TLR2、TLR4及相关细胞因子在军团菌感染作用机制的实验研究
摘要
目的
①探索建立小鼠军团菌感染模型的条件。
②初步阐明TLR2、TLR4在军团菌感染的作用机制,了解军团菌感染作用的分子靶点,为军团菌病的防治提供依据。
③探讨相关细胞因子(IL-6、TNF-α)在小鼠军团菌感染中的作用。
方法
1.从北京维通利华实验动物技术有限公司购买80只6-7周SPF级BALB/C小鼠,每组8只,雌雄各半。其中40只小鼠采用鼻内接种50ul 1.2×109/ml军团菌菌悬液,作为染菌组,建立军团菌感染模型,军团菌菌悬液的浓度根据麦氏比浊管确定。另外40只小鼠鼻内接种50ul无菌生理盐水作为对照组,分别于12小时、1天、3天、5天、7天麻醉小鼠,摘取眼球取血,解剖小鼠。
2.对染菌组和对照组的小鼠,分别于12小时、1天、3天、5天、7天处死,并进行下述研究:①取左肺上叶、肾脏、脾脏、肝脏少许,固定做病理切片。②采用Real-time RT PCR法测定小鼠肺组织中TLR2、TLR4、MyD88 mRNA的表达水平。③ELISA法检测小鼠肺组织匀浆液中细胞因子(IL-6、TNF-α)表达水平。
3.采用SPSS16.0统计软件进行数据的录入和分析。
结果
①病理切片结果显示:染菌组小鼠肺组织间质有炎性细胞浸润,且随着时间延长炎症有所加重,肺毛细血管壁有血管出血,说明造模成功。染菌组小鼠肾脏肾小球内有出血,且有炎性细胞浸润。染菌组小鼠脾脏髓质内可见出血,中性粒细胞浸润。尚未见染菌组小鼠肝脏有病理改变。
②脏器系数结果显示:染菌组和对照组之间肺脏脏器系数差异有统计学意义(F=13.987,P<0.001),各个时间点差异有统计学意义(F=3.035,P=0.023),分组和时间点交互作用差异无统计学意义(F=1.232,P=0.305)。染菌组和对照组之间脾脏脏器系数差异有统计学意义(F=40.585,P<0.001),各个时间点之间差异有统计学意义(F=4.525,P=0.003),分组和时间点之间交互作用差异无统计学意义(F=1.173,P=0.330)。染菌组和对照组之间肾脏脏器系数差异有统计学意义(F=20.473,P<0.001),各个时间点之间差异有统计学意义(F=5.025,P=0.001),分组和时间点之间交互作用差异无统计学意义(F=1.131,P=0.274)。染菌组和对照组之间心脏脏器系数差异无统计学意义(F=0.061,P=0.805),各个时间点之间差异也无统计学意义(F=1.528,P=0.204),分组和时间点之间交互作用差异无统计学意义(F=1.144,P=0.343)。染菌组和对照组之间肝脏脏器系数差异无统计学意义(F=0.590,P=0.478),各个时间点之间差异有统计学意义(F=37.952,P<0.001),分组和时间点之间交互作用差异无统计学意义(F=2.303,P=0.067)。染菌组和对照组之间脑脏器系数差异无统计学意义(F=0.031,P=0.861),各个时间点之间差异无统计学意义(F=1.221,P=0.310),分组和时间点之间交互作用差异无统计学意义(F=0.355,P=0.840)。③比较染菌组和对照组TLR2、TLR4、MyD88 mRNA相对表达量,real-time RT-PCR检测结果显示在染菌组和对照组小鼠肺组织TLR2 mRNA之间表达水平差异无统计学意义(F=0.032,P=0.858),各个时间点差异无统计学意义(F=0.068,P=0.991),分组和时间点之间交互作用差异无统计学意义(F=0.269,P=0.897)。染菌组和对照组小鼠肺组织TLR4 mRNA表达水平差异无统计学意义(F=0.321,P=0.573),各个时间点差异无统计学意义(F=0.443,P=0.777),分组和时间点之间交互作用差异无统计学意义(F=0.616,P=0.625)。染菌组和对照组肺组织MyD88 mRNA表达水平差异无统计学意义(F=0.711,P=0.402),各个时间点差异无统计学意义(F=0.367,P=0.831),分组和时间点之间交互作用差异无统计学意义(F=1.031,P=0.398)。
④染菌组和对照组小鼠肺组织IL-6的浓度差异有统计学意义(F=69.18,P<0.001),各个时间点差异有统计学意义(F=5.289,P<0.001),分组和时间点之间交互作用差异有统计学意义(F=8.686,P<0.001)。染菌组和对照组小鼠肺组织TNF-α的浓度差异有统计学意义(F=24.6,P<0.001),各个时间点差异有统计学意义(F=14.230,P<0.001),分组和时间点之间交互作用差异有统计学意义(F=13.987,P<0.001)。
结论:
①通过鼻内接种50ul 1.2×109/ml军团菌菌悬液能够建立军团菌感染的小鼠模型。
②本次研究尚未发现TLR2、TLR4、MyD88参与抗军团菌感染。
③IL-6和TNF-α与军团菌感染有关。
Objective
①To explore the conditions of establishment of mice Legionella infection model.
②To initially stated TLR2, TLR4’s action in Legionella infection mechanism, look into the molecular targets of effects against Legionella infection and provide evidence for Legionella prevention and control.
③To discuss related cytokines’(IL-6、TNF-α)role in mice infection of Legionella pneumophila.
Methods
1. Bought 80 SPF level 6-7 week BALB / C mice from Beijing Vital River Laboratory Animal Technology Company, N=8, male/female.40 mice intranasally inoculated with Legionella 50ul 1.2×109/ml bacterial suspension were as infection group, to establish Legionella infection model. The concentration of Legionella bacteria suspension was determined by Maxwell turbidity tube. Another 40 mice were inoculated with 50ul sterile saline nasal as the control group , All mice were anesthetized on 12 hours, 1 day, 3 days, 5 days and 7 days respectively. Bleed by removal of the eye, and dissect the mice.
2. Killed the infection and control groups of mice on 12 hours, 1 day, 3 days, 5 days and 7 days respectively, and conduct the following studies:①Done fixed biopsy with the upper lobe of left lung, kidney, spleen, and small piece of liver.②Determinated the mouse lung tissue’s TLR2, TLR4 and MyD88 mRNA expression levels in mouse lung tissue using the Real-time RT PCR .③Assay the cytokines (IL-6, TNF-α) in mouse lung homogenate by ELISA.
3. SPSS16.0 statistical software was used for data entry and analysis.
Results
①Pathology results showed that, mice in infection group had inflammatory cell infiltration within interstitial of lung tissue, which increased with time. Walls of pulmonary capillary vessels haemorrhage suggested that modeling successfully. Mice in this group hemorrhaged in glomerulus, and had inflammatory cell within filtration. These mice also hemorrhaged in spleen medulla, and had neutrophil infiltration. There had not been pathological changes of liver in these mice.
②The result of lung/body coefficient shows that there is statistical significance in the lung/body coefficient difference between infection group and control group(F=13.987,P<0.001), the difference of each timing shows statistical significance(F=3.035,P=0.023),the interaction difference of grouping and timing shows no statistical significance(F=1.232,P=0.305).There is statistical significance in the results of the difference of spleen/body coefficient between infection group and control group(F=40.585,P<0.001),the difference of each timing also shows statistical significance(F=4.525,P=0.003),and the interaction difference of grouping and timing shows no statistical significance(F=1.173,P=0.330). There is statistical significance in the results of the difference of kidney/body coefficient between infection group and control group(F=20.473,P<0.001),the difference of each timing also shows statistical significance(F=5.025,P=0.001),and the interaction difference of grouping and timing shows no statistical significance(F=1.131,P=0.274)There is no statistical significance in the results of the difference of heart/body coefficient between infection group and control group( F=0.061,P=0.805),the difference of each timing also shows no statistical significance(F=1.528,P=0.204),and the interaction difference of grouping and timing shows no statistical significance(F=1.144,P=0.343).There is no statistical significance in the results of the difference of liver/body coefficient between infection group and control group(F=0.590,P=0.478),the difference of each timing shows statistical significance(F=37.952,P<0.001),and the interaction difference of grouping and timing shows no statistical significance(F=2.303,P=0.067).There is no statistical significance in the results of the difference of brain/body coefficient between infection group and control group(F=0.031,P=0.861),the difference of each timing also shows no statistical significance(F=1.221,P=0.310),and the interaction difference of grouping and timing shows no statistical significance(F=0.355,P=0.840).
③Compare with Relative expression of TLR2、TLR4、MyD88 mRNA in infection group and control group, the real-time RT-PCR testing result shows that there is no statistical significance of TLR2 mRNA expression between infection group and control group in Lung Tissue of mice (F=0.032,P=0.858), the difference of each timing also shows no statistical (F=0.068,P=0.991), and the interaction difference of grouping and timing shows no statistical significance(F=0.269,P=0.897).There is no statistical significance in expression difference between expression infection group and control group of TLR4 mRNA in Lung Tissue of mice (F=0.321,P=0.573), the difference of each timing also shows no statistical significance (F=0.443,P=0.777), and the interaction difference of grouping and timing shows no statistical significance(F=0.616,P=0.625).There is no statistical significance in expression difference between expression infection group and control group of MyD88mRNA in Lung Tissue of mice (F=0.711,P=0.402), the difference of each timing also shows no statistical significance(F=0.367,P=0.831), and the interaction difference of grouping and timing shows no statistical significance(F=1.031,P=0.398).
④The difference of IL-6 concentrations expression between infection group and control group of Lung Tissue of mice shows statistical significance (F=69.18,P<0.001),the difference of each timing also shows statistical significance(F=5.289,P<0.001), and the interaction difference of grouping and timing shows statistical significance(F=8.686,P<0.001).The difference of TNF-αconcentrations expression between infection group and control group of Lung Tissue of mice shows statistical significance (F=24.6,P<0.001), the difference of each timing also shows statistical significance(F=14.230,P<0.001), and the interaction difference of grouping and timing shows statistical significance(F=13.987,P<0.001).
Conclusion
①Mouse intranasally inoculated by 50ul 1.2×109 /ml bacterial suspension of Legionella infection can establish Legionella model well.
②This study has not yet found that TLR2, TLR4 and MyD88 involved in anti-Legionella infection. IL-6 and TNF-αwere related with Legionella infection.
①探索建立小鼠军团菌感染模型的条件。
②初步阐明TLR2、TLR4在军团菌感染的作用机制,了解军团菌感染作用的分子靶点,为军团菌病的防治提供依据。
③探讨相关细胞因子(IL-6、TNF-α)在小鼠军团菌感染中的作用。
方法
1.从北京维通利华实验动物技术有限公司购买80只6-7周SPF级BALB/C小鼠,每组8只,雌雄各半。其中40只小鼠采用鼻内接种50ul 1.2×109/ml军团菌菌悬液,作为染菌组,建立军团菌感染模型,军团菌菌悬液的浓度根据麦氏比浊管确定。另外40只小鼠鼻内接种50ul无菌生理盐水作为对照组,分别于12小时、1天、3天、5天、7天麻醉小鼠,摘取眼球取血,解剖小鼠。
2.对染菌组和对照组的小鼠,分别于12小时、1天、3天、5天、7天处死,并进行下述研究:①取左肺上叶、肾脏、脾脏、肝脏少许,固定做病理切片。②采用Real-time RT PCR法测定小鼠肺组织中TLR2、TLR4、MyD88 mRNA的表达水平。③ELISA法检测小鼠肺组织匀浆液中细胞因子(IL-6、TNF-α)表达水平。
3.采用SPSS16.0统计软件进行数据的录入和分析。
结果
①病理切片结果显示:染菌组小鼠肺组织间质有炎性细胞浸润,且随着时间延长炎症有所加重,肺毛细血管壁有血管出血,说明造模成功。染菌组小鼠肾脏肾小球内有出血,且有炎性细胞浸润。染菌组小鼠脾脏髓质内可见出血,中性粒细胞浸润。尚未见染菌组小鼠肝脏有病理改变。
②脏器系数结果显示:染菌组和对照组之间肺脏脏器系数差异有统计学意义(F=13.987,P<0.001),各个时间点差异有统计学意义(F=3.035,P=0.023),分组和时间点交互作用差异无统计学意义(F=1.232,P=0.305)。染菌组和对照组之间脾脏脏器系数差异有统计学意义(F=40.585,P<0.001),各个时间点之间差异有统计学意义(F=4.525,P=0.003),分组和时间点之间交互作用差异无统计学意义(F=1.173,P=0.330)。染菌组和对照组之间肾脏脏器系数差异有统计学意义(F=20.473,P<0.001),各个时间点之间差异有统计学意义(F=5.025,P=0.001),分组和时间点之间交互作用差异无统计学意义(F=1.131,P=0.274)。染菌组和对照组之间心脏脏器系数差异无统计学意义(F=0.061,P=0.805),各个时间点之间差异也无统计学意义(F=1.528,P=0.204),分组和时间点之间交互作用差异无统计学意义(F=1.144,P=0.343)。染菌组和对照组之间肝脏脏器系数差异无统计学意义(F=0.590,P=0.478),各个时间点之间差异有统计学意义(F=37.952,P<0.001),分组和时间点之间交互作用差异无统计学意义(F=2.303,P=0.067)。染菌组和对照组之间脑脏器系数差异无统计学意义(F=0.031,P=0.861),各个时间点之间差异无统计学意义(F=1.221,P=0.310),分组和时间点之间交互作用差异无统计学意义(F=0.355,P=0.840)。③比较染菌组和对照组TLR2、TLR4、MyD88 mRNA相对表达量,real-time RT-PCR检测结果显示在染菌组和对照组小鼠肺组织TLR2 mRNA之间表达水平差异无统计学意义(F=0.032,P=0.858),各个时间点差异无统计学意义(F=0.068,P=0.991),分组和时间点之间交互作用差异无统计学意义(F=0.269,P=0.897)。染菌组和对照组小鼠肺组织TLR4 mRNA表达水平差异无统计学意义(F=0.321,P=0.573),各个时间点差异无统计学意义(F=0.443,P=0.777),分组和时间点之间交互作用差异无统计学意义(F=0.616,P=0.625)。染菌组和对照组肺组织MyD88 mRNA表达水平差异无统计学意义(F=0.711,P=0.402),各个时间点差异无统计学意义(F=0.367,P=0.831),分组和时间点之间交互作用差异无统计学意义(F=1.031,P=0.398)。
④染菌组和对照组小鼠肺组织IL-6的浓度差异有统计学意义(F=69.18,P<0.001),各个时间点差异有统计学意义(F=5.289,P<0.001),分组和时间点之间交互作用差异有统计学意义(F=8.686,P<0.001)。染菌组和对照组小鼠肺组织TNF-α的浓度差异有统计学意义(F=24.6,P<0.001),各个时间点差异有统计学意义(F=14.230,P<0.001),分组和时间点之间交互作用差异有统计学意义(F=13.987,P<0.001)。
结论:
①通过鼻内接种50ul 1.2×109/ml军团菌菌悬液能够建立军团菌感染的小鼠模型。
②本次研究尚未发现TLR2、TLR4、MyD88参与抗军团菌感染。
③IL-6和TNF-α与军团菌感染有关。
Objective
①To explore the conditions of establishment of mice Legionella infection model.
②To initially stated TLR2, TLR4’s action in Legionella infection mechanism, look into the molecular targets of effects against Legionella infection and provide evidence for Legionella prevention and control.
③To discuss related cytokines’(IL-6、TNF-α)role in mice infection of Legionella pneumophila.
Methods
1. Bought 80 SPF level 6-7 week BALB / C mice from Beijing Vital River Laboratory Animal Technology Company, N=8, male/female.40 mice intranasally inoculated with Legionella 50ul 1.2×109/ml bacterial suspension were as infection group, to establish Legionella infection model. The concentration of Legionella bacteria suspension was determined by Maxwell turbidity tube. Another 40 mice were inoculated with 50ul sterile saline nasal as the control group , All mice were anesthetized on 12 hours, 1 day, 3 days, 5 days and 7 days respectively. Bleed by removal of the eye, and dissect the mice.
2. Killed the infection and control groups of mice on 12 hours, 1 day, 3 days, 5 days and 7 days respectively, and conduct the following studies:①Done fixed biopsy with the upper lobe of left lung, kidney, spleen, and small piece of liver.②Determinated the mouse lung tissue’s TLR2, TLR4 and MyD88 mRNA expression levels in mouse lung tissue using the Real-time RT PCR .③Assay the cytokines (IL-6, TNF-α) in mouse lung homogenate by ELISA.
3. SPSS16.0 statistical software was used for data entry and analysis.
Results
①Pathology results showed that, mice in infection group had inflammatory cell infiltration within interstitial of lung tissue, which increased with time. Walls of pulmonary capillary vessels haemorrhage suggested that modeling successfully. Mice in this group hemorrhaged in glomerulus, and had inflammatory cell within filtration. These mice also hemorrhaged in spleen medulla, and had neutrophil infiltration. There had not been pathological changes of liver in these mice.
②The result of lung/body coefficient shows that there is statistical significance in the lung/body coefficient difference between infection group and control group(F=13.987,P<0.001), the difference of each timing shows statistical significance(F=3.035,P=0.023),the interaction difference of grouping and timing shows no statistical significance(F=1.232,P=0.305).There is statistical significance in the results of the difference of spleen/body coefficient between infection group and control group(F=40.585,P<0.001),the difference of each timing also shows statistical significance(F=4.525,P=0.003),and the interaction difference of grouping and timing shows no statistical significance(F=1.173,P=0.330). There is statistical significance in the results of the difference of kidney/body coefficient between infection group and control group(F=20.473,P<0.001),the difference of each timing also shows statistical significance(F=5.025,P=0.001),and the interaction difference of grouping and timing shows no statistical significance(F=1.131,P=0.274)There is no statistical significance in the results of the difference of heart/body coefficient between infection group and control group( F=0.061,P=0.805),the difference of each timing also shows no statistical significance(F=1.528,P=0.204),and the interaction difference of grouping and timing shows no statistical significance(F=1.144,P=0.343).There is no statistical significance in the results of the difference of liver/body coefficient between infection group and control group(F=0.590,P=0.478),the difference of each timing shows statistical significance(F=37.952,P<0.001),and the interaction difference of grouping and timing shows no statistical significance(F=2.303,P=0.067).There is no statistical significance in the results of the difference of brain/body coefficient between infection group and control group(F=0.031,P=0.861),the difference of each timing also shows no statistical significance(F=1.221,P=0.310),and the interaction difference of grouping and timing shows no statistical significance(F=0.355,P=0.840).
③Compare with Relative expression of TLR2、TLR4、MyD88 mRNA in infection group and control group, the real-time RT-PCR testing result shows that there is no statistical significance of TLR2 mRNA expression between infection group and control group in Lung Tissue of mice (F=0.032,P=0.858), the difference of each timing also shows no statistical (F=0.068,P=0.991), and the interaction difference of grouping and timing shows no statistical significance(F=0.269,P=0.897).There is no statistical significance in expression difference between expression infection group and control group of TLR4 mRNA in Lung Tissue of mice (F=0.321,P=0.573), the difference of each timing also shows no statistical significance (F=0.443,P=0.777), and the interaction difference of grouping and timing shows no statistical significance(F=0.616,P=0.625).There is no statistical significance in expression difference between expression infection group and control group of MyD88mRNA in Lung Tissue of mice (F=0.711,P=0.402), the difference of each timing also shows no statistical significance(F=0.367,P=0.831), and the interaction difference of grouping and timing shows no statistical significance(F=1.031,P=0.398).
④The difference of IL-6 concentrations expression between infection group and control group of Lung Tissue of mice shows statistical significance (F=69.18,P<0.001),the difference of each timing also shows statistical significance(F=5.289,P<0.001), and the interaction difference of grouping and timing shows statistical significance(F=8.686,P<0.001).The difference of TNF-αconcentrations expression between infection group and control group of Lung Tissue of mice shows statistical significance (F=24.6,P<0.001), the difference of each timing also shows statistical significance(F=14.230,P<0.001), and the interaction difference of grouping and timing shows statistical significance(F=13.987,P<0.001).
Conclusion
①Mouse intranasally inoculated by 50ul 1.2×109 /ml bacterial suspension of Legionella infection can establish Legionella model well.
②This study has not yet found that TLR2, TLR4 and MyD88 involved in anti-Legionella infection. IL-6 and TNF-αwere related with Legionella infection.
引文
[1]Diedereu BM. Legionella spp. and Legionnaires’disease. Journal of Infection, 2008,56(1):1-12
[2] Gilmour MW,Bernard K,Tracz DM et al.Molecular typing of a Legionella pneumophila outbreak in Ontario, Canada.Journal of Medical Microbiology, 2007,56(Pt3):336-341
[3] Rosalyn E O'Loughlin,Lon Kightlinger, Matthew C Werpy , et al. Outbreak of Legionnaires’disease associated with a decorative fountain: an enrironmental and case-control study. BMC Infectious Disease, 2007,7(93):1-9
[4] Palusińska-Szysz M, Cendrowska-Pinkosz M,et,al. Occurrence and pathogenicity of the family of Legionellaceae. Postepy Hig Med Dosw, 2008;62:337-353
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