induced by BCG+ lipopolysaccharide in mice. J. Zhongguo Yao Li Xue Bao 1997 Mar;18(2):185-188
11 Tsuji H, Mukaida N, Kaneko S, et al. Alleviation of lipopolysaccharide-induced IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12, and IL-18 production. J Immunol 1999 Jan 15;162(2):1049-1055
12 Hase K, Kadota S, Basnet P, et al. Protective effect of celosian, an acidic polysarride, on chemically and immunologically liver injuries. Biol Pham Bull 1996 Apr, 19(4):567-572
13 Santucci L, Fiorucci S, Cammilleri F , et al.Galeectin-1 exerts immunomodulatory and protective effects on concanavalin A-induced hepatitis in mice. Hepatology 2000 Feb;31(3):399-406
14 Matsui K, Yoshimoto T, Tsutsui H, et al. Propionibacterium acnes treatment dimishes CD4+NK1.1T cells but induces type-1 T cells in the liver by induction of IL-12 and IL-18 prouduction from Kuffer cells. J Immunol. 1997 Jul 1;159(1):97-106
15 Chang JT, Segal BM, Nakanishi K, et al.The costimulatory effect of IL-18 on the induction of antigen-specific IFN-gamma production by resting T cells is IL-12 dependent and is mediated by up-regulation of
IL-12 receptor beta2 subnit. Eur J Immunol.2000Apr;30(4):1113-1119
16 Mishima S, Xu D, Lu Q.acterial translocation is inhibited in inducible nitric oxide sythase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth.Arch surg 1997 Nov;132(11):1190-1195
17 Roulston A, Lin R, Beauparlant P, et al. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors regulation of HIV-I and cytokin expression by NF-κB. Mcrobiol Rev,1995;59:481-505
18 Baeuerle PA.The inducible transerption activator NF-κB regulation by distinct protein subunits. Biochmica et Biophysica Acta.1991;1072(1):63—80
19 Grove M,Plumb M. C / EBP, NF-κB and c-Ets faimily memhers and transcrptional regulation of the cellspecific and iducible macrophage inflammatory protein-1 immediate-early gene. Mol CellBiol,1993,13:5276—5289
20 Dinarello CA.Interleukin-18, a proinflammatory cytokine.Eur Cytokine Netw 2000, sep,1(3):483-486
21 顾大勇，曾祥元。内毒素诱导肺血管内皮细胞ICAM-1的表达及NP-κ作用。中国微循环2002；2(6)：25-28
22 Schutt C. Fighting infection:the role of lipopolysaccharide binding proteins CD14 and LBP. Pathobiology,1999, 67(5-6):227-229
23 Su GL, Klein RD, Aminlari A, et al. kupffer cell activation by Lipopolysaccharide in rats:role for LBP and toil-like receptor 4.
Hepatology,2000, 31(4):932-936
24 Schumann RR, Zweigner J. A novel acute-phase maker:LPB. Clin Chem LAb Med, 1999, 37(3):271-274
25 Tsutsui H, Martsui K, Kawada N, et al. IL-18 accont for both TNF-alpha and Fasligand-mediated hepatotoxic phthways inendotoxin-induced liver injury in mice. J. Immonp;1997 Oct 15;159(8):3961-3967
26 袁建成，周立新，秦孝健，等。内毒素诱导的肝细胞及枯否细胞凋亡与肝脏损伤的关系。中华医学杂志，1998，78(6)：423-425。
27 Myers ML, Schook LB. immunotoxicity of nitrosamines. Experimental immunotoxicology.1996, pp.351-366
28 Leist M, Gantner F, Bohlinger L, et al.TNF-induced hepatocyapoptosis precedes liver failure in experiment murine shock models.Am J Path,1995,146:1220-1234
29 Tsutsui H, Martsui K, Okamara H, et al. Pathophysiological roles of interleukin-18 in inflammatory liver disease. Immunoiogical Reviews,2000,174:192-209
30 Luster MI, Simeonova PP,Gallucci RM,et al.Role of inflammation in chemical-induced hepatotoxity.Toxicology,2001,120:317-321
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