不同剂量精氨酸对肝衰竭大鼠免疫调节作用的实验研究
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摘要
目的
本研究通过D-氨基半乳糖盐酸盐诱导，复制大鼠急性肝衰竭模型，观察不同剂量精氨酸对肝衰竭大鼠肝肾功能、营养状况和免疫功能的影响，并探讨其机制，为临床救治肝衰竭病人提供实验依据和理论基础。
方法
1．急性肝衰竭大鼠模型的复制
选用健康雄性Wistar大鼠10只，随机分成正常对照组(normal control，NC)和肝衰竭组(hepatic failure control，HFC)，肝衰竭组采用D-半乳糖盐酸盐诱导法。实验鼠在禁食12小时后，将10％的D-半乳糖盐酸盐溶液，1．2g／kg一次腹腔注射，造成大鼠急性肝衰竭模型，对照组注射等量生理盐水。造模后24小时对大鼠肝、肾功能，血浆蛋白、糖、脂代谢进行检测，光镜下观察肝脏组织病理变化。另取6只观察大鼠的一般体征及存活情况。
2．不同剂量精氨酸对肝衰大鼠免疫调节作用的实验研究
选用健康雄性Wistar大鼠60只，随机分为六组，即A(正常对照组)、B(肝衰竭对照组)、C(精氨酸强化Ⅰ组，0．4 g·kg~(-1)·d~(-1))、D(精氨酸强化Ⅱ组，0．8 g·kg~(-1)·d~(-1))、E(精氨酸强化Ⅲ组，1．6 g·kg~(-1)·d~(-1))、F(精氨酸强化Ⅳ组，3．2 g·kg~(-1)·d~(-1))。以精氨酸强化Ⅳ组中氮量为准，其他肝衰竭组用甘氨酸补足氮量，使其达到等氮。造模后24小时开始营养治疗，正常对照组给予普通饲料。实验周期14天。实验开始后第14天对大鼠肝、肾功能，凝血机制、血浆蛋白、糖、脂代谢、免疫功能等指标进行检测，光镜下观察肝脏组织病理变化。
结果
1．急性肝衰竭大鼠模型的复制
模型组大鼠以D-半乳糖诱导后，24小时后逐渐出现活动减少，饮食下降、嗜睡、反应迟钝或过度，部分大鼠出现狂燥、抽搐，全身毛潮湿直立且无光泽，尿呈深黄色，眼、口腔出血、大便带血等。造模后48小时至72小时之间死亡3只(死亡率50％)。生化指标模型组大鼠与正常大鼠差别有统计学意义(P<0．05)。模型组大鼠肝脏可见显著病理改变。
2．不同剂量精氨酸对肝衰竭大鼠免疫调节作用的实验研究
(1)精氨酸对肝衰竭大鼠死亡率、体重、摄食量的影响精氨酸使大鼠死亡率降低，但各组间差别无统计学意义(P>0．05)。肝衰后大鼠体重和摄食量明显降低(P<0．05)，3d后体重和摄食量开始恢复。到实验结束各组大鼠体重和摄食量差别无统计学意义(P>0．05)。
(2)精氨酸对肝衰竭大鼠氮平衡和血浆蛋白的影响肝衰竭后各组大鼠处于负氮平衡，到第10天，各组大鼠恢复了正氮平衡，以D、E组恢复较好。精氨酸强化后，D、E组TP、ALB、PA、RBP含量高于B组，差别有统计学意义(P<0．05)。
(3)精氨酸对肝衰竭大鼠肝肾功能的影响强化精氨酸后使肝衰竭大鼠ALT、AST、ALP、TBIL、BUN、Cr、GLU、TG、CHLO、MDA较肝衰竭对照组有所改善，在精氨酸4个剂量组中，D、E组肝肾功能指标的恢复较好。
(4)精氨酸对肝衰竭大鼠免疫功能的影响肝衰竭后大鼠血清中IgA、IgM、IgG、IL-2、IL-10、IGF-1均有不同程度下降，肝衰竭各组大鼠血清中TNF-α含量均升高，B、C组较A组比较差别有统计学意义(P<0．05)；强化精氨酸后，各项指标有所改善，精氨酸4个剂量组中，以D、E组恢复较好。D、E组IgA、IgM含量高于B组，差别有统计学意义(P<0．05)；D、E、F组IL-2含量高于B组，差别有统计学意义(P<0．05)；NO含量F组高于A、B组，差别有统计学意义(P<0．05)，精氨酸4个剂量组之间差别无统计学意义(P>0．05)。
(5)病理结果显示D、E组大鼠肝脏恢复较B、C、F组好，炎性反应程度较轻。
结论
1．D-氨基半乳糖盐酸盐可复制大鼠急性肝衰竭模型，大鼠一般体征、死亡率、各项生化检测、肝脏病理均显示模型复制成功，达到模型成功标准。
2．精氨酸可以减轻肝衰后机体应激状态，增强肝衰竭大鼠的细胞免疫、体液免疫功能，改善蛋白质代谢，促进营养状况的恢复等。采用的4个不同剂量显示了其量效关系，以1．6 g·kg~(-1)·d~(-1)较好，在安全有效剂量下，有利于急性肝衰竭大鼠肝脏细胞代谢的恢复、肝脏酶系和肝脏功能的改善、提高免疫功能、凝血功能的恢复和蛋白质的合成。
Objective
To observe the effects of different dose arginine on liver-renal function, nutritional status and immune function in hepatic failure rats induced by the D-Galactosamine Hydrochloride, and explore the mechanism further to provide experimental data and rationale for remedy clinical hepatic failure patients.
Methods
1. The AHF model in rats
10 healthy male wistar rats were randomly divided into normal control (NC) and hepatic failure control (HFC) groups. The rats in HFC group were induced by the D-Galactosamine Hydrochloride. After abrosia 12 hours, the rats, were injected 10% D-galactosamine 1.2g/kg into abdominal cavity, to cause the model of acute hepatic failure, the NC were injected normal sodium. The liver-renal function, plasma protein, glyc- lipid metabolism and the pathological change of liver were observed after 24 hours. Another 6 were observed general objective sign and survival.
2.The study on immunological regulation of different, dose arginine in AHF rats
60 healthy male wistar rats were randomly divided into six groups: A (NC), B(HFC), C(ArgⅠ,0.4 g·kg~(-1)·d~(-1)),D(ArgⅡ,0.8 g·kg~(-1)·d~(-1)), E(ArgⅢ, 1.6g·kg~(-1)·d~(-1)), F(ArgⅣ, 3.2g·kg~(-1)·d~(-1)). The glycine was used to make up for nitrogen for other hepatic failure groups. The nutritional therapy was started after 24 hours. NCgroup was gived common animal feeds. The liver-renal function, clotting mechanism, plasma protein, glyc- lipid metabolism, immune function and the pathological change of liver were observed at 14 d.
Results
1. The AHF model in rats
After injection of D-Galactosamine Hydrochloride, the rats of model group appeared activity reduce, food-intake descend, lethargy, dull or excessus of reaction, crazy, twitch, deep yellow urine,bleeding from mouth ,eye and stool, the capill of all over the body was moist and none gloss. 3 were died in 6 rats between 48h and 72h. The indexof biochemistry detection in model group were significantly difference than those in NC group (P<0.05). The liver was found obvious pathological change in model group.
2. The study on immunological regulation of different dose arginine in AHF rats
(1) The effects of arginine on death rate,weight and food-intake in AHF rats: Arginine maked the death rate lower than HFC group, but the difference there was no statistical significance in six groups.The weight and food-intake were significantly lower than those in group A (P<0.05). The recover of weight and food-intake after 3 days, until the end of experiment (P<0.05).
(2) The effect of arginine on nitrogen balance and plasma protein in AHF rats: Hepatic failure rats were negative nitrogen balance until 10 days. The serum contents of TP, ALB, PA, RBP in group D and group E were significantly higher than those in group B (P<0.05).
(3) The effect of arginine on liver-renal function AHF rats: The serum contents of ALT、AST、ALP、TBIL、BUN、Cr、GLU、TG、CHLO、MDA in Arg groups were significantly better than those in group B (P<0.05). In four Arg groups, liver-renal function in group D and group E were better than those in group C and group F.
(4) The effect of arginine on immune function AHF rats: The serum contents of IgA、IgM、IgG、IL-2、IL-10、IGF-1 in groupB, group C, group D, group E, group F were lower than those in group A. While the TNF-a in group B and group C were higher than that in group A (P<0.05). The IgA and IgM in in group D and group E were higher than those in group B (P<0.05).The IL-2 in group D, group E, group F were higher than those in group B (P<0.05).The NO in group F were higher than those in group A and group B (P<0.05).
(5) The pathological change of liver in group D and group E was better than that in groupB, group C, group F,inflammatory reaction was slighter than other groups.
Conclusion
1. D-Galactosamine Hydrochloride could be used in copying the acute hepatic failure model in rats. General objective, death rate, biochemistry detection, the pathological change of liver were obvious. The rats could reach the level model success.
2. Arginine could relieve the physical stringent state of AHF rats ,enhancing the function of immune, improving protein metabolism, promoting the retrieve of nutritional status. Adoptive four diffenent dose manifested dose-effect relationship, 1.6 g·kg~(-1)·d~(-1) was better than low and high dose. At secure and curative dose, arginine was in favour of the retrieve of liver cell metabolism and clotting mechanism, improving liver enzyme system and function, enhancing the function of immune and synthesis of protein.
本研究通过D-氨基半乳糖盐酸盐诱导，复制大鼠急性肝衰竭模型，观察不同剂量精氨酸对肝衰竭大鼠肝肾功能、营养状况和免疫功能的影响，并探讨其机制，为临床救治肝衰竭病人提供实验依据和理论基础。
方法
1．急性肝衰竭大鼠模型的复制
选用健康雄性Wistar大鼠10只，随机分成正常对照组(normal control，NC)和肝衰竭组(hepatic failure control，HFC)，肝衰竭组采用D-半乳糖盐酸盐诱导法。实验鼠在禁食12小时后，将10％的D-半乳糖盐酸盐溶液，1．2g／kg一次腹腔注射，造成大鼠急性肝衰竭模型，对照组注射等量生理盐水。造模后24小时对大鼠肝、肾功能，血浆蛋白、糖、脂代谢进行检测，光镜下观察肝脏组织病理变化。另取6只观察大鼠的一般体征及存活情况。
2．不同剂量精氨酸对肝衰大鼠免疫调节作用的实验研究
选用健康雄性Wistar大鼠60只，随机分为六组，即A(正常对照组)、B(肝衰竭对照组)、C(精氨酸强化Ⅰ组，0．4 g·kg~(-1)·d~(-1))、D(精氨酸强化Ⅱ组，0．8 g·kg~(-1)·d~(-1))、E(精氨酸强化Ⅲ组，1．6 g·kg~(-1)·d~(-1))、F(精氨酸强化Ⅳ组，3．2 g·kg~(-1)·d~(-1))。以精氨酸强化Ⅳ组中氮量为准，其他肝衰竭组用甘氨酸补足氮量，使其达到等氮。造模后24小时开始营养治疗，正常对照组给予普通饲料。实验周期14天。实验开始后第14天对大鼠肝、肾功能，凝血机制、血浆蛋白、糖、脂代谢、免疫功能等指标进行检测，光镜下观察肝脏组织病理变化。
结果
1．急性肝衰竭大鼠模型的复制
模型组大鼠以D-半乳糖诱导后，24小时后逐渐出现活动减少，饮食下降、嗜睡、反应迟钝或过度，部分大鼠出现狂燥、抽搐，全身毛潮湿直立且无光泽，尿呈深黄色，眼、口腔出血、大便带血等。造模后48小时至72小时之间死亡3只(死亡率50％)。生化指标模型组大鼠与正常大鼠差别有统计学意义(P<0．05)。模型组大鼠肝脏可见显著病理改变。
2．不同剂量精氨酸对肝衰竭大鼠免疫调节作用的实验研究
(1)精氨酸对肝衰竭大鼠死亡率、体重、摄食量的影响精氨酸使大鼠死亡率降低，但各组间差别无统计学意义(P>0．05)。肝衰后大鼠体重和摄食量明显降低(P<0．05)，3d后体重和摄食量开始恢复。到实验结束各组大鼠体重和摄食量差别无统计学意义(P>0．05)。
(2)精氨酸对肝衰竭大鼠氮平衡和血浆蛋白的影响肝衰竭后各组大鼠处于负氮平衡，到第10天，各组大鼠恢复了正氮平衡，以D、E组恢复较好。精氨酸强化后，D、E组TP、ALB、PA、RBP含量高于B组，差别有统计学意义(P<0．05)。
(3)精氨酸对肝衰竭大鼠肝肾功能的影响强化精氨酸后使肝衰竭大鼠ALT、AST、ALP、TBIL、BUN、Cr、GLU、TG、CHLO、MDA较肝衰竭对照组有所改善，在精氨酸4个剂量组中，D、E组肝肾功能指标的恢复较好。
(4)精氨酸对肝衰竭大鼠免疫功能的影响肝衰竭后大鼠血清中IgA、IgM、IgG、IL-2、IL-10、IGF-1均有不同程度下降，肝衰竭各组大鼠血清中TNF-α含量均升高，B、C组较A组比较差别有统计学意义(P<0．05)；强化精氨酸后，各项指标有所改善，精氨酸4个剂量组中，以D、E组恢复较好。D、E组IgA、IgM含量高于B组，差别有统计学意义(P<0．05)；D、E、F组IL-2含量高于B组，差别有统计学意义(P<0．05)；NO含量F组高于A、B组，差别有统计学意义(P<0．05)，精氨酸4个剂量组之间差别无统计学意义(P>0．05)。
(5)病理结果显示D、E组大鼠肝脏恢复较B、C、F组好，炎性反应程度较轻。
结论
1．D-氨基半乳糖盐酸盐可复制大鼠急性肝衰竭模型，大鼠一般体征、死亡率、各项生化检测、肝脏病理均显示模型复制成功，达到模型成功标准。
2．精氨酸可以减轻肝衰后机体应激状态，增强肝衰竭大鼠的细胞免疫、体液免疫功能，改善蛋白质代谢，促进营养状况的恢复等。采用的4个不同剂量显示了其量效关系，以1．6 g·kg~(-1)·d~(-1)较好，在安全有效剂量下，有利于急性肝衰竭大鼠肝脏细胞代谢的恢复、肝脏酶系和肝脏功能的改善、提高免疫功能、凝血功能的恢复和蛋白质的合成。
Objective
To observe the effects of different dose arginine on liver-renal function, nutritional status and immune function in hepatic failure rats induced by the D-Galactosamine Hydrochloride, and explore the mechanism further to provide experimental data and rationale for remedy clinical hepatic failure patients.
Methods
1. The AHF model in rats
10 healthy male wistar rats were randomly divided into normal control (NC) and hepatic failure control (HFC) groups. The rats in HFC group were induced by the D-Galactosamine Hydrochloride. After abrosia 12 hours, the rats, were injected 10% D-galactosamine 1.2g/kg into abdominal cavity, to cause the model of acute hepatic failure, the NC were injected normal sodium. The liver-renal function, plasma protein, glyc- lipid metabolism and the pathological change of liver were observed after 24 hours. Another 6 were observed general objective sign and survival.
2.The study on immunological regulation of different, dose arginine in AHF rats
60 healthy male wistar rats were randomly divided into six groups: A (NC), B(HFC), C(ArgⅠ,0.4 g·kg~(-1)·d~(-1)),D(ArgⅡ,0.8 g·kg~(-1)·d~(-1)), E(ArgⅢ, 1.6g·kg~(-1)·d~(-1)), F(ArgⅣ, 3.2g·kg~(-1)·d~(-1)). The glycine was used to make up for nitrogen for other hepatic failure groups. The nutritional therapy was started after 24 hours. NCgroup was gived common animal feeds. The liver-renal function, clotting mechanism, plasma protein, glyc- lipid metabolism, immune function and the pathological change of liver were observed at 14 d.
Results
1. The AHF model in rats
After injection of D-Galactosamine Hydrochloride, the rats of model group appeared activity reduce, food-intake descend, lethargy, dull or excessus of reaction, crazy, twitch, deep yellow urine,bleeding from mouth ,eye and stool, the capill of all over the body was moist and none gloss. 3 were died in 6 rats between 48h and 72h. The indexof biochemistry detection in model group were significantly difference than those in NC group (P<0.05). The liver was found obvious pathological change in model group.
2. The study on immunological regulation of different dose arginine in AHF rats
(1) The effects of arginine on death rate,weight and food-intake in AHF rats: Arginine maked the death rate lower than HFC group, but the difference there was no statistical significance in six groups.The weight and food-intake were significantly lower than those in group A (P<0.05). The recover of weight and food-intake after 3 days, until the end of experiment (P<0.05).
(2) The effect of arginine on nitrogen balance and plasma protein in AHF rats: Hepatic failure rats were negative nitrogen balance until 10 days. The serum contents of TP, ALB, PA, RBP in group D and group E were significantly higher than those in group B (P<0.05).
(3) The effect of arginine on liver-renal function AHF rats: The serum contents of ALT、AST、ALP、TBIL、BUN、Cr、GLU、TG、CHLO、MDA in Arg groups were significantly better than those in group B (P<0.05). In four Arg groups, liver-renal function in group D and group E were better than those in group C and group F.
(4) The effect of arginine on immune function AHF rats: The serum contents of IgA、IgM、IgG、IL-2、IL-10、IGF-1 in groupB, group C, group D, group E, group F were lower than those in group A. While the TNF-a in group B and group C were higher than that in group A (P<0.05). The IgA and IgM in in group D and group E were higher than those in group B (P<0.05).The IL-2 in group D, group E, group F were higher than those in group B (P<0.05).The NO in group F were higher than those in group A and group B (P<0.05).
(5) The pathological change of liver in group D and group E was better than that in groupB, group C, group F,inflammatory reaction was slighter than other groups.
Conclusion
1. D-Galactosamine Hydrochloride could be used in copying the acute hepatic failure model in rats. General objective, death rate, biochemistry detection, the pathological change of liver were obvious. The rats could reach the level model success.
2. Arginine could relieve the physical stringent state of AHF rats ,enhancing the function of immune, improving protein metabolism, promoting the retrieve of nutritional status. Adoptive four diffenent dose manifested dose-effect relationship, 1.6 g·kg~(-1)·d~(-1) was better than low and high dose. At secure and curative dose, arginine was in favour of the retrieve of liver cell metabolism and clotting mechanism, improving liver enzyme system and function, enhancing the function of immune and synthesis of protein.
引文
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[2] 齐玉梅，靳继德，张明，等．单能源与双能源全营养液对急性肝衰竭大鼠氮代 谢影响的比较[J]．营养学报，2000，22(1)：223-227．
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[13]彭曦，汪仕良，尤忠义，等．醋酸精氨酸对严重烧伤家兔免疫功能的影响及其 量效关系[J]．中国危重病急救医学,2002,14(7)：404-406．
[14]廖丹，谢青，周霞秋，等．肝细胞移植对急性肝衰竭大鼠的治疗作用及移植细 胞生物学特性的研究[J]．肝脏,2000,5(2)：66-69．
[15] 张立军，于则利，孟庆敏，等．肝细胞移植治疗大鼠急性药物性肝功能衰竭 的疗效观察[J]．腹部外科，2003，16(3)：185-186．
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[19] Gorini P, Fogli L, Morsiani E, et ah Acute and fulminant liver failure: experimental models[J]. Ann Ital Chir 2000, 71(3):293-300.
[20] Contini S,Pezzarossa A, Sansoni P, et al. Hepatocellular transplantation in rats with toxic induced liver failure:results of iso-, allo- and xenografts[J]. Ital J Surg Sci. I, 1983, 13(1):25-30.
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[23] Kasravi FB, Wang L, Wang XD, et ah Bacterial translocation in acute liver injury induced by D-galactosamine[J]. Hepatology. 1996,23(1):97-103.
[24] Hirai S, Kaai S, Mito M, et ah Encapsulated hepatocyte transplantation for the treatment of D-galactosaminee induced acute hepatic failure in rats[J]. Eur Res,1993,25(4):193-202.
[25] 本刊编委会．比较医学与人类疾病动物模型[J]．实验动物与比较医学,2006， 26(2)：121-125．
[26] 杜智，李涛，张金卷，等.肝干细胞移植治疗大鼠暴发性肝功能衰竭的实验研 究[J]．生物医学工程与临床,2006,10(6)：346-349．
[27] Tong BC,Barbul A.Cellular and physiological effects of arginine [J].Mini RevMed Chem,2004,4(8):823-832.
[28] Swanson B, Keithley JK, Zeller JM, et al. A pilot study of the safety andefficacy of supplemental arginine to enhance immune function in persons with??HIV/AIDS[J]. Nutrition, 2002 ,18(7-8):688-690.
[29] Stechmiller JK,Childless B,Cowan L.Arginine supplementationand woundhealing[J].Nutr Clin Prac,2005,20(l):52-61.
[30] Wittmann F,Prix N,Mayr S,et al.L-arginine improves woundhealing aftertrauma-hemorrhage by increasing collagen synthesis[J].J Trauma, 2005,59(1):162-168.
[31] Calder PC.Immunonutrition in surgical and critically ill patients [J]. Br JNutr.,2007 ,98(1): 133-139.
[32] Lind DS. Arginine and cancer [J]. J Nutr,2004, 134(10): 2837S-2841S.
[33] Barbul A,Wasserkrug HL,Seifter,et al.Immunostimulatory effects of argininein normal and injured rats.J Surg Res,1980,29(3):228-235.
[34] Yeh CL, Hsu CS, Chen SC, et al. Effect of arginine on cellular adhesionmolecule expression and leukocyte transmigration in endothelial cellsstimulated by biological fluid from surgical patients[J]. Shock. 2007,28(1):39-44.
[35] 王先远，高兰兴．精氨酸对烧伤大鼠细胞因子的影响[J]．营养学报，1996， 18(4)：392-397．
[36] Barbul A,Wasserkmg HL,Penberthy LT,et al.Optimal levels of arginine in maintenance intravenous hyperalimentation[J] .JPEN J Parenter Enteral Nutr,1984,8(3):281-284.
[37] 李亚红．病毒性肝炎患者凝血及纤溶指标检测的意义[J]．广东医学，1999， 20(4)：276-277．
[38] 祝美琴，黄晓云．血浆凝血酶原时间检测对重型肝炎预后的影响[J]．齐齐哈 尔医学院学报,2003,24(11)：1246-1247．
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[40] Rondana M,Milani L,MeAd C,et al.Value of prealbumin plasma levels as liver test[J].Digestion,1987,37(2):72-78.
[41]李嘉．病毒性肝炎患者血清视黄醇结合蛋白和前白蛋白的检测及意义[J]．天 津医药,2002,30(1 1)：665-666．
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[59] Szende B, Tyihak E, Trezl L.Szende B, Tyihak E, Trezl L. Role of arginine and B its methylated derivatives in cancer biology and treatment[J]. Cancer Cell Int. 2001,1(1):3.
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