支气管哮喘患者血清白细胞介素（IL）-18的水平变化及IL-18对小鼠过敏性炎症的调节机制研究
摘要
【目的】探讨哮喘患者血清中IL-18、总IgE、Th1和Th2类细胞因子水平变化的相关性及IL-18对小鼠过敏性炎症的调节机制。
【方法】随机收集哮喘急性发作期患者50例,健康对照者50例血清。采用双抗体夹心酶联免疫吸附试验(ELISA)分别检测血清IL-18、总IgE、IL-8、IL-4、IFN-γ水平。雌性BALB/c小鼠78只,8-10周龄,按随机数字表法分为阴性对照组、生理盐水(normal saline, NS)组、IL-18组、IL-18结合蛋白(binding protein, BP)组、Eotaxin组、IL-18+Eotaxin组、IL-18BP+Eotaxin组,除阴性对照组外每组设非致敏对照组,每组6只,各致敏组小鼠分别在第1、7、13、19、20、21天腹腔注射致敏液OVA,最后一次激发前10min、30min、1h分别给与IL-18、IL-18BP、Eotaxin、IL-18+Eotaxin、IL-18BP+Eotaxin腹腔注射,末次激发3小时后收集腹腔灌洗液,用ELISA法观察小鼠腹腔灌洗液(PLF)上清中IgE、IL-6、IL-12分泌情况;瑞士染色细胞涂片计数肥大细胞(MC)和嗜酸性粒细胞(EOS),流式细胞术检测PLF中T细胞和单核细胞PAR-1、2、4的表达, CD4+CD25+Treg和Th17的表达。非致敏组小鼠与致敏组同步喂养,给药步骤同致敏组,末次用药后3小时处死,其余检测同致敏组。
【结果】哮喘组IL-18、IL-8、IL-4均高于对照组,但IFN-γ水平低于试剂盒的检测范围。哮喘组血清总IgE水平明显高于对照组,IL-18与IL-8、IL-4、总IgE,IL-4与总IgE之间分别存在正相关。对小鼠PLF进行涂片并瑞士染色分类计数细胞发现IL-18、Eotaxin、IL-18+Eotaxin组MC及EOS细胞数明显增高,IL-18BP组MC及EOS细胞数明显减少,IL-18BP+Eotaxin与NS组相比无明显差异,但各组MC及EOS均高于阴性对照组(P<0.05)。ELISA结果显示,致敏小鼠PLF上清总IgE水平都显著高于阴性对照组,与NS组比较,IL-18、IL-18+Eotaxin组总IgE水平明显降低,而IL-18BP、Eotaxin、IL-18BP+Eotaxin组总IgE水平明显升高(P<0.05);未致敏状态与致敏状态趋势一致且均低于对应致敏组(P<0.05)。致敏小鼠PLF上清IL-6水平均高于阴性对照组,IL-18、IL-18+Eotaxin刺激IL-6的分泌,IL-18BP、Eotaxin、IL-18BP+Eotaxin抑制IL-6的分泌;未致敏IL-6水平均低于对应致敏组(P<0.05)。致敏小鼠PLF上清IL-12水平在IL-18刺激后明显升高,IL-18BP、Eotaxin、IL-18+Eotaxin、IL-18BP+Eotaxin干预后降低(P<0.05);未致敏组IL-12水平在IL-18作用后降低,且低于对应致敏组,其他组IL-12水平均升高且高于对应致敏组(P<0.05)。
流式细胞术提示致敏小鼠的PLF中IL-18BP、Eotaxin诱导的T淋巴细胞、单核细胞PAR-1、4的表达明显高于NS组,而IL-18作用后的表达低于NS组;此外,IL-18+Eotaxin、IL-18BP+Eotaxin诱导单核细胞PAR-1、4表达升高,而T淋巴细胞的表达降低(P<0.05)。IL-18、Eotaxin诱导的T淋巴细胞PAR-2的表达明显高于NS组,IL-18BP、IL-18BP+Eotaxin作用后的表达低于NS组,但是,只有IL-18BP+Eotaxin诱导单核细胞PAR-2的表达升高,其它均降低(P<0.05)。CD4~+CD25~+T淋巴细胞数在IL-18、IL-18+Eotaxin、IL-18BP+Eotaxin诱导后明显多于NS组,而在IL-18BP、Eotaxin干预后明显少于NS组(P<0.05);同阴性对照组相比,各致敏组CD4~+CD25~+T淋巴细胞数均减少(P<0.05)。Th17细胞数在IL-18、Eotaxin、IL-18+Eotaxin诱导后增加,而在IL-18BP、IL-18BP+Eotaxin干预后减少(P<0.05)。
未致敏小鼠PLF中IL-18诱导的单核细胞PAR-1、4的表达明显高于NS组,而IL-18BP、Eotaxin、IL-18BP+Eotaxin作用后的T淋巴细胞、单核细胞的表达明显低于NS组(P<0.05)。IL-18BP诱导的T淋巴细胞、单核细胞PAR-2的表达明显高于NS组,而IL-18、Eotaxin作用后的表达低于NS组(P<0.05)。CD4~+CD25~+T淋巴细胞、Th17细胞数量在IL-18、Eotaxin诱导后明显多于NS组,而在IL-18BP干预后明显少于NS组(P<0.05);同致敏组相比IL-18BP、Eotaxin作用的T细胞PAR-1、4的表达降低,其余各组均增高(P<0.05)。
【结论】哮喘患者血清IL-18水平增高提示该细胞因子参与哮喘的发病过程。IL-18调节过敏性小鼠腹腔灌洗液T淋巴细胞和单核细胞PARs表达、CD4+CD25+T淋巴细胞及Th17细胞数,刺激IL-6及IL-12分泌的作用部分揭示了其在过敏性炎症中的作用机制。
OBJECTIVE: To investigate the correlation among serum levels of IL-18 ,total IgE ,Th1 and Th2 type cytokine in the patients with asthma ,and the regulatory mechanism of IL-18 in mouse allergic inflammatory.
METHOD: 50 patients with acute asthma attack (group asthms) and 50 healthy subjects (group contronl) for the measurements of total IgE, IL-18, IL-8, IL-4 and IFN-γwith ELISA.78 femal BALB/c mices were randomly divided into 13 groups. They are normal group,NS group,IL-18 group,IL-18BP group,Eotaxin group, IL-18+Eotaxin group, IL-18BP+Eotaxin group.Every group had a unsensitive control and contained 6 mice.All mouses exclude normal group were immunized intraperitoneally with ovalbumin(OVA) on 1,7,13, 19 ,20 ,21d, OVA-sensitized mice were injected intraperitoneally with murine rIL-18,IL-18BP,Eotaxin, IL-18+Eotaxin, IL-18BP+Eotaxin (1ug) at 10min,30min and 1 h before the last intraperitoneally OVA challenge. As a control,OVA-sensitized mice were injected intraperitoneally with 0.9% saline.The peritoneal lavage fluid was then collected at 3h after OVA or saline intraperitoneal.The immunoglobulinE (IgE),IL-6,IL-12 in the mice supernatants of PLF were observed by the means of enzyme linked immunosorbent assay (ELISA),PLF cell differentials were determined by counting 500 cells stained with Wright-Giemsa solution,expression of PARs , CD4~+CD25~+Treg,Th17 cell were analyzed by flowcytometry.Unsensitive control group were fed in the same condition with all sensitive groups and other administer were alike with sensitive groups.
RESULTS: In asthmatic group,serum IL-18,IL-8 and IL-4 in group asthma were increased compaired with group C.The total IgE level in asthmatics was also increased compaired with group C.Serum levels of IL-18 was positively correlated with that of IL-8,IL-4 and total IgE,and IL-4 was positively correlated with that of total IgE.The level of total serum IgE were increased significantly in OVA- sensitized /challenged mice compared with the control group(P<0.05), administration of IL-18 reduced the levels of total serum IgE compared with other groups in both sensitive and unsensitive groups(P<0.05).IL-18 induced IL-12 and IL-6 release in sensitived mouse PLF supernatant,and there was decreased IL-12 and increased IL-6 in unsensitive group(P<0.05).The eosinophil and mast cell infiltration into the PLF of IL-18, Eotaxin and IL-18+Eotaxin groups were significantly increased compared with those in group NS.The administration of IL-18BP significantly decreased OVA- induced eosinophil and mast cell recruitment into the PLF. Which was not significantly different between group IL-18BP+Eotaxin and NS.
Flow cytometry demonstrated that in sensitived group PLF PAR-1 and PAR-4 expression on T-cells and monocytes in group IL-18BP and Eotaxin were increased over those in group NS,but in group IL-18 was decreased, however PAR-1 and PAR-4 expression on monocytes in group IL-18+Eotaxin, IL-18BP+Eotaxin were increase which not on T-cells(P<0.05).PAR-2 expression on T-cells in group IL-18 and Eotaxin were increased comparied with NS, but in group IL-18BP and IL-18BP+Eotaxin were decreased,however the PAR-2 expression on monocytes in group IL-18BP+Eotaxin was increase which not on(P<0.05).Treament with IL-18,IL-18+Eotaxin, IL-18BP+Eotaxin led to a sharp increase of CD4~+CD25~+Treg but not IL-18BP and Eotaxin(P<0.05). CD4~+CD25~+Treg in all sensitive groups were increased compared with those in group control . IL-18,Eotaxin,IL-18+Eotaxin induce Th17 cell to differentiate, modulation were blocked by administration of IL-18BP and IL-18BP+ Eotaxin(P<0.05).In unsensitive group, PAR-1 and PAR-4 expression on monocytes in group IL-18 were increased over those in group NS, but decreased on monocytes and T-cells in IL-18BP,Eotaxin and IL-18BP+Eotaxin(P<0.05). PAR-2 expression on T-cells and monocytes in group IL-18BP was increased comparied with NS ,but in group IL-18 and Eotaxin were decreased(P<0.05). Administration of induce number of CD4~+CD25~+Treg and Th17 cell in IL-18 and Eotaxin groups were higher than those of the NS group, while it was fewer in IL-18BP group(P<0.05).
In unsensitive groups all of above were increased compared with corresponding sensitive groups excluded PAR-1 and PAR-4 expression on T-cells in IL-18BP and Eotaxin groups(P<0.05);
CONCLUSION: Increased serum levels of IL-18 indicate that the cytokine is likely to participate in the pathogenesis of asthma.The effect that IL-18 could modulate expression of PARs on T-cells and monocytes, the number of CD4~+CD25~+Treg,Th17 cell ,and stimulate IL-6 and IL-12 release reveals the mechanism of of IL-18 in the allergic inflammation partly.
【方法】随机收集哮喘急性发作期患者50例,健康对照者50例血清。采用双抗体夹心酶联免疫吸附试验(ELISA)分别检测血清IL-18、总IgE、IL-8、IL-4、IFN-γ水平。雌性BALB/c小鼠78只,8-10周龄,按随机数字表法分为阴性对照组、生理盐水(normal saline, NS)组、IL-18组、IL-18结合蛋白(binding protein, BP)组、Eotaxin组、IL-18+Eotaxin组、IL-18BP+Eotaxin组,除阴性对照组外每组设非致敏对照组,每组6只,各致敏组小鼠分别在第1、7、13、19、20、21天腹腔注射致敏液OVA,最后一次激发前10min、30min、1h分别给与IL-18、IL-18BP、Eotaxin、IL-18+Eotaxin、IL-18BP+Eotaxin腹腔注射,末次激发3小时后收集腹腔灌洗液,用ELISA法观察小鼠腹腔灌洗液(PLF)上清中IgE、IL-6、IL-12分泌情况;瑞士染色细胞涂片计数肥大细胞(MC)和嗜酸性粒细胞(EOS),流式细胞术检测PLF中T细胞和单核细胞PAR-1、2、4的表达, CD4+CD25+Treg和Th17的表达。非致敏组小鼠与致敏组同步喂养,给药步骤同致敏组,末次用药后3小时处死,其余检测同致敏组。
【结果】哮喘组IL-18、IL-8、IL-4均高于对照组,但IFN-γ水平低于试剂盒的检测范围。哮喘组血清总IgE水平明显高于对照组,IL-18与IL-8、IL-4、总IgE,IL-4与总IgE之间分别存在正相关。对小鼠PLF进行涂片并瑞士染色分类计数细胞发现IL-18、Eotaxin、IL-18+Eotaxin组MC及EOS细胞数明显增高,IL-18BP组MC及EOS细胞数明显减少,IL-18BP+Eotaxin与NS组相比无明显差异,但各组MC及EOS均高于阴性对照组(P<0.05)。ELISA结果显示,致敏小鼠PLF上清总IgE水平都显著高于阴性对照组,与NS组比较,IL-18、IL-18+Eotaxin组总IgE水平明显降低,而IL-18BP、Eotaxin、IL-18BP+Eotaxin组总IgE水平明显升高(P<0.05);未致敏状态与致敏状态趋势一致且均低于对应致敏组(P<0.05)。致敏小鼠PLF上清IL-6水平均高于阴性对照组,IL-18、IL-18+Eotaxin刺激IL-6的分泌,IL-18BP、Eotaxin、IL-18BP+Eotaxin抑制IL-6的分泌;未致敏IL-6水平均低于对应致敏组(P<0.05)。致敏小鼠PLF上清IL-12水平在IL-18刺激后明显升高,IL-18BP、Eotaxin、IL-18+Eotaxin、IL-18BP+Eotaxin干预后降低(P<0.05);未致敏组IL-12水平在IL-18作用后降低,且低于对应致敏组,其他组IL-12水平均升高且高于对应致敏组(P<0.05)。
流式细胞术提示致敏小鼠的PLF中IL-18BP、Eotaxin诱导的T淋巴细胞、单核细胞PAR-1、4的表达明显高于NS组,而IL-18作用后的表达低于NS组;此外,IL-18+Eotaxin、IL-18BP+Eotaxin诱导单核细胞PAR-1、4表达升高,而T淋巴细胞的表达降低(P<0.05)。IL-18、Eotaxin诱导的T淋巴细胞PAR-2的表达明显高于NS组,IL-18BP、IL-18BP+Eotaxin作用后的表达低于NS组,但是,只有IL-18BP+Eotaxin诱导单核细胞PAR-2的表达升高,其它均降低(P<0.05)。CD4~+CD25~+T淋巴细胞数在IL-18、IL-18+Eotaxin、IL-18BP+Eotaxin诱导后明显多于NS组,而在IL-18BP、Eotaxin干预后明显少于NS组(P<0.05);同阴性对照组相比,各致敏组CD4~+CD25~+T淋巴细胞数均减少(P<0.05)。Th17细胞数在IL-18、Eotaxin、IL-18+Eotaxin诱导后增加,而在IL-18BP、IL-18BP+Eotaxin干预后减少(P<0.05)。
未致敏小鼠PLF中IL-18诱导的单核细胞PAR-1、4的表达明显高于NS组,而IL-18BP、Eotaxin、IL-18BP+Eotaxin作用后的T淋巴细胞、单核细胞的表达明显低于NS组(P<0.05)。IL-18BP诱导的T淋巴细胞、单核细胞PAR-2的表达明显高于NS组,而IL-18、Eotaxin作用后的表达低于NS组(P<0.05)。CD4~+CD25~+T淋巴细胞、Th17细胞数量在IL-18、Eotaxin诱导后明显多于NS组,而在IL-18BP干预后明显少于NS组(P<0.05);同致敏组相比IL-18BP、Eotaxin作用的T细胞PAR-1、4的表达降低,其余各组均增高(P<0.05)。
【结论】哮喘患者血清IL-18水平增高提示该细胞因子参与哮喘的发病过程。IL-18调节过敏性小鼠腹腔灌洗液T淋巴细胞和单核细胞PARs表达、CD4+CD25+T淋巴细胞及Th17细胞数,刺激IL-6及IL-12分泌的作用部分揭示了其在过敏性炎症中的作用机制。
OBJECTIVE: To investigate the correlation among serum levels of IL-18 ,total IgE ,Th1 and Th2 type cytokine in the patients with asthma ,and the regulatory mechanism of IL-18 in mouse allergic inflammatory.
METHOD: 50 patients with acute asthma attack (group asthms) and 50 healthy subjects (group contronl) for the measurements of total IgE, IL-18, IL-8, IL-4 and IFN-γwith ELISA.78 femal BALB/c mices were randomly divided into 13 groups. They are normal group,NS group,IL-18 group,IL-18BP group,Eotaxin group, IL-18+Eotaxin group, IL-18BP+Eotaxin group.Every group had a unsensitive control and contained 6 mice.All mouses exclude normal group were immunized intraperitoneally with ovalbumin(OVA) on 1,7,13, 19 ,20 ,21d, OVA-sensitized mice were injected intraperitoneally with murine rIL-18,IL-18BP,Eotaxin, IL-18+Eotaxin, IL-18BP+Eotaxin (1ug) at 10min,30min and 1 h before the last intraperitoneally OVA challenge. As a control,OVA-sensitized mice were injected intraperitoneally with 0.9% saline.The peritoneal lavage fluid was then collected at 3h after OVA or saline intraperitoneal.The immunoglobulinE (IgE),IL-6,IL-12 in the mice supernatants of PLF were observed by the means of enzyme linked immunosorbent assay (ELISA),PLF cell differentials were determined by counting 500 cells stained with Wright-Giemsa solution,expression of PARs , CD4~+CD25~+Treg,Th17 cell were analyzed by flowcytometry.Unsensitive control group were fed in the same condition with all sensitive groups and other administer were alike with sensitive groups.
RESULTS: In asthmatic group,serum IL-18,IL-8 and IL-4 in group asthma were increased compaired with group C.The total IgE level in asthmatics was also increased compaired with group C.Serum levels of IL-18 was positively correlated with that of IL-8,IL-4 and total IgE,and IL-4 was positively correlated with that of total IgE.The level of total serum IgE were increased significantly in OVA- sensitized /challenged mice compared with the control group(P<0.05), administration of IL-18 reduced the levels of total serum IgE compared with other groups in both sensitive and unsensitive groups(P<0.05).IL-18 induced IL-12 and IL-6 release in sensitived mouse PLF supernatant,and there was decreased IL-12 and increased IL-6 in unsensitive group(P<0.05).The eosinophil and mast cell infiltration into the PLF of IL-18, Eotaxin and IL-18+Eotaxin groups were significantly increased compared with those in group NS.The administration of IL-18BP significantly decreased OVA- induced eosinophil and mast cell recruitment into the PLF. Which was not significantly different between group IL-18BP+Eotaxin and NS.
Flow cytometry demonstrated that in sensitived group PLF PAR-1 and PAR-4 expression on T-cells and monocytes in group IL-18BP and Eotaxin were increased over those in group NS,but in group IL-18 was decreased, however PAR-1 and PAR-4 expression on monocytes in group IL-18+Eotaxin, IL-18BP+Eotaxin were increase which not on T-cells(P<0.05).PAR-2 expression on T-cells in group IL-18 and Eotaxin were increased comparied with NS, but in group IL-18BP and IL-18BP+Eotaxin were decreased,however the PAR-2 expression on monocytes in group IL-18BP+Eotaxin was increase which not on(P<0.05).Treament with IL-18,IL-18+Eotaxin, IL-18BP+Eotaxin led to a sharp increase of CD4~+CD25~+Treg but not IL-18BP and Eotaxin(P<0.05). CD4~+CD25~+Treg in all sensitive groups were increased compared with those in group control . IL-18,Eotaxin,IL-18+Eotaxin induce Th17 cell to differentiate, modulation were blocked by administration of IL-18BP and IL-18BP+ Eotaxin(P<0.05).In unsensitive group, PAR-1 and PAR-4 expression on monocytes in group IL-18 were increased over those in group NS, but decreased on monocytes and T-cells in IL-18BP,Eotaxin and IL-18BP+Eotaxin(P<0.05). PAR-2 expression on T-cells and monocytes in group IL-18BP was increased comparied with NS ,but in group IL-18 and Eotaxin were decreased(P<0.05). Administration of induce number of CD4~+CD25~+Treg and Th17 cell in IL-18 and Eotaxin groups were higher than those of the NS group, while it was fewer in IL-18BP group(P<0.05).
In unsensitive groups all of above were increased compared with corresponding sensitive groups excluded PAR-1 and PAR-4 expression on T-cells in IL-18BP and Eotaxin groups(P<0.05);
CONCLUSION: Increased serum levels of IL-18 indicate that the cytokine is likely to participate in the pathogenesis of asthma.The effect that IL-18 could modulate expression of PARs on T-cells and monocytes, the number of CD4~+CD25~+Treg,Th17 cell ,and stimulate IL-6 and IL-12 release reveals the mechanism of of IL-18 in the allergic inflammation partly.
引文
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[18] Takeshi Kimura,Zenichiro Kato,Hidenori Ohnishi,et al.Expression, Purificat- ion and Structural Analysis of Human IL-18 Binding Protein: A Potent Therapeutic Molecule for Allergy[J].Allergology International, 2008, 57(4):367-376.
[19]姚奇健,何韶衡,林小平,夏秋季豚草过敏患者血清中类胰蛋白酶、IL-8、IL-12及嗜酸性粒细胞趋化因子水平变化及临床意义[J],第四军医大学学报,2007, 28(3):263-265.
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[22] Salagianni M,Wong KL,Thomas MJ,et al.An essential role for IL-18 in CD8 T cell-mediated suppression of gE responses[J].Immunol,2007,178(8): 4771-4778.
[23]邱忠民,吕寒静,杨忠民,等.白细胞介素6对哮喘小鼠气道炎症和上皮下纤维化的影响[J].临床免疫学,2003,19(10):709 -712.
[24] Durrant DM, Metzger DW,IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression[J]. Mucosal Immunol.2010,Epub ahead of print.
[25] Chow JY,Wong CK,Cheung PF,et al.Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation[J].Cell Mol Immunol, 2010,7(1):26-34.
[26] Ye Q,Nakamura S,Sarria R,et al.Interleukin 12,interleukin 18,and tumor necr- osis factor alpha release by alveolar macrophages:acute and chronic hypersensitivity pneumonitis[J].Allergy Asthma Immunol,2009,102(2): 149-154.
[27] Holla LI.Interleukin-18 in asthma and other allergies[J],Clin Exp Allergy, 2003, 33(8):1023-1025.
[28] Su X, Camerer E, Hamilton JR, et al. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide- dependent mechanisms [J]. Immunol,2005,175(4):2598-2605.
[29] De-Campo BA,Henry PJ.Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation[J].Br J Pharmacol, 2005, 144(8):1100-1108.
[30] Danahay H,Withey L,Poll CT,et al.Protease-activated receptor-2 -mediated inhibition of ion transport in human bronchial epithelial cells[J].Am J Physiol Cell Physiol,2001,280(6):1455-1464.
[31] Kannan S.Role of protease-activated receptors in neutrophil degra nulation[J].Med Hypotheses,2002,59(3):266-267.
[32] Camerer E,Kataoka H,Kahn M,et al.Genetic evidence that protease- activated receptors mediate factor Xa signaling in endothelial cells[J].Biol Chem, 2002, 277(18):16081-16087.
[33] Houle S,Papez MD,Ferazzini M,et al.Neutrophils and the kallikrein-kinin system in proteinase-activated receptor 4-mediated inflammation in rodents[J].Br J Pharmacol,2005,146(5):670-678.
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[37] Shi HJ,Qin XJ.CD4+CD25+regulatory T lymphocytes in allergy and asthma [J].Allergy,2005,60(8):986-995.
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[39] Suto A,Nakajima H,Kagami SI,et al.Role of CD4+CD25+regulatory T cells in T helper 2 cell- mediated allergic inflammation in the airways[J]. A m Respir Crit Care Med,2001,164(4):680-687.
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[42] Chakir J,Shannon J,Molet S,et al. Airway remodelingassociated mediators in moderate to severe asthma:effect of steroids on TGF-β,IL-11,IL-17,and type I and type III collagen expression[J].Allergy Clin Immunol, 2003, 111(6):1293-1298.
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[44] Bullens DM,Truyen E,Coteur L,et al.IL-17 mRNA in sputum of asthmatic patients:linking T cell driven inflammation and granulocytic influx[J]. Respir Res, 2006,3(7):135-144.
[45] Nakae S,Suto H,Berry GJ,Mast cell-derived TNF can promote Th17 cell- dependent neutrophil recruitment in ovalbumin-challenged OTII mice[J]. Blood, 2007,109(9):3640-3648.
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[1]陆超,殷道华,金惠铭.类胰蛋白酶与疾病[J].中国病理生理杂志, 2002,18 (6):718-721.
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[6] Caughey GH. Mast cell tryp tases and chymases in inflammation and host defense[J].Immunol Rev,2007,217:141-154.
[7] Ribatti D, Nico B, Maxia C,et al. Neovascularization and mastcellswith tryp tase activity increase simultaneously in human pterygium[J].J Cell Mol Med, 2007, 11 (3):585-589.
[8] Huang C,Friend DS,QiuWT,et al. Induction of a selective and persistent extravas ation of neutrophils into the peritoneal cavity by tryptase mouse mast cell p rotease 6 [J].J Immunol,1998,160(4):1910-1919.
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[10]肖继明,徐军,陈锐华.冠心病患者血浆内皮素水平与心脏收缩功能的研究[J].医学研究生学报,2008,21(11):1175-1177.
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[12] Fineschi V, Monasterolo G, Rosi R. Fetal anaphylactic shock during a fluorescein angiography[J].Forensic Sci Int,1999,100(12):137-142.
[13]陆超,王雪雯,赵凤娣,等.人血清类胰蛋白酶含量测定方法的建立[J].复旦学报(医学版),2003,30(1):66-67.
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[16] Velasco G,Campo M,Manrique OJ,et al.Toll-like receptor4 or 2 agonists decrease allergic inflammation[J].Am J Respir Cell Mol Biol, 2005, 32(3): 218- 224.
[17] Claudia TH,Valentina M,Hubertus H,et al.Pollenassociated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization[J].J Exp Med,2005,201(4):627-636.
[18] Takeshi Kimura,Zenichiro Kato,Hidenori Ohnishi,et al.Expression, Purificat- ion and Structural Analysis of Human IL-18 Binding Protein: A Potent Therapeutic Molecule for Allergy[J].Allergology International, 2008, 57(4):367-376.
[19]姚奇健,何韶衡,林小平,夏秋季豚草过敏患者血清中类胰蛋白酶、IL-8、IL-12及嗜酸性粒细胞趋化因子水平变化及临床意义[J],第四军医大学学报,2007, 28(3):263-265.
[20] Noah TL,Frederick W,Henderson MM,et al.Nasal lavage cytokines in norml, allergic and asthmatic schoolage children[J].Am J Respir Crit Care Med, 1995, 152(4):1290-1296.
[21] Sears MR,Burrows B,Flannery EM,et al.Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children[J].N Engl J Med,1991,325(15):1067-1071.
[22] Salagianni M,Wong KL,Thomas MJ,et al.An essential role for IL-18 in CD8 T cell-mediated suppression of gE responses[J].Immunol,2007,178(8): 4771-4778.
[23]邱忠民,吕寒静,杨忠民,等.白细胞介素6对哮喘小鼠气道炎症和上皮下纤维化的影响[J].临床免疫学,2003,19(10):709 -712.
[24] Durrant DM, Metzger DW,IL-12 can alleviate Th17-mediated allergic lung inflammation through induction of pulmonary IL-10 expression[J]. Mucosal Immunol.2010,Epub ahead of print.
[25] Chow JY,Wong CK,Cheung PF,et al.Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation[J].Cell Mol Immunol, 2010,7(1):26-34.
[26] Ye Q,Nakamura S,Sarria R,et al.Interleukin 12,interleukin 18,and tumor necr- osis factor alpha release by alveolar macrophages:acute and chronic hypersensitivity pneumonitis[J].Allergy Asthma Immunol,2009,102(2): 149-154.
[27] Holla LI.Interleukin-18 in asthma and other allergies[J],Clin Exp Allergy, 2003, 33(8):1023-1025.
[28] Su X, Camerer E, Hamilton JR, et al. Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide- dependent mechanisms [J]. Immunol,2005,175(4):2598-2605.
[29] De-Campo BA,Henry PJ.Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation[J].Br J Pharmacol, 2005, 144(8):1100-1108.
[30] Danahay H,Withey L,Poll CT,et al.Protease-activated receptor-2 -mediated inhibition of ion transport in human bronchial epithelial cells[J].Am J Physiol Cell Physiol,2001,280(6):1455-1464.
[31] Kannan S.Role of protease-activated receptors in neutrophil degra nulation[J].Med Hypotheses,2002,59(3):266-267.
[32] Camerer E,Kataoka H,Kahn M,et al.Genetic evidence that protease- activated receptors mediate factor Xa signaling in endothelial cells[J].Biol Chem, 2002, 277(18):16081-16087.
[33] Houle S,Papez MD,Ferazzini M,et al.Neutrophils and the kallikrein-kinin system in proteinase-activated receptor 4-mediated inflammation in rodents[J].Br J Pharmacol,2005,146(5):670-678.
[34] Moffatt JD,Lever R,Page CP.Effects of inhaled thrombin receptor agonists in mice[J].Br J Pharmacol,2004,143(2):269-275.
[35] Roche N,RG Stirling,S Lim ,et al.Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages [J]. Allergy Clin Immunol,2003,111(2): 367-373.
[36] AugéC,Balz-Hara D,Steinhoff M,et al.Protease-activated receptor-4 (PAR4):a role as inhibitor of visceral pain and hypersensitivity[J]. Neurogastroenterol Motil,2009,21(11):1129-1132.
[37] Shi HJ,Qin XJ.CD4+CD25+regulatory T lymphocytes in allergy and asthma [J].Allergy,2005,60(8):986-995.
[38] Shi HZ,Li S.Regulatory CD4+CD25+T lymphocytes in peripheralblood from patients with atopic asthma[J].Clin Immunol,2004,113(2):172-178.
[39] Suto A,Nakajima H,Kagami SI,et al.Role of CD4+CD25+regulatory T cells in T helper 2 cell- mediated allergic inflammation in the airways[J]. A m Respir Crit Care Med,2001,164(4):680-687.
[40] Mangan PR,Harrington LE,Quinn DB,et al.Transforming growth factor-beta induces development of the Th17 lineage[J].Nature,2006,441 (7): 231- 234.
[41] Barczyk A,Pierzchala W,Sozanska E.Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine[J].Respir Med,2003,97(6):726-733.
[42] Chakir J,Shannon J,Molet S,et al. Airway remodelingassociated mediators in moderate to severe asthma:effect of steroids on TGF-β,IL-11,IL-17,and type I and type III collagen expression[J].Allergy Clin Immunol, 2003, 111(6):1293-1298.
[43] Sun YC,Zhou QT,Yao WZ.Sputum interleukin-17 is increased and associated with airway neutrophilia in patients with severe asthma [J].Chin Med J(Engl),2005, 118(11):953-956.
[44] Bullens DM,Truyen E,Coteur L,et al.IL-17 mRNA in sputum of asthmatic patients:linking T cell driven inflammation and granulocytic influx[J]. Respir Res, 2006,3(7):135-144.
[45] Nakae S,Suto H,Berry GJ,Mast cell-derived TNF can promote Th17 cell- dependent neutrophil recruitment in ovalbumin-challenged OTII mice[J]. Blood, 2007,109(9):3640-3648.
[46] Harrington LE,Hatton RD,Mangan PR,et al.Interleukin 17 -producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J].Nat Immunol,2005,6(11):1123-1132.
[1]陆超,殷道华,金惠铭.类胰蛋白酶与疾病[J].中国病理生理杂志, 2002,18 (6):718-721.
[2] Randall B, Butbs J, Halsey JF. Elevated postmortent tryp tase in the absence of anaphylaxis[J].J Forensic Sci,1995, 40(2):208-211.
[3] Cairns JA , WallsAF. Mast cell tryp tase stimulates the synthesis of type I collagen in human lung fibroblasts [J].J Clin Invest,1997,99 (6): 1313-1321.
[4]王代红,袁发焕,张耀全.肥大细胞类胰蛋白酶对人肾成纤维细胞作用机制探讨[J].中华肾脏病杂志,2005,21(2):112-113.
[5] Sommerhoff CP. Mast cell tryp tases and airway remodeling[J].Am J Resp ir Crit CareMed,2001,164(102):52-58.
[6] Caughey GH. Mast cell tryp tases and chymases in inflammation and host defense[J].Immunol Rev,2007,217:141-154.
[7] Ribatti D, Nico B, Maxia C,et al. Neovascularization and mastcellswith tryp tase activity increase simultaneously in human pterygium[J].J Cell Mol Med, 2007, 11 (3):585-589.
[8] Huang C,Friend DS,QiuWT,et al. Induction of a selective and persistent extravas ation of neutrophils into the peritoneal cavity by tryptase mouse mast cell p rotease 6 [J].J Immunol,1998,160(4):1910-1919.
[9]马希刚,曹相原.慢性阻塞性肺疾病不同时期细胞间黏附分子-1和E2选择素的表达及意义[J].医学研究生学报,2007,20(10):1051-1053.
[10]肖继明,徐军,陈锐华.冠心病患者血浆内皮素水平与心脏收缩功能的研究[J].医学研究生学报,2008,21(11):1175-1177.
[11] Blair RJ,Meng H,MarcheseMJ,et al.Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor[J].J Clin Invest,1997,99 (11):2691-2700.
[12] Fineschi V, Monasterolo G, Rosi R. Fetal anaphylactic shock during a fluorescein angiography[J].Forensic Sci Int,1999,100(12):137-142.
[13]陆超,王雪雯,赵凤娣,等.人血清类胰蛋白酶含量测定方法的建立[J].复旦学报(医学版),2003,30(1):66-67.
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