肺间质树突状细胞在多器官功能障碍综合征中的免疫激活与免疫耐受作用研究
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摘要
目的：1.探讨肺间质树突状细胞(DCs)的免疫表型及功能变化在MODS模型早期过度炎症反应和晚期免疫抑制中的作用。2.证实MODS期肺间质DCs存在免疫耐受现象,探讨DCs负向调节作用对肺组织损伤的影响。3.应用N-乙酰-L-半胱氨酸(NAC)和Flt3配体(Flt3L)分别针对MODS早期过度炎症和晚期免疫抑制中DCs功能进行实验性干预调节,观察减轻肺组织损伤和改善脏器功能的效果。
方法：腹腔注射酵母多糖复制Balb／c小鼠MODS模型。主要实验分组：急性损伤组(n=30)：酵母多糖注射后48h取材；NAC治疗组(n=30)：酵母多糖注射后3h、6h、12h、18h、24h、36h皮下注射NAC(100mg／kg体重),48h取材；MODS组(n=30)：酵母多糖注射后10d取材；Flt3L治疗组(n=20)：酵母多糖注射后48h开始每日皮下注射rFlt3L(10μg／只,连续注射7d),第10d取材；对照组(n=20)：以等量生理盐水替代酵母多糖和NAC或rFlt3L按上述时间注射。每组小鼠按不同时间点麻醉后摘眼球取血,肺血管灌注,摘取双侧肺,按不同实验分别进行固定、超低温冻存、酶消化或匀浆处理。自动生化分析仪检测CO2、ALT、AST、Cr等血生化指标。生化法检测肺组织MPO活性。ELISA法检测血清和肺组织匀浆TNF-α含量。光镜观察肺组织病理变化,CD205免疫组化和CD11c免疫荧光标记肺间质DCs。密度梯度离心分离肺低密度单个核细胞,MACS磁珠分选DCs,流式细胞术进行DCs鉴定和免疫表型分析(I-Ad、CD86、PD-L1)。扫描和透射电镜观察DCs的超微形态。凝胶电泳迁移率变动分析法检测DCs胞核内NF-κB含量和活性。Real-time PCR检测DCs的CCR5/CCR7mRNA表达。体外LPS刺激DCs,ELISA法检测DCs孵育上清液细胞因子IL-12p70和IL-10含量。
结果：1.正常Balb／c小鼠肺间质DCs分为三个亚群：髓系CD11c+CD11b+DCs、类浆系CD11c+CD45R＼B220+DCs、淋巴系CD11c+CD11b-／CD45R＼B220-DCs,分别占肺单个核细胞比例的6.35%、1.96%、3.21%。肺间质DCs高表达髓系标志物CD11b(39.59%),低表达MHC-Ⅱ／Ⅰ-Ad(8.97%)和共刺激分子CD86(3.16%)。DCs表面见长1-2μm树枝状突起,细胞器不发达,未见各级溶酶体和吞噬颗粒,细胞核形状不规则。2.急性损伤组(与对照组比较),血CO2含量降低,肺组织和血清TNF-α水平显著上升。肺含水量增加,肺组织MPO活性显著增高。肺间质CD11c+DCs数量增加,DCs体积增大,表面突起增多、变长。DCs表面I-Ad和共刺激分子CD86表达显著增高,趋化因子受体CCR5表达显著增加,CCR7表达轻度升高。DCs的NF-κB胞核内转移和活性增加。3.NAC治疗组(与急性损伤组比较),肺含水量、肺组织MPO活性和TNF-α水平明显降低,血CO2含量升高,DCs的NF-κB细胞核内转移和活性降低,DCs表面I-Ad和CD86表达降低,CCR5和CCR7表达下降。实验鼠急性损伤期死亡率降低20%。4.MODS组,血清ALT、AST、脂肪酶、淀粉酶和肌苷水平较对照组显著升高,血葡萄糖水平明显下降。肺间质髓系与类浆系DCs亚群比例及CD205+DCs数量较对照组明显降低,而淋巴系DCs比例明显升高。DCs表达I-Ad和CD86较对照组和急性损伤组明显下降,DCs表达耐受性分子PD-L1增高十分显著。电镜下DCs多呈退变与凋亡改变。在体外实验LPS刺激后,DCs分泌IL-12p70水平较对照组和急性损伤组明显下降而IL-10水平显著升高。5.Flt3L治疗组(与MODS组比较),髓系和类浆系DCs亚群比例较MODS组明显增加,淋巴系DCs比例降低。DCs表达I-Ad+、CD86及CD205+DCs数量较MODS组显著增加,DCs表达PD-L1明显下降。体外LPS刺激后,DCs分泌IL-12p70水平显著回升。肺组织损伤明显减轻,血清ALT、AST和肌苷水平较MODS组均有明显下降,血糖水平上升。实验鼠MODS期死亡率降低12%。
结论：1．利用密度梯度离心和免疫磁珠分离、纯化肺间质DCs,获得DCs纯度高,活性良好,免疫表型稳定,但操作步骤复杂,技术要求较高。2.MODS急性损伤期,肺间质DCs大量成熟活化导致免疫应答反应亢进和炎症反应失控。肺间质DCs功能紊乱是引起肺过度炎症损伤的主要免疫细胞学因素。3.N-乙酰-L-半胱氨酸体内干预能够降低肺间质DCs的NF-κB胞核内转移和活性,从而抑制DCs分化成熟和趋化迁移,减弱炎症反应,进而减轻MODS急性损伤期的肺组织损伤。4.MODS期,肺间质DCs活性减低(表达I-Ad和CD86比例下降),发生免疫耐受(DCs表达PD-L1显著升高),并通过大量分泌IL-10发挥负向免疫调节作用。DCs的免疫耐受作用参与诱导和促进了免疫抑制与肺功能衰竭。5.Flt3L体内扩增DCs作用能够增加肺间质髓系和类浆系DCs亚群及成熟DCs比例,致DCs分泌IL-12p70增加,正向免疫调节作用增强。Flt3L可以明显逆转MODS期肺间质DCs的免疫耐受状态,进而减轻肺组织损伤和改善脏器功能。
Objective:1. To explore the relationship between immunophenotype and immunologic function of lung dendritic cells (DCs) and excessive inflammation and immunosuppression in multiple organs dysfunction syndrome (MODS).2. To confirm the immunologic tolerance of lung DCs in the stage of MODS and to explore its effect on immunosuppression.3. To observe the effects of alleviating lung damage and improving lung function by applying N-acetyl-L-cysteine (NAC) and fms-like tyrosine kinase 3 ligand(Flt3L) to regulate DCs'function in excessive inflammation and immunosuppression in MODS respectively.
Methods:The model of MODS was replicated by zymosan injecting into the peritoneal cavity of Balb/c mice. The experimental groups were mainly divided as below:(1) acute damage groups (n=30). (2)NAC treating groups (n=30). (3)MODS groups (n=30). (4)Flt3L treating groups (n=20). (5)Control groups (n=20). The subcutaneous administration of NAC in dose of 100mg/kg body weight was at 3h, 6h,12h,18h,24h and 36h after zymosan injection. The subcutaneous administration of Flt3L in dose of 10μg/per day and per mouse, consecutive injection in 7 days was at 48h after zymosan injection. Symptom and mortality of the mice were observed. Biochemical indicator of CO2, ALT, AST and creatinine were detected by automatic biochemical analysator. MPO in lung tissue was measured by biochemical analysis. Pathological changes of lung were observed by light microscope. Specific surface markers CD205 and CDllc of lung DCs were detected by immunohistochemistry and immunofluorescence. Lung low density mononuclear cells were separated by density gradient centrifugation and then DCs were isolated by MACS microbeads. Purity identification and DCs'phenotypes of I-Ad, CD86 and PD-L1 were analyzed by flow cytometry. Ultrastructure of DCs was observed by scanning and transmission electron microscope. The protein and activity of NF-κB in the DCs' nuclear were detected electrophoretic mobility shift assay. The expression of CCR5/CCR7mRNA in DCs was measured by by real-time quantitative PCR. TNF-a from lung tissue homogenate and serum and IL-12p70 and IL-10 ELISA in supernatant were determined by ELISA kits.
Results:In acute damage groups(comparing with control groups), the proportion of CO2 in blood decreased. The level of TNF-a, MPO and water content in lung increased dramatically. The numbers of CD11c+DCs rise. The significantly elevated expression of I-Ad, CD86 and CCR5 in DCs were detected. The activity of NF-κB in the DCs' nuclear increased notably. In NAC treating groups (comparing with acute damage groups), the level of TNF-a, MPO and water content in lung decreased notably, and the proportion of CO2 in blood increased. The remarkable decreased expression of I-Ad, CD86, CCR5 and CCR7 in DCs were measured. The activity of NF-κB in the DCs'nuclear declined. The mortality of the mice declined 20%. In MODS groups, the level of ALT, AST, lipase, amylase and creatinine increased dramatically and glucose decreased in serum comparing with control groups. The proportion myeloid and plasmacytoid DCs and CD205+DCs declined, but lymphoid DCs increased with comparison to that of control groups. The remarkable decreased expression of I-Ad and CD86 in DCs were measured, and DCs expressed high-level tolerant molecule PD-L1 markedly. DCs appeared morphologic change of apoptosis and degeneration. DCs secreted more IL-10 and less IL12-p70 after LPS stimulation in vitro contrast to control and acute damage groups. In Flt3L treating groups (comparing with MODS groups), the proportion myeloid and plasmacytoid DCs and CD205+DCs increased, and lymphoid DCs decreased. The remarkable increased expression of I-Ad and CD86 in DCs were detected, and DCs expressed low-level tolerant molecule PD-L1. DCs secreted more IL12-p70 after LPS stimulation in vitro. The mortality of the mice declined 12%.
Conclusions:1.Isolated by density gradient centrifugation and MACS microbeads, Lung DCs acquired high purity and activity and stable phenotypes.2. In the stage of acute damage, the activation and maturation of lung DCs induced excessive immune response and inflammation, which caused inflammatory damage in lung.3. NAC had the effect on lightening lung damage in the stage of acute damage by inhibiting the maturation and migration of DCs with less NF-κB shift to nuclear.4. In the stage of MODS, lung DCs presented inactivition and induce immunologic tolerance. DCs excreted overmuch IL-10 to have effect on negative immunologic regulation and participated in immunosuppression.5. After Flt3L administration in vivo, lung DCs presented amplification and induce positive immunologic regulation. Flt3L reversed DCs'immunologic tolerance, which lightening lung injury and protect organ function.
方法：腹腔注射酵母多糖复制Balb／c小鼠MODS模型。主要实验分组：急性损伤组(n=30)：酵母多糖注射后48h取材；NAC治疗组(n=30)：酵母多糖注射后3h、6h、12h、18h、24h、36h皮下注射NAC(100mg／kg体重),48h取材；MODS组(n=30)：酵母多糖注射后10d取材；Flt3L治疗组(n=20)：酵母多糖注射后48h开始每日皮下注射rFlt3L(10μg／只,连续注射7d),第10d取材；对照组(n=20)：以等量生理盐水替代酵母多糖和NAC或rFlt3L按上述时间注射。每组小鼠按不同时间点麻醉后摘眼球取血,肺血管灌注,摘取双侧肺,按不同实验分别进行固定、超低温冻存、酶消化或匀浆处理。自动生化分析仪检测CO2、ALT、AST、Cr等血生化指标。生化法检测肺组织MPO活性。ELISA法检测血清和肺组织匀浆TNF-α含量。光镜观察肺组织病理变化,CD205免疫组化和CD11c免疫荧光标记肺间质DCs。密度梯度离心分离肺低密度单个核细胞,MACS磁珠分选DCs,流式细胞术进行DCs鉴定和免疫表型分析(I-Ad、CD86、PD-L1)。扫描和透射电镜观察DCs的超微形态。凝胶电泳迁移率变动分析法检测DCs胞核内NF-κB含量和活性。Real-time PCR检测DCs的CCR5/CCR7mRNA表达。体外LPS刺激DCs,ELISA法检测DCs孵育上清液细胞因子IL-12p70和IL-10含量。
结果：1.正常Balb／c小鼠肺间质DCs分为三个亚群：髓系CD11c+CD11b+DCs、类浆系CD11c+CD45R＼B220+DCs、淋巴系CD11c+CD11b-／CD45R＼B220-DCs,分别占肺单个核细胞比例的6.35%、1.96%、3.21%。肺间质DCs高表达髓系标志物CD11b(39.59%),低表达MHC-Ⅱ／Ⅰ-Ad(8.97%)和共刺激分子CD86(3.16%)。DCs表面见长1-2μm树枝状突起,细胞器不发达,未见各级溶酶体和吞噬颗粒,细胞核形状不规则。2.急性损伤组(与对照组比较),血CO2含量降低,肺组织和血清TNF-α水平显著上升。肺含水量增加,肺组织MPO活性显著增高。肺间质CD11c+DCs数量增加,DCs体积增大,表面突起增多、变长。DCs表面I-Ad和共刺激分子CD86表达显著增高,趋化因子受体CCR5表达显著增加,CCR7表达轻度升高。DCs的NF-κB胞核内转移和活性增加。3.NAC治疗组(与急性损伤组比较),肺含水量、肺组织MPO活性和TNF-α水平明显降低,血CO2含量升高,DCs的NF-κB细胞核内转移和活性降低,DCs表面I-Ad和CD86表达降低,CCR5和CCR7表达下降。实验鼠急性损伤期死亡率降低20%。4.MODS组,血清ALT、AST、脂肪酶、淀粉酶和肌苷水平较对照组显著升高,血葡萄糖水平明显下降。肺间质髓系与类浆系DCs亚群比例及CD205+DCs数量较对照组明显降低,而淋巴系DCs比例明显升高。DCs表达I-Ad和CD86较对照组和急性损伤组明显下降,DCs表达耐受性分子PD-L1增高十分显著。电镜下DCs多呈退变与凋亡改变。在体外实验LPS刺激后,DCs分泌IL-12p70水平较对照组和急性损伤组明显下降而IL-10水平显著升高。5.Flt3L治疗组(与MODS组比较),髓系和类浆系DCs亚群比例较MODS组明显增加,淋巴系DCs比例降低。DCs表达I-Ad+、CD86及CD205+DCs数量较MODS组显著增加,DCs表达PD-L1明显下降。体外LPS刺激后,DCs分泌IL-12p70水平显著回升。肺组织损伤明显减轻,血清ALT、AST和肌苷水平较MODS组均有明显下降,血糖水平上升。实验鼠MODS期死亡率降低12%。
结论：1．利用密度梯度离心和免疫磁珠分离、纯化肺间质DCs,获得DCs纯度高,活性良好,免疫表型稳定,但操作步骤复杂,技术要求较高。2.MODS急性损伤期,肺间质DCs大量成熟活化导致免疫应答反应亢进和炎症反应失控。肺间质DCs功能紊乱是引起肺过度炎症损伤的主要免疫细胞学因素。3.N-乙酰-L-半胱氨酸体内干预能够降低肺间质DCs的NF-κB胞核内转移和活性,从而抑制DCs分化成熟和趋化迁移,减弱炎症反应,进而减轻MODS急性损伤期的肺组织损伤。4.MODS期,肺间质DCs活性减低(表达I-Ad和CD86比例下降),发生免疫耐受(DCs表达PD-L1显著升高),并通过大量分泌IL-10发挥负向免疫调节作用。DCs的免疫耐受作用参与诱导和促进了免疫抑制与肺功能衰竭。5.Flt3L体内扩增DCs作用能够增加肺间质髓系和类浆系DCs亚群及成熟DCs比例,致DCs分泌IL-12p70增加,正向免疫调节作用增强。Flt3L可以明显逆转MODS期肺间质DCs的免疫耐受状态,进而减轻肺组织损伤和改善脏器功能。
Objective:1. To explore the relationship between immunophenotype and immunologic function of lung dendritic cells (DCs) and excessive inflammation and immunosuppression in multiple organs dysfunction syndrome (MODS).2. To confirm the immunologic tolerance of lung DCs in the stage of MODS and to explore its effect on immunosuppression.3. To observe the effects of alleviating lung damage and improving lung function by applying N-acetyl-L-cysteine (NAC) and fms-like tyrosine kinase 3 ligand(Flt3L) to regulate DCs'function in excessive inflammation and immunosuppression in MODS respectively.
Methods:The model of MODS was replicated by zymosan injecting into the peritoneal cavity of Balb/c mice. The experimental groups were mainly divided as below:(1) acute damage groups (n=30). (2)NAC treating groups (n=30). (3)MODS groups (n=30). (4)Flt3L treating groups (n=20). (5)Control groups (n=20). The subcutaneous administration of NAC in dose of 100mg/kg body weight was at 3h, 6h,12h,18h,24h and 36h after zymosan injection. The subcutaneous administration of Flt3L in dose of 10μg/per day and per mouse, consecutive injection in 7 days was at 48h after zymosan injection. Symptom and mortality of the mice were observed. Biochemical indicator of CO2, ALT, AST and creatinine were detected by automatic biochemical analysator. MPO in lung tissue was measured by biochemical analysis. Pathological changes of lung were observed by light microscope. Specific surface markers CD205 and CDllc of lung DCs were detected by immunohistochemistry and immunofluorescence. Lung low density mononuclear cells were separated by density gradient centrifugation and then DCs were isolated by MACS microbeads. Purity identification and DCs'phenotypes of I-Ad, CD86 and PD-L1 were analyzed by flow cytometry. Ultrastructure of DCs was observed by scanning and transmission electron microscope. The protein and activity of NF-κB in the DCs' nuclear were detected electrophoretic mobility shift assay. The expression of CCR5/CCR7mRNA in DCs was measured by by real-time quantitative PCR. TNF-a from lung tissue homogenate and serum and IL-12p70 and IL-10 ELISA in supernatant were determined by ELISA kits.
Results:In acute damage groups(comparing with control groups), the proportion of CO2 in blood decreased. The level of TNF-a, MPO and water content in lung increased dramatically. The numbers of CD11c+DCs rise. The significantly elevated expression of I-Ad, CD86 and CCR5 in DCs were detected. The activity of NF-κB in the DCs' nuclear increased notably. In NAC treating groups (comparing with acute damage groups), the level of TNF-a, MPO and water content in lung decreased notably, and the proportion of CO2 in blood increased. The remarkable decreased expression of I-Ad, CD86, CCR5 and CCR7 in DCs were measured. The activity of NF-κB in the DCs'nuclear declined. The mortality of the mice declined 20%. In MODS groups, the level of ALT, AST, lipase, amylase and creatinine increased dramatically and glucose decreased in serum comparing with control groups. The proportion myeloid and plasmacytoid DCs and CD205+DCs declined, but lymphoid DCs increased with comparison to that of control groups. The remarkable decreased expression of I-Ad and CD86 in DCs were measured, and DCs expressed high-level tolerant molecule PD-L1 markedly. DCs appeared morphologic change of apoptosis and degeneration. DCs secreted more IL-10 and less IL12-p70 after LPS stimulation in vitro contrast to control and acute damage groups. In Flt3L treating groups (comparing with MODS groups), the proportion myeloid and plasmacytoid DCs and CD205+DCs increased, and lymphoid DCs decreased. The remarkable increased expression of I-Ad and CD86 in DCs were detected, and DCs expressed low-level tolerant molecule PD-L1. DCs secreted more IL12-p70 after LPS stimulation in vitro. The mortality of the mice declined 12%.
Conclusions:1.Isolated by density gradient centrifugation and MACS microbeads, Lung DCs acquired high purity and activity and stable phenotypes.2. In the stage of acute damage, the activation and maturation of lung DCs induced excessive immune response and inflammation, which caused inflammatory damage in lung.3. NAC had the effect on lightening lung damage in the stage of acute damage by inhibiting the maturation and migration of DCs with less NF-κB shift to nuclear.4. In the stage of MODS, lung DCs presented inactivition and induce immunologic tolerance. DCs excreted overmuch IL-10 to have effect on negative immunologic regulation and participated in immunosuppression.5. After Flt3L administration in vivo, lung DCs presented amplification and induce positive immunologic regulation. Flt3L reversed DCs'immunologic tolerance, which lightening lung injury and protect organ function.
引文
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