粉尘螨提取液致敏CXCR3基因敲除小鼠肺部变应性炎症的研究
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摘要
哮喘是一种包括嗜酸性粒细胞在内的多种炎性细胞浸润、Th1和Th2源性细胞因子产生失衡及气道高反应性为特征的气道慢性变态反应性炎症性疾病。CD4~+CD25~+T细胞与γδT细胞在哮喘气道炎症反应中发挥着不容忽视的作用。多种细胞因子与趋化因子及其受体参与了哮喘的气道炎症反应,CXCR3受体及其配体是与Th1型细胞应答密切关联的炎症相关因子,但其作用机制还不清楚。本文利用CXCR3受体基因敲除小鼠构建哮喘的动物模型,探讨CD4~+CD25~+T细胞、γδT细胞与CXCR3受体及其配体在哮喘发病中的作用。
实验中,用HE染色计数BALF中不同种细胞的数量并观察肺组织的病理改变;BCA法测定BALF中的蛋白浓度;ELISA法检测小鼠BALF以及脾细胞培养上清中的炎症因子IL-4、IFN-γ的表达情况;流式细胞学检测肺组织、脾组织细胞中CD4~+T细胞、CD8~+T细胞、CD4~+CD25~+T细胞和γδT细胞的比例;RT-PCR检测肺组织中Mig、IP-10、TGF-β、IL-10和Foxp3的mRNA水平。
结果表明,使用粉尘螨提取液反复多次腹腔注射进行致敏,继而以雾化吸入的方式激发可以成功构建过敏性哮喘小鼠模型,致敏组BALF中的细胞总数、嗜酸性粒细胞数、IL-4和脾细胞培养上清中IL-4的含量较对照组显著升高、IFN-γ含量显著降低(P＜0.01)。致敏组CD4~+CD25~+T细胞占CD4~+T细胞的比值在肺组织中显著高于对照组(P＜0.05),脾组织中显著低于对照组(P＜0.05),且小鼠肺组织TGF-β和IL-10的mRNA表达水平显著低于对照组(P＜0.05)。致敏组γδT细胞占CD3~+T细胞的比值在肺组织中显著高于对照组(P＜0.05),脾组织中显著低于对照组(P＜0.05)。CXCR3~(-/-)基因敲除小鼠BALF中总细胞数、嗜酸性粒细胞数、淋巴细胞和蛋白含量以及脾细胞培养上清中IL-4的浓度较野生型显著升高(P＜0.01),且CXCR3~(-/-)小鼠肺组织中Mig、IP-10 mRNA的表达,均较野生型小鼠显著降低(P＜0.05)。
实验证实CD4~+CD25~+T细胞参与了肺部气道变应性炎症反应,在炎症应答中发挥着一定的调节作用,它的调节作用可能依赖于IL-10与TGF-β来实现,因而通过上调IL-10与TGF-β细胞因子的表达可能能够抑制哮喘的炎症反应。γδT细胞从外周聚集到炎症部位,参与了肺部变态反应性炎症反应,其具体机制还有待于进一步研究。CXCR3~(-/-)基因敲除小鼠较野生型C57BL/6小鼠的炎症应答更加严重,说明CXCR3受体与它的配体Mig、IP-10和I-TAC在哮喘肺部炎症的发生发展中可能共同发挥着对抗炎症的作用,是哮喘的保护性因素。促进患者CXCR3受体及其配体的表达,或许可以成为一个新的预防和治疗哮喘的策略。
Asthma is a chronic obstructive airway disease featuring eosinophilic airway inflammation,airway hyperesponssiveness(AHR) to bronchospasmogenic stimuli, mucus hypersecretion,airway remodeling,elevated serum levels of allergen-specific IgE and unbalanced Th1/Th2 immune responses.CD4~+CD25~+T cell andγδT cell participate in the allergic airway inflammation.Cytokines and chemokines play a key role in orchestrating the chronic inflammation of asthma.CXCR3 receptor and its ligands are nearly correlative with Th1 immune response.In this paper,we explore the function of CD4~+CD25~+T cell,γδT cell and CXCR3 by setting up an asthma mice model sensitized and challenged with house dust mite extracts Dermatophagoides farinae.
In this study,pathological manifestation of the lung,cell counts and classification in BALF were studied;protein in the BALF was detected by BCA;IL-4 and IFN-γ,levels in BALF and spleen supernatants were detected by ELISA;CD4~+T cell,CD8~+T cell,CD4~+CD25~+T cell andγδT cell in the lung and spleen were detected by flow cytometry;the expression of Mig,IP-10,TGF-β,IL-10 and Foxp3 mRNA were detected by RT-PCR.
In the end,we found that there was pulmonary eosinophilic inflammation in the mice sensitized and challenged with house dust mite extracts.Total cells counts, eosinophil counts and IL-4 levels in BALF and cultured splenocyte supernatants enhanced significantly while IFN-γdecreased(P＜0.01) in HDM Groups.The proportion of CD4~+CD25~+T cell in HDM groups increased significantly(P＜0.05) in the lung while decreased significantly(P＜0.05) in the spleen.The expression of TGF-βand IL-10 mRNA in the HDM groups were lower than the control groups (P＜0.05).The proportion ofγδT cell in HDM groups increased significantly(P＜0.05) in the lung while decreased significantly(P＜0.05) in the spleen.The changes of total cells counts,eosinophil counts,lymphocyte counts,protein in the BALF,IL-4 in the splenocyte supematants and pathological manifestation of the lung were more intensive in CXCR3~(-/-) mice than C57BL/6 wild-type mice.Further more,the expression of Mig,IP-10 mRNA in CXCR3~(-/-) mice lung were lower than C57BL/6 wild-type mice(P＜0.05).
CD4~+CD25~+T cell modulates the allergic pulmonary inflammatory reaction depended on IL-10 and TGF-β.The allergic pulmonary inflammation may be suppressed by uprising IL-10 and TGF-β.γδT cell participates in the allergic pulmonary inflammation,but the immanent mechanism needs further study.As compared with C57BL/6 wild-type mice,CXCR3~(-/-)mice were more sensitized to allergic pulmonary inflammation model.CXCR3 and its ligands(Mig,IP-10 and I-TAC) play an anti-inflammatory role during the pathogenic process in this animal model.They may be protective factors for asthma patients.Promoting the expression of CXCR3 and its ligands could be a new target for preventing and curing asthma.
实验中,用HE染色计数BALF中不同种细胞的数量并观察肺组织的病理改变;BCA法测定BALF中的蛋白浓度;ELISA法检测小鼠BALF以及脾细胞培养上清中的炎症因子IL-4、IFN-γ的表达情况;流式细胞学检测肺组织、脾组织细胞中CD4~+T细胞、CD8~+T细胞、CD4~+CD25~+T细胞和γδT细胞的比例;RT-PCR检测肺组织中Mig、IP-10、TGF-β、IL-10和Foxp3的mRNA水平。
结果表明,使用粉尘螨提取液反复多次腹腔注射进行致敏,继而以雾化吸入的方式激发可以成功构建过敏性哮喘小鼠模型,致敏组BALF中的细胞总数、嗜酸性粒细胞数、IL-4和脾细胞培养上清中IL-4的含量较对照组显著升高、IFN-γ含量显著降低(P＜0.01)。致敏组CD4~+CD25~+T细胞占CD4~+T细胞的比值在肺组织中显著高于对照组(P＜0.05),脾组织中显著低于对照组(P＜0.05),且小鼠肺组织TGF-β和IL-10的mRNA表达水平显著低于对照组(P＜0.05)。致敏组γδT细胞占CD3~+T细胞的比值在肺组织中显著高于对照组(P＜0.05),脾组织中显著低于对照组(P＜0.05)。CXCR3~(-/-)基因敲除小鼠BALF中总细胞数、嗜酸性粒细胞数、淋巴细胞和蛋白含量以及脾细胞培养上清中IL-4的浓度较野生型显著升高(P＜0.01),且CXCR3~(-/-)小鼠肺组织中Mig、IP-10 mRNA的表达,均较野生型小鼠显著降低(P＜0.05)。
实验证实CD4~+CD25~+T细胞参与了肺部气道变应性炎症反应,在炎症应答中发挥着一定的调节作用,它的调节作用可能依赖于IL-10与TGF-β来实现,因而通过上调IL-10与TGF-β细胞因子的表达可能能够抑制哮喘的炎症反应。γδT细胞从外周聚集到炎症部位,参与了肺部变态反应性炎症反应,其具体机制还有待于进一步研究。CXCR3~(-/-)基因敲除小鼠较野生型C57BL/6小鼠的炎症应答更加严重,说明CXCR3受体与它的配体Mig、IP-10和I-TAC在哮喘肺部炎症的发生发展中可能共同发挥着对抗炎症的作用,是哮喘的保护性因素。促进患者CXCR3受体及其配体的表达,或许可以成为一个新的预防和治疗哮喘的策略。
Asthma is a chronic obstructive airway disease featuring eosinophilic airway inflammation,airway hyperesponssiveness(AHR) to bronchospasmogenic stimuli, mucus hypersecretion,airway remodeling,elevated serum levels of allergen-specific IgE and unbalanced Th1/Th2 immune responses.CD4~+CD25~+T cell andγδT cell participate in the allergic airway inflammation.Cytokines and chemokines play a key role in orchestrating the chronic inflammation of asthma.CXCR3 receptor and its ligands are nearly correlative with Th1 immune response.In this paper,we explore the function of CD4~+CD25~+T cell,γδT cell and CXCR3 by setting up an asthma mice model sensitized and challenged with house dust mite extracts Dermatophagoides farinae.
In this study,pathological manifestation of the lung,cell counts and classification in BALF were studied;protein in the BALF was detected by BCA;IL-4 and IFN-γ,levels in BALF and spleen supernatants were detected by ELISA;CD4~+T cell,CD8~+T cell,CD4~+CD25~+T cell andγδT cell in the lung and spleen were detected by flow cytometry;the expression of Mig,IP-10,TGF-β,IL-10 and Foxp3 mRNA were detected by RT-PCR.
In the end,we found that there was pulmonary eosinophilic inflammation in the mice sensitized and challenged with house dust mite extracts.Total cells counts, eosinophil counts and IL-4 levels in BALF and cultured splenocyte supernatants enhanced significantly while IFN-γdecreased(P＜0.01) in HDM Groups.The proportion of CD4~+CD25~+T cell in HDM groups increased significantly(P＜0.05) in the lung while decreased significantly(P＜0.05) in the spleen.The expression of TGF-βand IL-10 mRNA in the HDM groups were lower than the control groups (P＜0.05).The proportion ofγδT cell in HDM groups increased significantly(P＜0.05) in the lung while decreased significantly(P＜0.05) in the spleen.The changes of total cells counts,eosinophil counts,lymphocyte counts,protein in the BALF,IL-4 in the splenocyte supematants and pathological manifestation of the lung were more intensive in CXCR3~(-/-) mice than C57BL/6 wild-type mice.Further more,the expression of Mig,IP-10 mRNA in CXCR3~(-/-) mice lung were lower than C57BL/6 wild-type mice(P＜0.05).
CD4~+CD25~+T cell modulates the allergic pulmonary inflammatory reaction depended on IL-10 and TGF-β.The allergic pulmonary inflammation may be suppressed by uprising IL-10 and TGF-β.γδT cell participates in the allergic pulmonary inflammation,but the immanent mechanism needs further study.As compared with C57BL/6 wild-type mice,CXCR3~(-/-)mice were more sensitized to allergic pulmonary inflammation model.CXCR3 and its ligands(Mig,IP-10 and I-TAC) play an anti-inflammatory role during the pathogenic process in this animal model.They may be protective factors for asthma patients.Promoting the expression of CXCR3 and its ligands could be a new target for preventing and curing asthma.
引文
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