肝枯否细胞铁蓄积对CCl_4致小鼠急性肝损伤的影响及机制
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摘要
铁蓄积会导致或加重肝损伤,同时肝损伤多伴随着铁蓄积现象的存在,研究发现,肝枯否细胞在铁蓄积与肝损伤的关系中起着重要作用,但是其详细作用机制还不甚清楚,有待进一步研究。
目的
通过对正常小鼠和肝枯否细胞铁蓄积小鼠建立CC14急性肝损伤模型,了解肝枯否细胞铁蓄积是否会加重肝损伤及其机制,为进一步揭示铁蓄积影响肝损伤的详细机制提供参考。
材料与方法
对引进小鼠饲养和配种,基因型鉴定的方法得到雄性FPN-/-(正常小鼠)和FPN-/-cre(肝枯否细胞铁蓄积小鼠)小鼠各16只。将其各分为对照组和实验组,每组8只,两对照组腹腔注射橄榄油,两实验组腹腔注射四氯化碳。24h后取血测定血清丙氨酸转移酶(Alanine transaminase,ALT).天门冬氨酸氨基转移酶(Transaminase, AST)水平。处死小鼠,称取肝重,计算肝脏指数。制备10%肝匀浆,测定肝组织中丙二醛(Malonaldehyde, MDA).超氧化物歧化酶(Superoxide dismutase, SOD).谷胱甘肽(Glutathione, GSH)含量。做石蜡切片HE染色和TUNEL染色,观察肝脏损伤程度和肝细胞凋亡情况。提取组织mRNA和蛋白,运用Real-time RT-PCR检测肝组织中TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA表达水平,运用Western Blot检测肝组织中P38. JNKs蛋白磷酸化水平、Caspase-2. Caspase-8的蛋白表达水平。
用SPSS12.0软件进行数据分析,所有数据均以(x±s)表示,组间比较采用单因素方差分析,两两比较采用S-N-K检验。以a=0.05为检验水准。
结果
1肝损伤指标情况、肝脏病理学情况
两实验组肝脏指数、ALT. AST. MDA均显著高于其对照组(P<0.05), SOD. GSH均显著低于其对照组(P<0.05)。两对照组肝脏指数、ALT. AST. MDA. SOD. GSH的差异无统计学意义(P＞0.05)。 FPN-/-cre实验组肝脏指数、ALT.AST、MDA均显著高于FPN-/-实验组(P＜0.05), SOD、GSH均低于FPN-/-实验组,差异无统计学意义(P>0.05)。
两对照组肝细胞结构正常,两实验组肝细胞结构破裂、排列紊乱,FPN-/-cre实验组比FPN-/-实验组更严重。2相关基因mRNA和蛋白表达水平、肝细胞凋亡情况
两实验组TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA水平均显著高于其对照组(P<0.05)。两对照组TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA水平差异无统计学意义(P＞0.05)。FPN-/-cre实验组TNF-a、IL-6、 Caspase-2的mRNA水平均显著高于FPN-/-实验组(P<0.05), TGF-β、Caspase-8的mRNA水平均高于FPN-/-实验组,差异无统计学意义(P>0.05)。
两实验组JNKs蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平均高于其对照组,差异无统计学意义(P>0.05),P38蛋白磷酸化水平均显著低于其对照组(P<0.05)。两对照组JNKs、P38蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平的差异无统计学意义(P>0.05)。FPN-/-cre实验组JNKs蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平均显著高于FPN-/-实验组(P<0.05),P38蛋白磷酸化水平显著低于FPN-/-实验组(P<0.05)。
与对照组相比,两实验组均出现了肝细胞凋亡现象,FPN-/-cre实验组比FPN-/-实验组更严重。
结论
1肝枯否细胞铁蓄积会加重CC14所致的急性肝损伤。
2肝枯否细胞铁蓄积加重肝损伤可能与铁蓄积刺激肝枯否细胞炎症因子分泌水平上调,直接刺激或者通过改变P38、JNKs通路活性,促进细胞凋亡因子分泌,加快肝细胞凋亡有关。
Iron accumulation can cause or worsen liver damage, meanwhile liver damage often accompanies with the existence of iron accumulation phenomenon. Some researches showed that liver Kupffer cell is a key factor between iron accumulation and liver damage. However, the mechanisms are still unknown and need to be further studied.
Objectives
The chronic model of carbon tetrachloride-induced hepatotoxicity is established in normal mice and mice with iron accumulation in liver Kupffer cells. It is studied whether iron accumulation in liver Kupffer cell could worsen liver damage and its mechanism. It will provide evidence for the detailed mechanism of the effect caused by iron accumulation to liver damage.
Materials and methods
The mice were kept in animal facility. Sixteen male FPN-/-(normal mice) and FPN-/-cre(mice with iron accumulation in liver Kupffer cells) mice were obtained through the genetic type identification. These two genetic types of mice were rand-omly divided into two contol groups and two experimental groups,8mice per group. The mice of two experimental groups were intraperitoneal injected with CCl4, while those of two contol groups were intraperitoneal injected with olive oil. Twenty-four hours after intraperitoneal injection, the levels of serum ALT and AST were detected. Then the mice were condemned to death, the livers were dissectted and weighed to calculate the liver index. Part of the liver tissue was prepared to make the10%liver tissue homogenate for the MDA, SOD and GSH levels detection. Part of the liver tis-sue was fixed with paraffin to do HE and TUNEL staining. The extent of liver dama-ge and the liver cell apoptosis were examined. Part of the liver tissue was prepared for mRNA and protein extraction. The TNF-a, IL-6, TGF-B, Caspase-2and Caspase-8mRNA expression levels were detected by Real-time RT-PCR. The P-P38, P-JNKs, Caspase-2and Caspase-8protein expression levels were detected by Western Blot.
The data were calculated x±S The One-Way AN OVA was carried out to analyze the difference among the groups and the S-N-K test was carried out to analyze the difference between each other by use of the SPSS12.0software. The significant level was set at a=0.05.
Results
1The liver damage indices and liver pathology results
The liver index, ALT, AST and MDA levels of the two experimental groups were significantly higher than those of their control groups(.P<0.05), while the SOD and GSH levels were significantly lower than those of their control groups (P<0.05). The differences of liver index, ALT, AST, MDA, SOD and GSH levels between the two control groups were not statistically significant(P>0.05). The liver index, ALT, AST and MDA levels of the FPN-/-cre experimental group were significantly higher than those of the FPN-/-experimental group (P<0.05). The SOD and GSH levels of the FPN-/-cre experimental group were lower than those of the FPN-/-experimental group and the differences were not statistically significant(P>0.05).
The liver cell structures of the two control groups were normal, while the liver cell structures of the two experimental groups fractured and disordered. The extent of the liver cell damage was more serious in FPN-/-cre experimental group than that in FPN-/-experimental group.
2The mRNA and protein expression levels of related genes and the cell apoptosis results
The TNF-a, IL-6, TGF-β, Caspase-2and Caspase-8mRNA levels of the two experimental groups were significantly higher than those of their control groups (P<0.05). The differences of the TNF-a, IL-6, TGF-B, Caspase-2and Caspase-8mRNA levels between the two control groups were not statistically significant (P>0.05). The TNF-a, IL-6and Caspase-2mRNA levels of the FPN-/-cre experi-mental group were significantly higher than those of the FPN-/-experimental group(P><0.05). The TGF-13and Caspase-8mRNA levels of the FPN-/-cre experi-mental group were higher than those of the FPN-/-experimental group and the differences were not statistically significant(P>0.05).
The P-JNKs, Caspase-2and Caspase-8protein levels of the two experimental groups were higher than those of their control groups and the differences were not statistically significant(P＞.0.05). The P-P38protein levels of the two experimental groups were significantly lower than those of their control groups(P<0.05). The differences of P-JNKs, P-P38, Caspase-2and Caspase-8protein levels between the two control groups were not significant(P>0.05). The P-JNKs, Caspase-2and Caspase-8protein levels of the FPN-/-cre experimental group were significantly higher than those of the FPN-/-experimental group(P<0.05), while the P-P38protein levels of the FPN-/-cre experimental group were significantly lower than those of the FPN-/-experimental group(P<0.05).
The liver cell apoptosis appeared in the two experimental groups while there was no apoptosis in the two control groups. The extent of the liver cell apoptosis was more serious in FPN-/-cre experimental group than that in FPN-/-experimental group.
Conclusion
1Iron accumulation in liver Kupffer cells can worsen liver damage induced by CCl4.
2The effect of iron accumulation in liver Kupffer cells to the liver damage may relate to the increasing of the inflammation factors secretion of the Kupffer cells caused by the iron accumulation, which could promote the cell apoptosis factor secretion through direct stimulation or the change of P38and JNKs pathways, then the liver cell apoptosis is promoted.
目的
通过对正常小鼠和肝枯否细胞铁蓄积小鼠建立CC14急性肝损伤模型,了解肝枯否细胞铁蓄积是否会加重肝损伤及其机制,为进一步揭示铁蓄积影响肝损伤的详细机制提供参考。
材料与方法
对引进小鼠饲养和配种,基因型鉴定的方法得到雄性FPN-/-(正常小鼠)和FPN-/-cre(肝枯否细胞铁蓄积小鼠)小鼠各16只。将其各分为对照组和实验组,每组8只,两对照组腹腔注射橄榄油,两实验组腹腔注射四氯化碳。24h后取血测定血清丙氨酸转移酶(Alanine transaminase,ALT).天门冬氨酸氨基转移酶(Transaminase, AST)水平。处死小鼠,称取肝重,计算肝脏指数。制备10%肝匀浆,测定肝组织中丙二醛(Malonaldehyde, MDA).超氧化物歧化酶(Superoxide dismutase, SOD).谷胱甘肽(Glutathione, GSH)含量。做石蜡切片HE染色和TUNEL染色,观察肝脏损伤程度和肝细胞凋亡情况。提取组织mRNA和蛋白,运用Real-time RT-PCR检测肝组织中TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA表达水平,运用Western Blot检测肝组织中P38. JNKs蛋白磷酸化水平、Caspase-2. Caspase-8的蛋白表达水平。
用SPSS12.0软件进行数据分析,所有数据均以(x±s)表示,组间比较采用单因素方差分析,两两比较采用S-N-K检验。以a=0.05为检验水准。
结果
1肝损伤指标情况、肝脏病理学情况
两实验组肝脏指数、ALT. AST. MDA均显著高于其对照组(P<0.05), SOD. GSH均显著低于其对照组(P<0.05)。两对照组肝脏指数、ALT. AST. MDA. SOD. GSH的差异无统计学意义(P＞0.05)。 FPN-/-cre实验组肝脏指数、ALT.AST、MDA均显著高于FPN-/-实验组(P＜0.05), SOD、GSH均低于FPN-/-实验组,差异无统计学意义(P>0.05)。
两对照组肝细胞结构正常,两实验组肝细胞结构破裂、排列紊乱,FPN-/-cre实验组比FPN-/-实验组更严重。2相关基因mRNA和蛋白表达水平、肝细胞凋亡情况
两实验组TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA水平均显著高于其对照组(P<0.05)。两对照组TNF-a、IL-6、TGF-β、Caspase-2、Caspase-8的mRNA水平差异无统计学意义(P＞0.05)。FPN-/-cre实验组TNF-a、IL-6、 Caspase-2的mRNA水平均显著高于FPN-/-实验组(P<0.05), TGF-β、Caspase-8的mRNA水平均高于FPN-/-实验组,差异无统计学意义(P>0.05)。
两实验组JNKs蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平均高于其对照组,差异无统计学意义(P>0.05),P38蛋白磷酸化水平均显著低于其对照组(P<0.05)。两对照组JNKs、P38蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平的差异无统计学意义(P>0.05)。FPN-/-cre实验组JNKs蛋白磷酸化水平、Caspase-2、Caspase-8蛋白水平均显著高于FPN-/-实验组(P<0.05),P38蛋白磷酸化水平显著低于FPN-/-实验组(P<0.05)。
与对照组相比,两实验组均出现了肝细胞凋亡现象,FPN-/-cre实验组比FPN-/-实验组更严重。
结论
1肝枯否细胞铁蓄积会加重CC14所致的急性肝损伤。
2肝枯否细胞铁蓄积加重肝损伤可能与铁蓄积刺激肝枯否细胞炎症因子分泌水平上调,直接刺激或者通过改变P38、JNKs通路活性,促进细胞凋亡因子分泌,加快肝细胞凋亡有关。
Iron accumulation can cause or worsen liver damage, meanwhile liver damage often accompanies with the existence of iron accumulation phenomenon. Some researches showed that liver Kupffer cell is a key factor between iron accumulation and liver damage. However, the mechanisms are still unknown and need to be further studied.
Objectives
The chronic model of carbon tetrachloride-induced hepatotoxicity is established in normal mice and mice with iron accumulation in liver Kupffer cells. It is studied whether iron accumulation in liver Kupffer cell could worsen liver damage and its mechanism. It will provide evidence for the detailed mechanism of the effect caused by iron accumulation to liver damage.
Materials and methods
The mice were kept in animal facility. Sixteen male FPN-/-(normal mice) and FPN-/-cre(mice with iron accumulation in liver Kupffer cells) mice were obtained through the genetic type identification. These two genetic types of mice were rand-omly divided into two contol groups and two experimental groups,8mice per group. The mice of two experimental groups were intraperitoneal injected with CCl4, while those of two contol groups were intraperitoneal injected with olive oil. Twenty-four hours after intraperitoneal injection, the levels of serum ALT and AST were detected. Then the mice were condemned to death, the livers were dissectted and weighed to calculate the liver index. Part of the liver tissue was prepared to make the10%liver tissue homogenate for the MDA, SOD and GSH levels detection. Part of the liver tis-sue was fixed with paraffin to do HE and TUNEL staining. The extent of liver dama-ge and the liver cell apoptosis were examined. Part of the liver tissue was prepared for mRNA and protein extraction. The TNF-a, IL-6, TGF-B, Caspase-2and Caspase-8mRNA expression levels were detected by Real-time RT-PCR. The P-P38, P-JNKs, Caspase-2and Caspase-8protein expression levels were detected by Western Blot.
The data were calculated x±S The One-Way AN OVA was carried out to analyze the difference among the groups and the S-N-K test was carried out to analyze the difference between each other by use of the SPSS12.0software. The significant level was set at a=0.05.
Results
1The liver damage indices and liver pathology results
The liver index, ALT, AST and MDA levels of the two experimental groups were significantly higher than those of their control groups(.P<0.05), while the SOD and GSH levels were significantly lower than those of their control groups (P<0.05). The differences of liver index, ALT, AST, MDA, SOD and GSH levels between the two control groups were not statistically significant(P>0.05). The liver index, ALT, AST and MDA levels of the FPN-/-cre experimental group were significantly higher than those of the FPN-/-experimental group (P<0.05). The SOD and GSH levels of the FPN-/-cre experimental group were lower than those of the FPN-/-experimental group and the differences were not statistically significant(P>0.05).
The liver cell structures of the two control groups were normal, while the liver cell structures of the two experimental groups fractured and disordered. The extent of the liver cell damage was more serious in FPN-/-cre experimental group than that in FPN-/-experimental group.
2The mRNA and protein expression levels of related genes and the cell apoptosis results
The TNF-a, IL-6, TGF-β, Caspase-2and Caspase-8mRNA levels of the two experimental groups were significantly higher than those of their control groups (P<0.05). The differences of the TNF-a, IL-6, TGF-B, Caspase-2and Caspase-8mRNA levels between the two control groups were not statistically significant (P>0.05). The TNF-a, IL-6and Caspase-2mRNA levels of the FPN-/-cre experi-mental group were significantly higher than those of the FPN-/-experimental group(P><0.05). The TGF-13and Caspase-8mRNA levels of the FPN-/-cre experi-mental group were higher than those of the FPN-/-experimental group and the differences were not statistically significant(P>0.05).
The P-JNKs, Caspase-2and Caspase-8protein levels of the two experimental groups were higher than those of their control groups and the differences were not statistically significant(P＞.0.05). The P-P38protein levels of the two experimental groups were significantly lower than those of their control groups(P<0.05). The differences of P-JNKs, P-P38, Caspase-2and Caspase-8protein levels between the two control groups were not significant(P>0.05). The P-JNKs, Caspase-2and Caspase-8protein levels of the FPN-/-cre experimental group were significantly higher than those of the FPN-/-experimental group(P<0.05), while the P-P38protein levels of the FPN-/-cre experimental group were significantly lower than those of the FPN-/-experimental group(P<0.05).
The liver cell apoptosis appeared in the two experimental groups while there was no apoptosis in the two control groups. The extent of the liver cell apoptosis was more serious in FPN-/-cre experimental group than that in FPN-/-experimental group.
Conclusion
1Iron accumulation in liver Kupffer cells can worsen liver damage induced by CCl4.
2The effect of iron accumulation in liver Kupffer cells to the liver damage may relate to the increasing of the inflammation factors secretion of the Kupffer cells caused by the iron accumulation, which could promote the cell apoptosis factor secretion through direct stimulation or the change of P38and JNKs pathways, then the liver cell apoptosis is promoted.
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