细胞凋亡相关基因及因素在大鼠酒精性肝病中的相关性研究
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摘要
目的
本研究通过酒精灌胃的方法建立酒精性肝病大鼠模型,探讨肝细胞凋亡相关基因及因素在酒精性肝病中的表达,为酒精性肝病发病机制的研究提供实验与理论依据。
方法
1.酒精性肝病动物模型的建立与分组:Wistar大鼠随机分为两组,模型组给予40%酒精8g/kg/d,分二次灌胃,共12周;对照组给予等量的生理盐水灌胃。实验第8、12周末处死动物,左心室采血离心保存待测血清指标。取肝组织一部分经10%中性福尔马林固定待做病理、凋亡及免疫组织化学检测;一部分肝组织经2.5%戊二醛固定待做电镜检查;另一部分肝组织-70℃液氮保存待做PCR法检测。
2.应用光镜(HE染色)和电镜分别观察肝组织病理变化和肝细胞超微结构变化,用TUNEL法检测肝细胞凋亡,用全自动生化仪分别检测血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)的含量,用免疫组化染色方法(采用SABC法)分别观察肝组织内的半胱天冬酶—3(Caspase-3)、B细胞淋巴瘤—2基因(Bcl-2)和核转录因子KB(NF-kB)表达,用硫代巴比妥酸法(TBA法)和黄嘌呤氧化酶法分别测定血清丙二醛(MDA)的含量和超氧化物歧化酶(SOD)的活力,用放射免疫分析法和免疫组化染色法分别观察血清和肝组织的肿瘤坏死因子—α(TNF-α)的水平,用PCR法测定肝细胞色素P450 2E1的表达。
结果
1.模型组与对照组比较血清ALT(116.12±14.30 vs 43.56±7.89)IU/L值和AST(248.83±20.25 vs 84.67±12.67)IU/L值明显升高,ALT/AST比值＞2,有统计学意义(P＜0.05)。
2.HE染色组织切片光镜下模型组与对照组比较,肝细胞明显肿胀,可见大小不等的脂肪空泡,部分处可见“嗜酸性小体”和点状、灶壮坏死,周围有炎性细胞浸润,肝组织内胶原纤维轻度增生;电镜下模型组与对照组比较肝细胞线粒体明显肿胀,嵴显示不清,部分呈空泡样变性,肝细胞内质网旺盛,可见肝细胞、肝窦内皮细胞凋亡。
3.凋亡的肝细胞主要分布在肝组织中点状、灶状和碎屑样坏死区及其周围,模型组(6.2±1.7%)肝细胞凋亡指数明显高于对照组(1.7±0.8%),且随造模时间延长模型组细胞凋亡指数明显增加,有显著性差异(P＜0.05)。
4.Caspase-3、Bcl-2和NF-B阳性细胞主要分布在中央静脉及肝细胞坏死灶周围,模型组Caspase-3、Bcl-2、NF-kB基因表达强度明显高于对照组(P＜0.05),且Bcl-2与NF-kB表达之间呈正相关(r=0.576,P＜0.01>。
5.与对照组相比模型组血清MDA(15.72±2.06 vs 41.53±7.43)nmol/ml含量明显升高,而血清SOD(636.82±138.60 vs 353.12±61.02)u/ml活力明显下降,两组间均有统计学意义(P＜0.05),且MDA与SOD呈负相关(r=-0.5818,P＜0.05)。
6.肝细胞凋亡指数与血清MDA呈正相关,与血清SOD呈负相关(r_(MDA)=0.6437,r_(SOD)=-0.5115,P＜0.05)。
7.与对照组相比模型组血清TNF-α(745.6±174.8 vs 1236.4±283.5)ng/L含量明显升高,两组间有统计学意义(P＜0.05),且肝细胞凋亡指数呈正相关(r=0.8358,P＜0.05)。
8.血清TNF-α与血清MDA呈正相关、与血清SOD呈负相关(r_(MDA)=0.4654,r_(SOD)=-0.38 17,P＜0.05)。
9.模型组肝组织TNF-α表达强度明显高于对照组,且随造模时间延长表达强度增强,有显著性差异(P＜0.05)。
10.肝组织TNF-α的表达与Caspase-3的表达呈正相关(r=0.648,P＜0.01),与NF-kB的表达呈正相关(r=0.678,P＜0.01>。
11.模型组肝组织CYP2E1的B基因(c1/c2),C基因(c2/c2)表达强度明显高于对照组,其差异有统计学意义(P＜0.05),且与对照组相比c1基因频率(53.4%)明显降低,c2基因频率(46.7%)明显升高,其差异有统计学意义(P＜0.05)。
结论
1.Caspase-3、Bcl-2、NF-kB参与酒精性肝病的肝细胞凋亡,其中NF-kB作为一种抑制凋亡的转录因子,通过对Bcl-2一类的下游抗凋亡基因表达的调节而发挥作用。
2.TNF-α和脂质过氧化损伤在酒精性肝病的肝细胞凋亡过程中起一定作用,并且TNF-α通过其受体介导Caspase-3活化参与酒精性肝病的肝细胞凋亡。
3.TNF-α活化NF-kB而共同参与酒精性肝病的肝细胞凋亡。
4.CYP2E1基因PstI及RsaI RFLPs参与酒精性肝病的肝细胞凋亡,其中c2基因在肝细胞凋亡中可能起决定作用。
Objective:To provide the experimental and theoretical basis for the pathogenesis of ALD by studying the expression and significance of apoptosis of hepatocyte and its closely related factors in the rat model of alcoholic liver disease (ALD) established by intragastric administration of alcohol.
Methods:(1) Establishment of animal model of ALD and grouping:Wistar rats were randomly divided into two groups-the model group and control group.The rat model of ALD was established by intragastric administration of 40%alcohol with 8 g / kg / d for 12 weeks,and the control group was administrated with equivalent volume of physiological saline.After killing the rats at 8 and 12 weeks,the blood was taken from left ve(?)tricle and was centrifugated,conserved to measure the liver function. Part of the liver tissue was fixed with 10%neutral formalin to do the examination of histopathology,apoptosis and immunohistochemistry,and with 2.5%glutaraldehyde to do the electron microscopy(EM),and was kept at -70℃with liquid nitrogen to do the PCR,respectively.(2) Pathological changes of the liver were observed by HE staining and EM,apoptosis of hepatocytes was detected by the TUNEL method, content of the alanine amino-transferase(ALT) and aspartate aminotransferase(AST) was detected by the automatic biochemical analyzer,expression of the cystein-dependent aspartate-specefic pro gramed-3(Caspase-3),B-cell leukemia-lymphoma -2(Bcl-2),nuclear factor-κB(NF-κB) and tumor necrosis factor-α(TNF-α) was observed by immunohistochemistry(SABC),content of the malondialdehyde (MDA) and activity of superoxide dismutase(SOD) in the liver was determined by the thiobarbituric acid(TBA) and xanthine oxidase enzyme,level of serum TNF-α was detected by the radioimmunoassay(RIA),and expression of the cytochrome P4502E1(CYP2E1) was analyzed by the PCR,respectively.
Results:(1) Values of serum ALT(116.12±14.30 vs 43.56±7.89 IU/L) and AST(248.83±20.25 vs 84.67±12.67 IU/L) in the model group were increased significantly as compared with those in the control group,the ratio of ALT and AST was larger than 2,and the difference was statistically significant(P＜0.05).(2) It was showed in liver tissue sections stained by HE staining under light microscope and EM in the model group as compared with those in the control group that obvious swelling of hepatocytes,different size of fat vacuoles in cytoplasm,the Councillman body, point and focus necrosis of hepatocytes with the infiltration of inflammatory cells,and mild hyperplasia of collagen fibers,mitochondrial swelling,unclear and vacuolar degeneration of crista mitochondriales,prosperity of endoplasmic reticulum, apoptosis of hepatocytes and endothelial cells of hepatic sinusoid occurred.(3) Apoptotic hepatocytes were mainly in and/or around the point,focus and piecemeal necrosis in liver tissue,and the apoptotic index of hepatocytes was significantly higher in the model group(6.2±1.7%) than that in the control group(1.7±0.8%, P＜0.05) and increased along with the time extension of making model of ALD.(4) The Caspase-3,Bcl-2 and NF-κB positive cells were mainly distributed around the central venous and necrotic foci of hepatocytes,and the intensity of gene expression of Caspase-3,Bcl-2,NF-κB was significantly higher in the model group than that in the control group(P＜0.05),and the expression between Bcl-2 and NF-κB was positively correlated(r=0.576,P＜0.01).(5) The content of serum MDA(15.72±2.06 vs 41.53±7.43 nmol/ml) was significantly increased and activity of SOD (636.82±138.60 vs 353.12±61.02 nmol/ml) was obviously decreased in the model group as compared with that in the control group,and the difference was statistically significant(P＜0.05),and there was negative correlation between MDA and SOD(r=-0.5818,P＜0.05).(6) Apoptotic index of hepatocytes was positively correlated with serum MDA,and negatively correlated with serum SOD(r_(MDA)=-0.6437,r_(SOD)=-0.5115,P＜0.05).(7) The content of serum TNF-α(745.6±174.8 ng/L) in the model group was obviously increased as compared with that in the control group(1236.4±283.5 ng/L),and there was significant difference between the two groups(P＜0.05),and was positively correlated with the apoptotic index of hepatocytes(r=0.8358,P＜0.05).(8) The content of serum TNF-αwas positively correlated with the MDA,but negatively correlated with the SOD(r_(MDA)=-0.4654, r_(SOD)=-0.3817,P＜0.05).(9) The expression of TNF-αwas higher in the model group than that in the control group(P＜0.05),and increased along with the time extension of making model of ALD.(10) The expression of TNF-αhad positive correlation with the Caspase-3 and NF-κB in liver tissue(r=0.648,r=0.678,P＜0.01),respectively.(11) The expression of CYP2E1 genotype B(c1/c2) and genotype C(c2/c2) in the liver tissue was significantly increased in the model group than that in the control group(P＜0.05),and the decreased gene frequency of c1(53.4%) and increased gene frequency of c2(46.7%) had statistically significant difference(P＜0.05).
Conclusion:(1) The Caspase-3,Bcl-2 and NF-κB genes participate in the apoptosis of hepatocytes in development and progress of ALD of rats,and NF-κB as a transcription factor for inhibiting apoptosis plays a role in regulating the expression of a downstream anti-apoptosis gene of Bcl-2.(2) The TNF-αand injuries of lipid peroxidation play an important role in the apoptotic process of hepatocytes in ALD, and TNF-αparticipates in the development of ALD through its receptor-mediated activation of Caspase-3.(3) The NF-κB activated by TNF-αparticipate concomitantly in the apoptosis of hepatocytes of ALD.(4) The restriction fragment length polymorphisms(RFLPs) of CYP2E1 genetic PstI and RsaI participate in the apoptosis of hepatocytes of ALD,in which the c2 gene plays a decisive action in the apoptosis of hepatocytes.
本研究通过酒精灌胃的方法建立酒精性肝病大鼠模型,探讨肝细胞凋亡相关基因及因素在酒精性肝病中的表达,为酒精性肝病发病机制的研究提供实验与理论依据。
方法
1.酒精性肝病动物模型的建立与分组:Wistar大鼠随机分为两组,模型组给予40%酒精8g/kg/d,分二次灌胃,共12周;对照组给予等量的生理盐水灌胃。实验第8、12周末处死动物,左心室采血离心保存待测血清指标。取肝组织一部分经10%中性福尔马林固定待做病理、凋亡及免疫组织化学检测;一部分肝组织经2.5%戊二醛固定待做电镜检查;另一部分肝组织-70℃液氮保存待做PCR法检测。
2.应用光镜(HE染色)和电镜分别观察肝组织病理变化和肝细胞超微结构变化,用TUNEL法检测肝细胞凋亡,用全自动生化仪分别检测血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)的含量,用免疫组化染色方法(采用SABC法)分别观察肝组织内的半胱天冬酶—3(Caspase-3)、B细胞淋巴瘤—2基因(Bcl-2)和核转录因子KB(NF-kB)表达,用硫代巴比妥酸法(TBA法)和黄嘌呤氧化酶法分别测定血清丙二醛(MDA)的含量和超氧化物歧化酶(SOD)的活力,用放射免疫分析法和免疫组化染色法分别观察血清和肝组织的肿瘤坏死因子—α(TNF-α)的水平,用PCR法测定肝细胞色素P450 2E1的表达。
结果
1.模型组与对照组比较血清ALT(116.12±14.30 vs 43.56±7.89)IU/L值和AST(248.83±20.25 vs 84.67±12.67)IU/L值明显升高,ALT/AST比值＞2,有统计学意义(P＜0.05)。
2.HE染色组织切片光镜下模型组与对照组比较,肝细胞明显肿胀,可见大小不等的脂肪空泡,部分处可见“嗜酸性小体”和点状、灶壮坏死,周围有炎性细胞浸润,肝组织内胶原纤维轻度增生;电镜下模型组与对照组比较肝细胞线粒体明显肿胀,嵴显示不清,部分呈空泡样变性,肝细胞内质网旺盛,可见肝细胞、肝窦内皮细胞凋亡。
3.凋亡的肝细胞主要分布在肝组织中点状、灶状和碎屑样坏死区及其周围,模型组(6.2±1.7%)肝细胞凋亡指数明显高于对照组(1.7±0.8%),且随造模时间延长模型组细胞凋亡指数明显增加,有显著性差异(P＜0.05)。
4.Caspase-3、Bcl-2和NF-B阳性细胞主要分布在中央静脉及肝细胞坏死灶周围,模型组Caspase-3、Bcl-2、NF-kB基因表达强度明显高于对照组(P＜0.05),且Bcl-2与NF-kB表达之间呈正相关(r=0.576,P＜0.01>。
5.与对照组相比模型组血清MDA(15.72±2.06 vs 41.53±7.43)nmol/ml含量明显升高,而血清SOD(636.82±138.60 vs 353.12±61.02)u/ml活力明显下降,两组间均有统计学意义(P＜0.05),且MDA与SOD呈负相关(r=-0.5818,P＜0.05)。
6.肝细胞凋亡指数与血清MDA呈正相关,与血清SOD呈负相关(r_(MDA)=0.6437,r_(SOD)=-0.5115,P＜0.05)。
7.与对照组相比模型组血清TNF-α(745.6±174.8 vs 1236.4±283.5)ng/L含量明显升高,两组间有统计学意义(P＜0.05),且肝细胞凋亡指数呈正相关(r=0.8358,P＜0.05)。
8.血清TNF-α与血清MDA呈正相关、与血清SOD呈负相关(r_(MDA)=0.4654,r_(SOD)=-0.38 17,P＜0.05)。
9.模型组肝组织TNF-α表达强度明显高于对照组,且随造模时间延长表达强度增强,有显著性差异(P＜0.05)。
10.肝组织TNF-α的表达与Caspase-3的表达呈正相关(r=0.648,P＜0.01),与NF-kB的表达呈正相关(r=0.678,P＜0.01>。
11.模型组肝组织CYP2E1的B基因(c1/c2),C基因(c2/c2)表达强度明显高于对照组,其差异有统计学意义(P＜0.05),且与对照组相比c1基因频率(53.4%)明显降低,c2基因频率(46.7%)明显升高,其差异有统计学意义(P＜0.05)。
结论
1.Caspase-3、Bcl-2、NF-kB参与酒精性肝病的肝细胞凋亡,其中NF-kB作为一种抑制凋亡的转录因子,通过对Bcl-2一类的下游抗凋亡基因表达的调节而发挥作用。
2.TNF-α和脂质过氧化损伤在酒精性肝病的肝细胞凋亡过程中起一定作用,并且TNF-α通过其受体介导Caspase-3活化参与酒精性肝病的肝细胞凋亡。
3.TNF-α活化NF-kB而共同参与酒精性肝病的肝细胞凋亡。
4.CYP2E1基因PstI及RsaI RFLPs参与酒精性肝病的肝细胞凋亡,其中c2基因在肝细胞凋亡中可能起决定作用。
Objective:To provide the experimental and theoretical basis for the pathogenesis of ALD by studying the expression and significance of apoptosis of hepatocyte and its closely related factors in the rat model of alcoholic liver disease (ALD) established by intragastric administration of alcohol.
Methods:(1) Establishment of animal model of ALD and grouping:Wistar rats were randomly divided into two groups-the model group and control group.The rat model of ALD was established by intragastric administration of 40%alcohol with 8 g / kg / d for 12 weeks,and the control group was administrated with equivalent volume of physiological saline.After killing the rats at 8 and 12 weeks,the blood was taken from left ve(?)tricle and was centrifugated,conserved to measure the liver function. Part of the liver tissue was fixed with 10%neutral formalin to do the examination of histopathology,apoptosis and immunohistochemistry,and with 2.5%glutaraldehyde to do the electron microscopy(EM),and was kept at -70℃with liquid nitrogen to do the PCR,respectively.(2) Pathological changes of the liver were observed by HE staining and EM,apoptosis of hepatocytes was detected by the TUNEL method, content of the alanine amino-transferase(ALT) and aspartate aminotransferase(AST) was detected by the automatic biochemical analyzer,expression of the cystein-dependent aspartate-specefic pro gramed-3(Caspase-3),B-cell leukemia-lymphoma -2(Bcl-2),nuclear factor-κB(NF-κB) and tumor necrosis factor-α(TNF-α) was observed by immunohistochemistry(SABC),content of the malondialdehyde (MDA) and activity of superoxide dismutase(SOD) in the liver was determined by the thiobarbituric acid(TBA) and xanthine oxidase enzyme,level of serum TNF-α was detected by the radioimmunoassay(RIA),and expression of the cytochrome P4502E1(CYP2E1) was analyzed by the PCR,respectively.
Results:(1) Values of serum ALT(116.12±14.30 vs 43.56±7.89 IU/L) and AST(248.83±20.25 vs 84.67±12.67 IU/L) in the model group were increased significantly as compared with those in the control group,the ratio of ALT and AST was larger than 2,and the difference was statistically significant(P＜0.05).(2) It was showed in liver tissue sections stained by HE staining under light microscope and EM in the model group as compared with those in the control group that obvious swelling of hepatocytes,different size of fat vacuoles in cytoplasm,the Councillman body, point and focus necrosis of hepatocytes with the infiltration of inflammatory cells,and mild hyperplasia of collagen fibers,mitochondrial swelling,unclear and vacuolar degeneration of crista mitochondriales,prosperity of endoplasmic reticulum, apoptosis of hepatocytes and endothelial cells of hepatic sinusoid occurred.(3) Apoptotic hepatocytes were mainly in and/or around the point,focus and piecemeal necrosis in liver tissue,and the apoptotic index of hepatocytes was significantly higher in the model group(6.2±1.7%) than that in the control group(1.7±0.8%, P＜0.05) and increased along with the time extension of making model of ALD.(4) The Caspase-3,Bcl-2 and NF-κB positive cells were mainly distributed around the central venous and necrotic foci of hepatocytes,and the intensity of gene expression of Caspase-3,Bcl-2,NF-κB was significantly higher in the model group than that in the control group(P＜0.05),and the expression between Bcl-2 and NF-κB was positively correlated(r=0.576,P＜0.01).(5) The content of serum MDA(15.72±2.06 vs 41.53±7.43 nmol/ml) was significantly increased and activity of SOD (636.82±138.60 vs 353.12±61.02 nmol/ml) was obviously decreased in the model group as compared with that in the control group,and the difference was statistically significant(P＜0.05),and there was negative correlation between MDA and SOD(r=-0.5818,P＜0.05).(6) Apoptotic index of hepatocytes was positively correlated with serum MDA,and negatively correlated with serum SOD(r_(MDA)=-0.6437,r_(SOD)=-0.5115,P＜0.05).(7) The content of serum TNF-α(745.6±174.8 ng/L) in the model group was obviously increased as compared with that in the control group(1236.4±283.5 ng/L),and there was significant difference between the two groups(P＜0.05),and was positively correlated with the apoptotic index of hepatocytes(r=0.8358,P＜0.05).(8) The content of serum TNF-αwas positively correlated with the MDA,but negatively correlated with the SOD(r_(MDA)=-0.4654, r_(SOD)=-0.3817,P＜0.05).(9) The expression of TNF-αwas higher in the model group than that in the control group(P＜0.05),and increased along with the time extension of making model of ALD.(10) The expression of TNF-αhad positive correlation with the Caspase-3 and NF-κB in liver tissue(r=0.648,r=0.678,P＜0.01),respectively.(11) The expression of CYP2E1 genotype B(c1/c2) and genotype C(c2/c2) in the liver tissue was significantly increased in the model group than that in the control group(P＜0.05),and the decreased gene frequency of c1(53.4%) and increased gene frequency of c2(46.7%) had statistically significant difference(P＜0.05).
Conclusion:(1) The Caspase-3,Bcl-2 and NF-κB genes participate in the apoptosis of hepatocytes in development and progress of ALD of rats,and NF-κB as a transcription factor for inhibiting apoptosis plays a role in regulating the expression of a downstream anti-apoptosis gene of Bcl-2.(2) The TNF-αand injuries of lipid peroxidation play an important role in the apoptotic process of hepatocytes in ALD, and TNF-αparticipates in the development of ALD through its receptor-mediated activation of Caspase-3.(3) The NF-κB activated by TNF-αparticipate concomitantly in the apoptosis of hepatocytes of ALD.(4) The restriction fragment length polymorphisms(RFLPs) of CYP2E1 genetic PstI and RsaI participate in the apoptosis of hepatocytes of ALD,in which the c2 gene plays a decisive action in the apoptosis of hepatocytes.
引文
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