透邪解毒法抗流感病毒作用机制研究
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摘要
本课题在深入分析流感病毒致病机理基础上,采用目前通用的流感动物模型、细胞模型,以肺指数、病死率为评价指标,证实金柴抗病毒胶囊对不同免疫状态流感动物模型的防治作用,以病毒-细胞、病毒-机体-免疫系统的相互作用作为研究对象,运用激光扫描共聚焦、实时荧光定量RT-PCR以及免疫印记Western-Blot等方法,从细胞、分子水平明确金柴抗病毒胶囊抗流感病毒的作用靶点,阐明抗流感病毒作用机制。
本研究分三部分。文献综述：主要对流感病毒致病机理以及中医药防治流行性感冒研究进展进行总结；实验研究：在明确金柴抗病毒胶囊防治流感作用基础上,从病毒-细胞、病毒-机体-免疫两方面对其抗病毒机制进行研究。理论探讨：结合流行性感冒的特点,探讨透邪解毒法防治流行性感冒的理论依据和优势。
1透邪解毒法治疗流行性感冒的理论探讨
流行性感冒属于中医“时行感冒”时行伤寒”时行疫病”等范畴,其病因为“非时之气”挟“时行疫毒”侵袭人体所致。由于社会发展、环境变迁以及人们生活、就医习惯的影响,流行性感冒的病邪性质和病机变化不再遵循固有的规律,探索其病机特点、证候演变规律,并以此确立新的治则治法是中医药行业的重要任务。
透邪解毒法是针对流行性感冒“在表之邪犹存,趋里之邪易郁化热”的病机特点而设,以此法为组方依据的金柴抗病毒胶囊由金银花、柴胡、蝉蜕等药组成,全方配伍轻清宣透、引邪外出,清热解毒祛除病因,参以培补正气抵御外邪,体现了“早期治疗,截断病势,防止传变”的立法宗旨。
2实验研究
2.1金柴抗病毒胶囊防治流感的作用研究
采用甲型H1N1流感病毒鼠肺适应株(FM/1/47株和PR/8/34株)滴鼻感染正常免疫状态和免疫低下小鼠造成肺炎模型,以肺指数和病死率为评价指标,评价金柴抗病毒胶囊对不同免疫状态小鼠甲型流感的防治作用,并与目前世界卫生组织推荐治疗流感主要药物达菲进行比较。实验结果显示：金柴抗病毒胶囊对正常免疫状态和免疫低下小鼠肺部炎症均有明显的治疗和预防作用,并在减轻肺指数、降低小鼠死亡率、延长小鼠生存时间上,与达菲比较无显著性差异(P>0.05)。
2.2金柴抗病毒胶囊抗流感病毒作用机制研究
2.2.1对流感病毒吸附环节的影响
通过药物先与细胞作用1小时后,加入流感病毒再作用1小时的方法,采用实时荧光定量RT-PCR,检测药物作用细胞后细胞中流感病毒HA-mRNA表达含量。实验结果显示：金柴抗病毒胶囊能显著减少细胞中流感病毒HA-mRNA的表达含量,提示金柴抗病毒胶囊可通过干预病毒对细胞吸附环节发挥抗流感病毒作用。
2.2.2对流感病毒-细胞膜融合的影响
通过药物与流感病毒同时作用细胞的方法,采用激光扫描共聚焦结合PH值敏感荧光染料,观察金柴抗病毒胶囊对流感病毒感染细胞后胞内PH值变化的影响。实验结果显示：金柴抗病毒胶囊能显著降低流感病毒感染细胞后引起胞内PH酸化的程度,提示金柴抗病毒胶囊可干预病毒-细胞膜融合环节发挥抗流感病毒的作用。
2.2.3对流感病毒转录与复制的影响
利用病毒感染细胞1小时后,加入相应稀释浓度的金柴抗病毒胶囊,作用48-72小时后,采用实时荧光定量RT-PCR法,检测细胞中流感病毒多聚酶PA亚基mRNA表达含量,观察金柴抗病毒胶囊对流感病毒多聚酶PA亚基mRNA表达的影响,进一步探讨其抗流感病毒作用靶点。实验结果显示：金柴抗病毒胶囊能显著降低细胞中流感病毒多聚酶PA亚基mRNA表达含量,提示金柴抗病毒胶囊抗病毒的作用机制与干预流感病毒的转录和复制有关。
2.2.4对流感病毒释放环节的影响
利用病毒感染细胞1小时后,加入相应稀释浓度的金柴抗病毒胶囊,作用72小时,采用荧光Elisa的方法,观察金柴抗病毒胶囊对流感病毒NA活性的影响。实验结果显示：金柴抗病毒胶囊对流感病毒NA活性没有明显的抑制作用,提示金柴抗病毒胶囊对流感病毒的释放环节没有影响作用。
2.2.5对病毒载量及γ-IFNmRNA表达的影响
通过甲型H1N1流感病毒鼠肺适应株(FM/1/47株)感染正常小鼠造成肺炎模型的方法,检测流感病毒感染小鼠后第1天、第3天、第5天以及第7天小鼠肺组织中病毒载量、γ-IFNmRNA的动态变化情况,探讨金柴抗病毒胶囊调节机体免疫机制抗病毒作用机理。实验结果显示：金柴抗病毒胶囊大、中、小3个剂量组对不同时间点肺组织中病毒载量的表达均有明显的降低作用,对相应时间点小鼠肺组织中γ-IFNmRNA的表达含量均有明显的升高作用,提示金柴抗病毒胶囊通过上调γ-IFNmRNA的表达发挥抗病毒作用。
2.2.6对干扰素诱导跨膜蛋白表达的影响
采用免疫印记Western-Blot的方法,观察流感病毒感染小鼠后第1天、第3天、第5天以及第7天肺组织中天然抗流感病毒蛋白-干扰素诱导跨膜蛋白(IFITM3)的动态变化情况,探讨金柴抗病毒胶囊抗流感病毒的作用靶点。实验结果显示：金柴抗病毒胶囊在流感病毒感染早期即可调节机体产生IFITM3发挥抗病毒作用,并且在其后几天内与模型组比较,其含量一直维持在一个较高水平,提示金柴抗病毒胶囊可调节机体免疫机制产生更多的IFITM3发挥抗流感病毒作用。
Based on the analysis of the influenza virus pathogenesis,the article uses the animal models of influenza and the models of cell and evaluates the lung index and mortality to indentify the effects of Jin Chai anti-vital capsule of animal models under differently immune status.Through the studies of the interaction of virus-cell and virus-body-immunity system and the uses of the methods of laser scanning confocal microscopy real-time fluorescent RT-PCR and Western-Blot,this experiment reveals the mechanism of Jin Chai antivital drugs on the molecular level and the effiency of the Tou Xie Jie Du to treat the influenza and provides the scientific proofs.
The article consists of three parts:The first part reveals the machanism of influenza virus pathogenesis and the effects of traditional chinese medicine.The second part reveals the theoretical basis and the advantages of Tou Xie Jie Du.The third part reveals the machanism from two facets:virus-cell and virus-body-immunity system.
1. Theoretical Discussion
The influenza belongs to the Chinese medical syndrome of Shi Xing Gan Mao,Shi Sing Shang San and Shi Xing Yi Bing Because of the influences of the social development and environmental change and the effects of the people's habits and medical practices, the nature of pathogenic factors and the mechanism of influenza pathology no longer adhere to inherent rules.The explosion of the character of pathogenesis and the regulation of syndrome is an important task of treaditional Chinese medicine.
2 Experimental Study
2.1 The role of prevention and treatment of influenza
Use the nose dropping method with influenza virus (FM/1/47 and PR/8/34 strains) to establish immunocompromised mouse model. Respectively do the theraputical administration and prophylactic administration to observe the lung weight and calculate the lung index and mortality.①Therapeutical effect:Jin Chai antivital capsules markedly decrease the lung index and mortality of mouse model with infuluenza virus and prolong the live time of the mouse model with infuluenza virus.③The antivital efficacy is not statistically significant between Jin Chai antivital capsules and Tamiflu.
2.2 Mechanism of anti-influenza virus
②Use Real-time PCR to observe the levels of HA-mRNA expression of influenza. The results show that Jin Chai antivital capsule can significantly reduce the levels of HA-mRNA expression of influenza and suggest the efficacy of Jin Chai antivital capsules through the intervention of the virus adhersion.
②Use the combination of laser scanning confocal fluorescencent dye which is sensitive to PH value, to observe Virus-cell membrane fusion, The results show that Jin Chai antivital capsule can improve the levels of PH value, and suggest the efficacy of Jin Chai antivital capsules through the intervention of the Virus-cell membrane fusion.
③Use Real-time PCR to observe the levels of PA-mRNA expression of influenza. The results show that Jin Chai antivital capsule can significantly reduce the levels of PA-mRNA expression of influenza and suggest Jin Chai antivital capsules effect on the Transcription and Replication.
④Use the Elisa method of fluorescence to observe the Jin Chai capsules on the NA, the results show that Jin Chai anti-viral capsules do not inhibit the efficacy of NA activity.
⑤Use Real-time PCR and Western-Blot method to observe the Jin Chai anti-virus Capsule effect on the interferon-y and natural anti-virus protein-interferon induces transmembrane protein,.the results show that Jin Chai anti-virus Capsule can improve the expression.of the interferon-yand interferon induced transmembrane protein expression.
本研究分三部分。文献综述：主要对流感病毒致病机理以及中医药防治流行性感冒研究进展进行总结；实验研究：在明确金柴抗病毒胶囊防治流感作用基础上,从病毒-细胞、病毒-机体-免疫两方面对其抗病毒机制进行研究。理论探讨：结合流行性感冒的特点,探讨透邪解毒法防治流行性感冒的理论依据和优势。
1透邪解毒法治疗流行性感冒的理论探讨
流行性感冒属于中医“时行感冒”时行伤寒”时行疫病”等范畴,其病因为“非时之气”挟“时行疫毒”侵袭人体所致。由于社会发展、环境变迁以及人们生活、就医习惯的影响,流行性感冒的病邪性质和病机变化不再遵循固有的规律,探索其病机特点、证候演变规律,并以此确立新的治则治法是中医药行业的重要任务。
透邪解毒法是针对流行性感冒“在表之邪犹存,趋里之邪易郁化热”的病机特点而设,以此法为组方依据的金柴抗病毒胶囊由金银花、柴胡、蝉蜕等药组成,全方配伍轻清宣透、引邪外出,清热解毒祛除病因,参以培补正气抵御外邪,体现了“早期治疗,截断病势,防止传变”的立法宗旨。
2实验研究
2.1金柴抗病毒胶囊防治流感的作用研究
采用甲型H1N1流感病毒鼠肺适应株(FM/1/47株和PR/8/34株)滴鼻感染正常免疫状态和免疫低下小鼠造成肺炎模型,以肺指数和病死率为评价指标,评价金柴抗病毒胶囊对不同免疫状态小鼠甲型流感的防治作用,并与目前世界卫生组织推荐治疗流感主要药物达菲进行比较。实验结果显示：金柴抗病毒胶囊对正常免疫状态和免疫低下小鼠肺部炎症均有明显的治疗和预防作用,并在减轻肺指数、降低小鼠死亡率、延长小鼠生存时间上,与达菲比较无显著性差异(P>0.05)。
2.2金柴抗病毒胶囊抗流感病毒作用机制研究
2.2.1对流感病毒吸附环节的影响
通过药物先与细胞作用1小时后,加入流感病毒再作用1小时的方法,采用实时荧光定量RT-PCR,检测药物作用细胞后细胞中流感病毒HA-mRNA表达含量。实验结果显示：金柴抗病毒胶囊能显著减少细胞中流感病毒HA-mRNA的表达含量,提示金柴抗病毒胶囊可通过干预病毒对细胞吸附环节发挥抗流感病毒作用。
2.2.2对流感病毒-细胞膜融合的影响
通过药物与流感病毒同时作用细胞的方法,采用激光扫描共聚焦结合PH值敏感荧光染料,观察金柴抗病毒胶囊对流感病毒感染细胞后胞内PH值变化的影响。实验结果显示：金柴抗病毒胶囊能显著降低流感病毒感染细胞后引起胞内PH酸化的程度,提示金柴抗病毒胶囊可干预病毒-细胞膜融合环节发挥抗流感病毒的作用。
2.2.3对流感病毒转录与复制的影响
利用病毒感染细胞1小时后,加入相应稀释浓度的金柴抗病毒胶囊,作用48-72小时后,采用实时荧光定量RT-PCR法,检测细胞中流感病毒多聚酶PA亚基mRNA表达含量,观察金柴抗病毒胶囊对流感病毒多聚酶PA亚基mRNA表达的影响,进一步探讨其抗流感病毒作用靶点。实验结果显示：金柴抗病毒胶囊能显著降低细胞中流感病毒多聚酶PA亚基mRNA表达含量,提示金柴抗病毒胶囊抗病毒的作用机制与干预流感病毒的转录和复制有关。
2.2.4对流感病毒释放环节的影响
利用病毒感染细胞1小时后,加入相应稀释浓度的金柴抗病毒胶囊,作用72小时,采用荧光Elisa的方法,观察金柴抗病毒胶囊对流感病毒NA活性的影响。实验结果显示：金柴抗病毒胶囊对流感病毒NA活性没有明显的抑制作用,提示金柴抗病毒胶囊对流感病毒的释放环节没有影响作用。
2.2.5对病毒载量及γ-IFNmRNA表达的影响
通过甲型H1N1流感病毒鼠肺适应株(FM/1/47株)感染正常小鼠造成肺炎模型的方法,检测流感病毒感染小鼠后第1天、第3天、第5天以及第7天小鼠肺组织中病毒载量、γ-IFNmRNA的动态变化情况,探讨金柴抗病毒胶囊调节机体免疫机制抗病毒作用机理。实验结果显示：金柴抗病毒胶囊大、中、小3个剂量组对不同时间点肺组织中病毒载量的表达均有明显的降低作用,对相应时间点小鼠肺组织中γ-IFNmRNA的表达含量均有明显的升高作用,提示金柴抗病毒胶囊通过上调γ-IFNmRNA的表达发挥抗病毒作用。
2.2.6对干扰素诱导跨膜蛋白表达的影响
采用免疫印记Western-Blot的方法,观察流感病毒感染小鼠后第1天、第3天、第5天以及第7天肺组织中天然抗流感病毒蛋白-干扰素诱导跨膜蛋白(IFITM3)的动态变化情况,探讨金柴抗病毒胶囊抗流感病毒的作用靶点。实验结果显示：金柴抗病毒胶囊在流感病毒感染早期即可调节机体产生IFITM3发挥抗病毒作用,并且在其后几天内与模型组比较,其含量一直维持在一个较高水平,提示金柴抗病毒胶囊可调节机体免疫机制产生更多的IFITM3发挥抗流感病毒作用。
Based on the analysis of the influenza virus pathogenesis,the article uses the animal models of influenza and the models of cell and evaluates the lung index and mortality to indentify the effects of Jin Chai anti-vital capsule of animal models under differently immune status.Through the studies of the interaction of virus-cell and virus-body-immunity system and the uses of the methods of laser scanning confocal microscopy real-time fluorescent RT-PCR and Western-Blot,this experiment reveals the mechanism of Jin Chai antivital drugs on the molecular level and the effiency of the Tou Xie Jie Du to treat the influenza and provides the scientific proofs.
The article consists of three parts:The first part reveals the machanism of influenza virus pathogenesis and the effects of traditional chinese medicine.The second part reveals the theoretical basis and the advantages of Tou Xie Jie Du.The third part reveals the machanism from two facets:virus-cell and virus-body-immunity system.
1. Theoretical Discussion
The influenza belongs to the Chinese medical syndrome of Shi Xing Gan Mao,Shi Sing Shang San and Shi Xing Yi Bing Because of the influences of the social development and environmental change and the effects of the people's habits and medical practices, the nature of pathogenic factors and the mechanism of influenza pathology no longer adhere to inherent rules.The explosion of the character of pathogenesis and the regulation of syndrome is an important task of treaditional Chinese medicine.
2 Experimental Study
2.1 The role of prevention and treatment of influenza
Use the nose dropping method with influenza virus (FM/1/47 and PR/8/34 strains) to establish immunocompromised mouse model. Respectively do the theraputical administration and prophylactic administration to observe the lung weight and calculate the lung index and mortality.①Therapeutical effect:Jin Chai antivital capsules markedly decrease the lung index and mortality of mouse model with infuluenza virus and prolong the live time of the mouse model with infuluenza virus.③The antivital efficacy is not statistically significant between Jin Chai antivital capsules and Tamiflu.
2.2 Mechanism of anti-influenza virus
②Use Real-time PCR to observe the levels of HA-mRNA expression of influenza. The results show that Jin Chai antivital capsule can significantly reduce the levels of HA-mRNA expression of influenza and suggest the efficacy of Jin Chai antivital capsules through the intervention of the virus adhersion.
②Use the combination of laser scanning confocal fluorescencent dye which is sensitive to PH value, to observe Virus-cell membrane fusion, The results show that Jin Chai antivital capsule can improve the levels of PH value, and suggest the efficacy of Jin Chai antivital capsules through the intervention of the Virus-cell membrane fusion.
③Use Real-time PCR to observe the levels of PA-mRNA expression of influenza. The results show that Jin Chai antivital capsule can significantly reduce the levels of PA-mRNA expression of influenza and suggest Jin Chai antivital capsules effect on the Transcription and Replication.
④Use the Elisa method of fluorescence to observe the Jin Chai capsules on the NA, the results show that Jin Chai anti-viral capsules do not inhibit the efficacy of NA activity.
⑤Use Real-time PCR and Western-Blot method to observe the Jin Chai anti-virus Capsule effect on the interferon-y and natural anti-virus protein-interferon induces transmembrane protein,.the results show that Jin Chai anti-virus Capsule can improve the expression.of the interferon-yand interferon induced transmembrane protein expression.
引文
[1]Hansen L.Commentarg:We need to determine who benefitsmost from flu treatments.[J]BMJ,2003,326: 1239.
[2]范鸣.抗病毒药达菲致神经精神类不良反应.[J]药学进展,2006(3)：139-140.
[3]Lackenby A,Hungnes O,Dudman SG,et al.Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe.[J]Euro Surveill,2008(5):8026.
[4]Nicoll A,Ciancio B,Kramarz P. Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications.[J]Euro Surveill,2008(5):8025.
[5]Influenza Project Team.Oseltamivir resistance in human seasonal influenza viruses (A/H1N1) in EU and EFTA countries an update. [J] Euro Surveill.2008(6):8032.
[6]曹洪欣,王喜军,于友华,等.中药复方安替威血清药物化学和抗SARS病毒实验研究.[J]中国中药杂志,2004,29(3)：281-283.
[7]曹洪欣,崔晓兰,赵静,等.安替威胶囊抗病毒药效学研究.[J]中国中医基础理论.2004,10(10),771-774.
[8]曹洪欣,崔晓兰,赵静,等.安替威胶囊治疗小鼠病毒性肺炎的作用机制研究.[J]中国中医基础理论,2005,30(13),1039-1041.
[9]崔晓兰,曹洪欣,赵静,等.安替威胶囊解热实验研究.[J]中医药学报2005,33(3),57-59.
[10]徐慧,曹洪欣,刘建勋,等安替威胶囊对迟发型超敏反应小鼠免疫功能的影响.[J]中医药学刊,2005,23(6)995-996.
[11]曹洪欣,翁维良SARS瘟疫研究[M].北京：中医古籍出版社389-396.
[12]金奇.医学分子病毒学[M].北京：科学出版社,2001：2.
[13]Gubaruva,Kaiserl,HaydenFG.Influenzavirus neuraminidase inhibitors[J]Lancet 2000(9206):827-835.
[14]Webby RJ,Swenson SL, Krauss SL,et al. Evolution of swine H3N2 influenza viruses in the United States.[J] Virol,2000 (18):8243-8251.
[15]Brown IH.The epidemiology and evolution of influenza viruses in pigs.[J]Vet Microbiol,2000 (12): 29-46
[16]Vincent A1,MaW,Lager K,et al.Swine influenza viruses a North American perspective.[J]Adv Virus Res,2008 (127):154.
[17]Outbreak news.Swine influenza.[J]Wkly EpidemiolRec,2009(18):149-153.
[18]Murpy BR,Webster RG.Orthomyxo viruses ology philadelphia Lippincott.[J]Raven Publishers,1996 (11):397.
[19]DeaS,BilodeauR,SauvageauR,etal Anti genicvariant of swine in fluenza virus causing proliferative and necrotizingpn eumoniainpigs.[J]VetDiagInvest,1992(4):380.
[20]Zhou MN,Senne DA,Landgraf JS.Genetic reass ortment of avian swine and human influenzaa virus in American pigs.[J]Virol,1999 (12):885.
[21]WebbyRG,SwensonSL,KraussSL,et al Evolution of swine H3N2 influenza viruses in the United States.[J]Virol,2000,(18):8243.
[22]Christopher,WolsenThe emergence of novel swine influenza viruses in North America.[J]VirusRes, 2002 (2):199.
[23]SugimuraT,YonemochiH,OgawaT,etal Isolation of combinant influenza virus(H1N2) from swine in Japan.[J]ArchVirol,1980 (3):27.
[24]GourreauJM,KaiserC,ValetteM,etal Isolation of two H1N2 influenza viruses from swine in France.[J]ArchVirol,1994,135(4):365.
[25]BrownIH,ChakravertyP,HarrisPA,et al Disease outbreak sinpigs in Great Britain due to aninfluenza A virus of H1N2 subtype.[J]VetRec,1995136(13):328.
[26]KarasinAI,AndersonRG,OlsenCW1 Genetic characterization of an H1N2 influenza virus isolated from a pig in Indian.[J]Jcl in Microbiol,2000,3(6):2453.
[27]QiX,LuCP Genetic characterization of novel rearsortant H1N2 influenza A viruses isolated from pigs in south eastern China.[J]ArchVirol,2006,15(16):2289.
[28]王勇,徐元勇,张传福,贾雷立,宋宏彬.甲型H1N1流感的研究进展.[J]解放军医学杂志,2009,34(6)：651-654.
[29]王大燕,高荣保,舒跃龙.甲型H1N1流感病毒快速核酸检测技术的建立.[J]病毒学报2009,5(25)1-3.
[30]Matrosovich M, Klenk HD. Natural and synthetic sialic acid-containing inhibitors influenza virus receptor binding.[J] Rev Med Virol,2003,13(2):85-97.
[31]Reuter JD, Myc A, Hayes MM, etal.Inhibition of viral adhesion and infection by sialic-acid-conjugated dendritic polymers.[J]Bioconjug Chem,1999,10(2):271-278.
[32]EuserinkM. Virologymapmaker for the world of influenza.[J] Science,2008,320 (5874):310-311.
[33]Krishnan,M.N,Ng,A,Sukumaran,B,Gilfoy,FD,Uchil,PD,Sultana,H,Brass,AL,Adametz,R,Tsui,M,Qian, F,etal. RNA interference screen for human genes as sociated with West Nile virus infection..[J]Nature 2008.455,242-245.
[34]Lamb,R.A., and Krug, R.M Orthomyxoviridae:The viruses and their replication, Lippincott Williams and Wilkins. [M] Fourth Edition Philadelphia 2001.
[35]Bullough PA, Hugson E M, Skehel J J, et al. Structure of influenza haemagglutinin at the pH of membrane fusion. [J]Nature,1994, (371)37-43.
[36]LiM L, Rao P, Krug R M. The active sites of the influenza cap dependent endonuclease are on different polymerase subunits. [J]EMBO J,2001, (20)2078-2086.
[37]GuilligayD et al. The structural basis for cap binding by influenza virus polymerase subunit PB2. [J]Nature Struct Biol,2008,15:500-506.
[38]Yoshimoto J, Kakui M, Iwasaki H, et al.Identification of a novel HA conformational change inhibitor of human influenza virus.[J]Arch Virol,1999,144(5):865-878.
[39]Fodo E, et al. A single amino acid mutation in the PA subunit of the influenza virus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs.[J]Virol,2002,76:8989-9001.
[40]Kawaguchi A, Naito T, Nagata K.Involvement of influenza virus PA subunit in assembly of functional RNA polymerase comp lexes.[J] Virol,2005,79:732-744.
[41]Sugiura A,Ueda M,Tobita K,EnomotoC. et al.Further isolation and characterization of temperature sensitive mutant of influenza virus.[J] Virology,1975,65:363-373.
[42]Fodor,E.A single aminoacid mutation in the PA subunit of the influence vitus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs.[J]Virol 2002.76,8989-9001.
[43]Jung,T E.Brownlee,G.G.A new prooter-binding site in the PBI subunit of the influenza A vitus polymerase.[J]Gen. Virol 2006(87):679-688.
[44]Kawaguchi,A,Naito,T. Nagata,K.Involvement of influenza vitus PA subunit in assembly of functional RNA polymerase complexes.[J]Virol.2005(79):732-744.
[45]Huarte,M Threonine 157 of influenza vitus PA subunit modulates RNA replication in infecetious vituses.[J]Virol.2003 (77):6007-6013.
[46]Fodor,E,Mingay,L,J,Crow,M,Deng,T. Brownlee.GGA single amino acid mutation in the PA subunit of the influenza vitus RNA polymerase promotes the generation of defective interfering RNAs.[J]Virol. 200377,5017-5020.
[47]Shen J, Kirk BD, Ma J, Wang Q. Diversifying selective pressure on influenza B virus hemagglutinin.[J]Med Virol.2009;81:114-124.
[48]Zurcher,T,de la luna,S,Sanz-Ezquerro,J,J,Nieto,A.&Ortin,J.Mutational analysis of the influenza vitus A/Victoria/3/75 PA protein:studies of interaction with PB1 protein and identification of a dominant negative mutant.[J]Gen. Virol,1996(77) 1745-1749.
[49]Hara,K. influenza vitus RNA polymerase PA subunit is a novel serine protease with Ser624 at the active site.[J] Genes Cells,2001(6)87-97.
[50]Rodriguez,A,Perez-Gonzalez,A.&Nieto,A.Influenza vitus infection causes specific degradation of the largest subunit of cellular RNA polymerase Ⅱ.[J]Virol,2007(81)5315-5324.
[51]Sanz-Ezquerro,JJ,Zurcher,Tde laLuna,S,Ortin,J.Nieto,A.The amino-terminal one-third of the influenza vitus RNA protein is responsible for the induction of proteolysis.[J]Virol.1996(70):1905-1911.
[52]Xiaojing He,Jie zhou,Yingfang Liu et al Crystal structure of the polymerase Pac-PBlN complex from an avian influenza H5N1 virus.[J] Nature,2008,454,1123-1126.
[53]Colman PM Influenza Virus nineuram inidase structure antibodies and inhibitors Protein.[J]Science,1994,3:1687-1689.
[54]Ohuchi M, Asaoka N etal Roles of neuram inidase in the initial stage influenza Virus infection.[J] Microbes and infection 2006,8:1287-1293.
[55]Calfee DP, Hayden FG. New approaches to influenza chemotherapy Neuraminidase inhibitors.[J] Drugs,1998,56:537-553.
[56]Jung,T.E.&Brownlee,G.G.A new prooter-binding site in the PBI subunit of the influenza A vitus polymerase.[J]Gen. Virol 2006,87,679-688.
[57]Kawaguchi,A,Naito,T. Nagata, K.Involvement of influenza vitus PA subunit in assembly of functional RNA polymerase complexes.[J]Virol.2005,79,732-744.
[58]Matsukura S, Kokubu F,Noda H,et al.Expression of IL-6 IL-8 and RANTES on human bronchial epithelial cells induced by influenza virus A.[J] Allergy Clin Immunol,1996,98:1080-1087.
[59]Adachi M.Matsukura S.Tokunaga H et al. Expression of cytokines on human bronchial epithelial cells induced by influenza virus A.[J]Arch Allergy Immunol,1997,113:307-311.
[60]Gern JE, French DA, Grindle KA, et al. Double-stranded RNA induces the synthesis of specific chemokines by bronchialepithelial cells.[J]Respir Cell Mol Biol,2003,28:731-737.
[61]Kaufmann A, Salentin R, Meyer RG,et al. Defense against influenza A virus infectionessential role of the chemokine system.[J]Immunobiology,2001,204(5):603-613.
[62]Tong HH, Long JP, Shannon PA,et al. Expression of cytokine and chemokine genes by human middle ear epithelial cells induced by influenza A virus and Streptococcus pneumoniae opacity variants. [J]Infect Immun,2003,71(8):4289-4296.
[63]Hayden FG, Fritz R, Lobo MC, and et al. Local and systemic cytokine responses during experimental human influenza A virus infection:Relation to symptom formation and host defense.[J]Clin Invest, 1998,101(3):643-649.
[64]Skoner DP,Gentile DA,Patel A,et al. Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus.[J] Infect Dis,1999180(1):10-14.
[65]Kaiser L, Fritz RS, Straus SE,et al. Symptom pathogenesis during acute influenza interleukin-6 and other cytokine responses.[J] Med Virol,2001,64(3):262-268.
[66]Houde M,D.J.Arora Stimulation of tumor necrosis factor secretion by purified influenza virus neuraminidase.[J]Cell Immunol,1990,129:104-111.
[67]Matsukura,Kokubu S,Noda FH,et al.Expression of IL-6、IL-8 and RANTES on human bronchial epithelial cells,NCI-H292, induced by influenza virus A.[J]Allergy Clin Immunol,1996,98:1080-1087.
[68]Lehmann C, Sprenger H, Nain M et al. Infection of macrophages by influenza A virus:characteristics of tumor necrosis factor-alpha (TNF-alpha) gene expression.[J]Res Virol,1996,147:123-130.
[69]Hussell T, Pennycook A, Openshaw PJ. Inhibition of tumor necrosis factor reduces the severity of virus-specific lungimmunopathology.[J]Eur Immunol,2001,31(9):2566-2573.
[70]Julkunen I,Sareneva T,Pirhonen J,et al. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression.[J]Cytokin Growth FactorRev,2001,12(2-3): 171-180.
[71]SarenevaT,MatikainenS,KurimotoM,etal.Influenza Avirus induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells.[J] Immunol,1998,160(12): 6032-6038.
[72]Liu B,Mori I,Hossain MJ,Dong L,et al.Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated ytotoxicity.[J]Gen Virol,2004, 85(Pt2):423-428.
[73]Seo SH,Webster RG.Tumor necrosis factor alpha exerts powerful anti-fluenza virus affects in lung epithelial cells.[J] Virol,2002,76(3):1071-1076.
[74]Bironca Activation and function of natural killer cell rsponses during viral infections[J]Immunol 1997, 9 (Ⅰ):24-34
[75]BROBERO E K, NYGARDAS M, SALMI A A, et al.Low copy numberdetection of herpes simplex virus type Ⅰ mRNA and mouse Thl type cytokine mRNAs by night cycler quantitative Real-time PCR.[J]Viral Methods 2003 112(1-2):53-65
[76]MOSMANNTR, SADS The expanding universe of T-cell subsets Thl Th2 and more cytokine.[J] Iruruuuol Todat 1996 17(3):138-146.
[77]TRINCH IERI G Biology of natural killer cells.[J] Adv Iruruuuol 1989 47 (Ⅰ):187-376.
[78]IWASHIROM, PE ERSON K, MESSER R.etal CD4(+) T cells and gamma interferon in the long-term control of persistent friend retrovims infections. [J] Viro j 2001,75 (Ⅰ):52-60.
[79]LIL,SAD S KAGID et al CD8 Tc1 and Tc2 cells secrte distinct cytokine patterns in vitra and inviuo but induce similar inflammatory reactions.[J].Jmmunoj1997,158(9):4152-4161,158(9):4152-4161.
[80]Abraham L.Brass, I-Chueh Huang, et al The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus,West Nile Virus, and Dengue Virus.[J]Cell,2009,139,1243-1254.
[81]Van Campen H. Influenza A virus replication is inhibited by tumor necrosis factor-invitro.[J]Arch Virol,1994,136:439-446.
[82]金奇主编.医学分子病毒学.[M]北京：科学出版社,2001,117.
[83]Nicole Schmitz, Michael Kurrer, Martin F etal. Interleukin-1Is Responsible for Acute Lung Immunopathology but Increases Survival of Respiratory Influenza Virus. [J]Infection Journal of Virology,2005,29(10):6441-6448.
[84]OdaT,AkaikeT,HamamotoT,etal.Oxygen radical sinpolymer conjugated influenza induced pathogenesis and treatment with pyran SOD.[J]Science,1989,244:974-976.
[85]Kinnula VL,Adler KB,Ackley NJ,et al. Release of reactive oxygen species by guinea pig tracheal epithelial cells in vitro.[J] Physiol Lung Cell Mol Physiol,1992,262:708-712.
[86]Ischiropoulos H, Zhu L, Beckman JS. Peroxynitrite formation from macrophage-derived nitricoxide. [J]Arch Biochem Biophys,1992,298:446-451.
[87]Akaike T, Noguchi Y, Ijiri S et al. Pathogenesis of influenza virus-induced pneumonia:involvement of both nitricoxide and oxygen radicals.[J]Proc Natl Acad Sci,1996,93:2448-2453.
[88]Knobil K,Choi AM,Weigand GW, et al. Role of oxidants in influenza virus induced gene expression. [J]Physiol Lung Cell Mol Physiol,1998,274:134-142.
[89]叶苓,杨守京,刘彦仿,等.流行性出血热尸检组织中热休克蛋白70mRNA的定位及分布.[J]中国病毒学,1998,19(4)：327-331.
[90]叶苓,杨守京,刘彦仿.汉滩病毒感染诱导热休克蛋白70表达.[J]中国病毒学,2000,15(2)：106-110.
[91]谭淼,邱仞之,蔡俊杰.热应激与热休克诱导兔肝、肺、心和肾热休克蛋白70合成的研究.[J]工业卫生与职业病,1996,22(1)：29-31.
[92]Medzhitov R,Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. [J]Nature,1997,388(6640):394-397.
[93]Takizawa T, Matsukawa S, Higuchi Y et al. Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells. [J] Gen Virol,1993,74:2347-2355.
[94]Mori I,Komatsu T,Takeuchi K,and et al. Invivo induction of apoptosis by influenza virus.[J]Gen Virol,1995,76 (Pt 11):2869-2873.
[95]Schultz-Cherry S,Krug RM,Hinshaw VS.Intruction of apoptosis by influenza virus.[J]Semin Virol, 1998,8:495-501.
[96]Ohta S,Yanaguhara K,Nagata K. Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor.[J]beta.Biochem,1997,324 (Pt3):777-782.
[97]Stacey Schultz-Cherry,Naomi Dybdahl-Sissoko, Gabriele Neumann, et al.Influenza Virus NS1 Protein Induces Apoptosis in Cultured Cells. [J]Journal of Virology,2001,75(17):7875-7881.
[98]Wang J.H, Devalia JL,Xia C.R,et al. Expression of RANTES by human bronchial epithelial cells in vitro and in vivo and the effect f corticosteroids. [J] Respir Cell Mol Biol,1996,14:27-35.
[99]Stasakova J, Ferko B,Kittel C, et al. A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages resulting in fast apoptosis and release of high levels of interleukins 1{beta} and 18.[J]Gen Virol,2005,86 (Pt 1):185-195.
[100]Stellato C,Beck LA,Gorgone GA,et al. Expression of the chemokine RANTES by a human bronchial epithelial cell line.[J] Immunol,1995,155:410-418.
[101]Salom D,Hill B R,Lear JD,Degrado W F,Ph-Dependent Tetramerization and Amantadine Binding of the T ransmembrane Helix of M2 From the Influenza a Virus.[J]Biochemistry,2000,39 (46):14160-14170.
[102]Jefferson T, Deeks J J, Demicheli V, Rivetti D, Rudin M, Amantadine and Rimantadine for Preventing and Treating Influenza a in Adults.[J] Cochrane DatabaseSyst Rev,2004,(3):D1169.
[103]Saito R, Sakai T, Sato I, Sano Y,Oshitani H, Sato M, Suzuki H,Frequency of Amantadine-Resistant Influenza a Viruses During Two Seasons Featuring Cocirculation of H1N1 and H3N2.[J]Journal Of Clinical Microbiology,2003,41 (5):2164-2165.
[104]Astrahan P,KassI,Cooper MA,Arkin IT,A Novel Method of Resistance for Influenza Against a Channel Blocking Antiviral Drug.[J]Proteins-Structure Function And Genetics,2004,55(2):251-257.
[105]Gubareva LV, Molecular Mechanisms of Influenza Virus Resistance to Neuraminidase Inhibitors.[J]Virus Research,2004,103 (1-2):199-203.
[106]Matrosovich M, Klenk H D, Natural and Synthetic Sialic Acid-Containing Inhibitors of Influenza Virus Receptor Binding.[J]Reviews In Medical Virology,2003,13 (2):85-97.
[107]Reuter J D,Myc A,Hayes M M,Gan Z,Roy R, Qin D,Yin R,Piehler L T, Esfand R, Tomalia D A,Jr Baker J R, Inhibition of Viral Adhesion and Infection by Sialic-Acid-Conjugated Dendritic Polymers. [J] Bioconjug Chem,1999,10 (2):271-278.
[108]Yoshimoto J, Kakui M, Iwasaki H, Fujiwara T, Sugimoto H, Hattori N, Identification of a Novel Ha Conformational Change Inhibitor of Human Influenza Virus.[J]Archives Of Virology,1999,144(5): 865-878.
[109]Wong J P, Christopher M E, Salazar A M, e al. Nucleic acidbased antiviral drugs against seasonal and avian influenza viruses.[J]Vaccine,2007,25(16):3175-3178.
[110]CooperN J, Sutton A J, Abrans K R, et al. Effectiveness of neuramini2 dase inhibitors in treatment and prevention of influenza A and B:sys2tematic review and meta2analyses of randomized controlled trials.[J]BHJ,2003,326 (7401):1235-1239.
[111]Fodor E, Brownlee G G. Influenza virus replication M Potter CW.[J]Influenza. Amsterdam Elsevier,2002:1229.
[112]Naffakh N, Massin P, Escriou N, et al. Genetic analysis of the compati bility between polymerase protein from human and avian strains of influenza A virus.[J]JGen Virol,2000,81:1283-1291.
[113]HaraK,Schmidt FI,CrowM,et al.Aminoacid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability,endonuclease activity cap binding and virus RNA promoter binding. [J] Virol,2006,80:7789-7798.
[114]Maier H J,Kashiwag T,Hara K, et al.Differential role of the influenza A virus polymerase PA subunit for VRNA and CRNA promoter biding.[J] Virology,2008,370:194-204.
[115]DiasA, BouvierD, Crepin T, et al. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. [J] N ature,2009,10:1038.
[116]张丽玲,梁卫,张丽萍,万筱荣,马建芳,扶正固本法预防感冒的临床与实验研究.[J]临床军医条志,2001,9(4)：14-15.
[117]李建生,任汉阳.培元解表方治疗老年人感冒综合征临床观察.[J]河南中医,1995,15(2)：26-27.
[118]张韧闻,刘福礼等益气清解法治疗流行性感冒.[J]山东中医志,2000,29(8)：460-461.
[119]金飏.注重守气解毒治疗流感高热临床观察.[J]新疆中医药,1998,16(1)：18.
[120]梁瑞明.感冒不可尽发表.[J]河南中医药学刊,2001,16(2)：74-75.
[123]耿荣安,衰志敏,宋宗良.固表祛毒退热治疗感冒200例.[J]陕西中医学院学报,2003,26(4)：12-13
[124]孟杰,程红.中医药治疗时行感冒78例.[J]河南中医,2002,22(5)：69-70.
[125]黄斌,谢秋芳.清凉涤暑法治湿热感冒97例.[J]江西中医药,1998,29(5)：18.
[126]李英杰.中西医治疗流感高热疗效分析.[J]现代中西医结合杂志,2001,10(3)：214.
[127]牛延献,史智勇.中药增强机体免疫功能研究进展.[J]中国兽医杂志,1998,3,38-40.
[128]杨占秋,余宏.临床病毒学[M].北京：中国医药科技出版社,2000,第1版,188.
[129]常曼丽,李洪源,刘电力,等.抗病毒1号中药有效部位抗流感病毒FM1的实验研究.[J]疾病控制杂志,2003,7(3)：201-203.
[130]彭慧琴,蔡卫民,项哨.茶多酚体外抗流感病毒A3的作用.[J]茶叶科学,2003,23(1)：80-81.
[131]杨子峰,徐活腾,刘妮,等.贯叶金丝桃醇提物抗流感病毒作用的研究.[J]现代中西医结合杂志,13(6)：712-713.
[132]朱明,夏瑶宾,白音夫,等.双解口服液抗流感病毒实验研究.[J]内蒙古中医药,2002(2)：38.
[133]张国红.中药抗病毒研究进展.[J]中外技术情报,1996,10：7-8.
[134]张宏秀,闻良珍,凌霞珍,等.中药金叶败毒制剂抑制巨细胞病毒感染ERK/MAPK信号通路的研究.[J]现代生物医学进展,2006,6(11)：1-3.
[135]左丽,陈力,唐晓敏等.黄芪A6组分对流感病毒感染小鼠的防治作用.[J]中国病毒学,1997,12(4)：342-345.
[136]胡兴昌,郑伟强,板蓝根粗提液抑制流感病毒的实验研究.[J]上海师范大学学报(自然科学版),2003,10(1)：62-64.
[137]TakizawaT Matsukawa S,HiguchiY,etal.Induction of programmed cell death by influenza virus infection in tissue culture cells.[J]Gen Virol,1993,74:2347-2355.
[138]Mori I,KomatsuT,Takeuchi K,etal.Invivo induction of apoptosis by influenza virus.[J]Gen Virol.1995,76 (Pt 11):2869-2873.
[139]Ippei Fujimoto, Jiehong Pan, Takenori Takizawa, et al.Virus Clearance through Apoptosis Dependent Phagocytosis of Influenza A Virus-Infected Cells by Macrophages.[J]Virology,2000, 74(7):3399-3403.
[140]陈志敏,邵洁,张群卫,等.穿孔素缺陷小鼠对流感病毒感染及其免疫功能的影响.[J]中华微生物学和免疫学杂志,2002,22(1)：49-52.
[141]孙坚,王农荣,陈世件,等.穿琥宁抑制流感病毒诱导狗肾传代细胞凋亡.[J]中国医院药学杂志,2003,7：405-407.
[142]郭惠,姚灿,何士勤.鱼腥草抗流感病毒诱导细胞凋亡的研究.[J]赣南医学院学报,2003,6：615-616.
[143]俞晶华,严红.清气凉营注射液作用机理的研究.[J]辽宁中医杂志,1999,26(9)：427-428.
[144]刘培民.升降散抗流感病毒实验研究.[J]山东中医药大学学报,2001,25(1)：43-45.
[145]欧敏,董建华,段蕴铀.清肺饮对流感病毒感染小鼠免疫功能的调节作用.[J]北京中医药大学学报,1998,21(6)：19-21.
[146]顾丽贞,王彦云,王勒渝,等.克感利咽口服液对流感性肺炎小鼠免疫功能的若干调节作用.[J]云南中医中药杂志,2001,22(2)：37-39.
[147]陈达,张永萍.天然药物中抗流感成分的研究.[J]医学导刊2008 4(4)103.
[148]史利卿,邱全瑛,吕燕宁,等.宣肺解毒颗粒剂对流感病毒肺炎小鼠血浆中细胞因子水平的影响.[J]北京中医药大学学报,1998,21(4)：23-25.
[149]欧敏,杜怀棠,段蕴铀.清肺饮对呼吸道病毒感染及其对NK、IFN-γ、IL-2的影响.[J]北京中医药大学学报,2002,25(4)：56-58.
[150]胡旭,邱全瑛,姜良铎.胚芽滋养胶囊对流感病毒感染小鼠血清IL-2和TNF-α水平的影响.[J]中国中医急症,2004,13(5)：306-307.
[151]张晓梅,姜良择,史利卿,等.灵丹草颗粒剂对上呼吸道感染患者IL-1、IL-6、TNF-α的影响.[J]中国医药学报,2001,16(4)：25-27.
[152]陈奇,中药药理研究方法学[M].北京：人民卫生出版社,1993,251-256.
[153]萨姆布鲁克,DW.拉塞尔著.分子克隆[M]上册3版.黄培堂等译.北京：科学出版社,2002.607-608.
[154]张国萍,吴丁兰,党华,等两种不同胞内pH敏感染料在激光扫描共聚焦显微镜中的应用.[J]细胞与分子免疫学杂志2009,25(6)：559-561.
[155]流感病毒更易攻击免疫低下人群[EB/OL].http://news.ifeng.com/mainland/171165061.stml.
[156]赵戈清,罗辉,陈东辉.不同剂量环磷酰胺诱导正常小鼠免疫抑制的研究.[J]免疫学杂志,2005,(3)：122-124.
[157]杨颖,蔡玟,黄志彪,等环磷酰胺致小鼠免疫功能低下模型建立与评价.[J]中国公共卫生2008(5)：581-583.
[2]范鸣.抗病毒药达菲致神经精神类不良反应.[J]药学进展,2006(3)：139-140.
[3]Lackenby A,Hungnes O,Dudman SG,et al.Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe.[J]Euro Surveill,2008(5):8026.
[4]Nicoll A,Ciancio B,Kramarz P. Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications.[J]Euro Surveill,2008(5):8025.
[5]Influenza Project Team.Oseltamivir resistance in human seasonal influenza viruses (A/H1N1) in EU and EFTA countries an update. [J] Euro Surveill.2008(6):8032.
[6]曹洪欣,王喜军,于友华,等.中药复方安替威血清药物化学和抗SARS病毒实验研究.[J]中国中药杂志,2004,29(3)：281-283.
[7]曹洪欣,崔晓兰,赵静,等.安替威胶囊抗病毒药效学研究.[J]中国中医基础理论.2004,10(10),771-774.
[8]曹洪欣,崔晓兰,赵静,等.安替威胶囊治疗小鼠病毒性肺炎的作用机制研究.[J]中国中医基础理论,2005,30(13),1039-1041.
[9]崔晓兰,曹洪欣,赵静,等.安替威胶囊解热实验研究.[J]中医药学报2005,33(3),57-59.
[10]徐慧,曹洪欣,刘建勋,等安替威胶囊对迟发型超敏反应小鼠免疫功能的影响.[J]中医药学刊,2005,23(6)995-996.
[11]曹洪欣,翁维良SARS瘟疫研究[M].北京：中医古籍出版社389-396.
[12]金奇.医学分子病毒学[M].北京：科学出版社,2001：2.
[13]Gubaruva,Kaiserl,HaydenFG.Influenzavirus neuraminidase inhibitors[J]Lancet 2000(9206):827-835.
[14]Webby RJ,Swenson SL, Krauss SL,et al. Evolution of swine H3N2 influenza viruses in the United States.[J] Virol,2000 (18):8243-8251.
[15]Brown IH.The epidemiology and evolution of influenza viruses in pigs.[J]Vet Microbiol,2000 (12): 29-46
[16]Vincent A1,MaW,Lager K,et al.Swine influenza viruses a North American perspective.[J]Adv Virus Res,2008 (127):154.
[17]Outbreak news.Swine influenza.[J]Wkly EpidemiolRec,2009(18):149-153.
[18]Murpy BR,Webster RG.Orthomyxo viruses ology philadelphia Lippincott.[J]Raven Publishers,1996 (11):397.
[19]DeaS,BilodeauR,SauvageauR,etal Anti genicvariant of swine in fluenza virus causing proliferative and necrotizingpn eumoniainpigs.[J]VetDiagInvest,1992(4):380.
[20]Zhou MN,Senne DA,Landgraf JS.Genetic reass ortment of avian swine and human influenzaa virus in American pigs.[J]Virol,1999 (12):885.
[21]WebbyRG,SwensonSL,KraussSL,et al Evolution of swine H3N2 influenza viruses in the United States.[J]Virol,2000,(18):8243.
[22]Christopher,WolsenThe emergence of novel swine influenza viruses in North America.[J]VirusRes, 2002 (2):199.
[23]SugimuraT,YonemochiH,OgawaT,etal Isolation of combinant influenza virus(H1N2) from swine in Japan.[J]ArchVirol,1980 (3):27.
[24]GourreauJM,KaiserC,ValetteM,etal Isolation of two H1N2 influenza viruses from swine in France.[J]ArchVirol,1994,135(4):365.
[25]BrownIH,ChakravertyP,HarrisPA,et al Disease outbreak sinpigs in Great Britain due to aninfluenza A virus of H1N2 subtype.[J]VetRec,1995136(13):328.
[26]KarasinAI,AndersonRG,OlsenCW1 Genetic characterization of an H1N2 influenza virus isolated from a pig in Indian.[J]Jcl in Microbiol,2000,3(6):2453.
[27]QiX,LuCP Genetic characterization of novel rearsortant H1N2 influenza A viruses isolated from pigs in south eastern China.[J]ArchVirol,2006,15(16):2289.
[28]王勇,徐元勇,张传福,贾雷立,宋宏彬.甲型H1N1流感的研究进展.[J]解放军医学杂志,2009,34(6)：651-654.
[29]王大燕,高荣保,舒跃龙.甲型H1N1流感病毒快速核酸检测技术的建立.[J]病毒学报2009,5(25)1-3.
[30]Matrosovich M, Klenk HD. Natural and synthetic sialic acid-containing inhibitors influenza virus receptor binding.[J] Rev Med Virol,2003,13(2):85-97.
[31]Reuter JD, Myc A, Hayes MM, etal.Inhibition of viral adhesion and infection by sialic-acid-conjugated dendritic polymers.[J]Bioconjug Chem,1999,10(2):271-278.
[32]EuserinkM. Virologymapmaker for the world of influenza.[J] Science,2008,320 (5874):310-311.
[33]Krishnan,M.N,Ng,A,Sukumaran,B,Gilfoy,FD,Uchil,PD,Sultana,H,Brass,AL,Adametz,R,Tsui,M,Qian, F,etal. RNA interference screen for human genes as sociated with West Nile virus infection..[J]Nature 2008.455,242-245.
[34]Lamb,R.A., and Krug, R.M Orthomyxoviridae:The viruses and their replication, Lippincott Williams and Wilkins. [M] Fourth Edition Philadelphia 2001.
[35]Bullough PA, Hugson E M, Skehel J J, et al. Structure of influenza haemagglutinin at the pH of membrane fusion. [J]Nature,1994, (371)37-43.
[36]LiM L, Rao P, Krug R M. The active sites of the influenza cap dependent endonuclease are on different polymerase subunits. [J]EMBO J,2001, (20)2078-2086.
[37]GuilligayD et al. The structural basis for cap binding by influenza virus polymerase subunit PB2. [J]Nature Struct Biol,2008,15:500-506.
[38]Yoshimoto J, Kakui M, Iwasaki H, et al.Identification of a novel HA conformational change inhibitor of human influenza virus.[J]Arch Virol,1999,144(5):865-878.
[39]Fodo E, et al. A single amino acid mutation in the PA subunit of the influenza virus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs.[J]Virol,2002,76:8989-9001.
[40]Kawaguchi A, Naito T, Nagata K.Involvement of influenza virus PA subunit in assembly of functional RNA polymerase comp lexes.[J] Virol,2005,79:732-744.
[41]Sugiura A,Ueda M,Tobita K,EnomotoC. et al.Further isolation and characterization of temperature sensitive mutant of influenza virus.[J] Virology,1975,65:363-373.
[42]Fodor,E.A single aminoacid mutation in the PA subunit of the influence vitus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs.[J]Virol 2002.76,8989-9001.
[43]Jung,T E.Brownlee,G.G.A new prooter-binding site in the PBI subunit of the influenza A vitus polymerase.[J]Gen. Virol 2006(87):679-688.
[44]Kawaguchi,A,Naito,T. Nagata,K.Involvement of influenza vitus PA subunit in assembly of functional RNA polymerase complexes.[J]Virol.2005(79):732-744.
[45]Huarte,M Threonine 157 of influenza vitus PA subunit modulates RNA replication in infecetious vituses.[J]Virol.2003 (77):6007-6013.
[46]Fodor,E,Mingay,L,J,Crow,M,Deng,T. Brownlee.GGA single amino acid mutation in the PA subunit of the influenza vitus RNA polymerase promotes the generation of defective interfering RNAs.[J]Virol. 200377,5017-5020.
[47]Shen J, Kirk BD, Ma J, Wang Q. Diversifying selective pressure on influenza B virus hemagglutinin.[J]Med Virol.2009;81:114-124.
[48]Zurcher,T,de la luna,S,Sanz-Ezquerro,J,J,Nieto,A.&Ortin,J.Mutational analysis of the influenza vitus A/Victoria/3/75 PA protein:studies of interaction with PB1 protein and identification of a dominant negative mutant.[J]Gen. Virol,1996(77) 1745-1749.
[49]Hara,K. influenza vitus RNA polymerase PA subunit is a novel serine protease with Ser624 at the active site.[J] Genes Cells,2001(6)87-97.
[50]Rodriguez,A,Perez-Gonzalez,A.&Nieto,A.Influenza vitus infection causes specific degradation of the largest subunit of cellular RNA polymerase Ⅱ.[J]Virol,2007(81)5315-5324.
[51]Sanz-Ezquerro,JJ,Zurcher,Tde laLuna,S,Ortin,J.Nieto,A.The amino-terminal one-third of the influenza vitus RNA protein is responsible for the induction of proteolysis.[J]Virol.1996(70):1905-1911.
[52]Xiaojing He,Jie zhou,Yingfang Liu et al Crystal structure of the polymerase Pac-PBlN complex from an avian influenza H5N1 virus.[J] Nature,2008,454,1123-1126.
[53]Colman PM Influenza Virus nineuram inidase structure antibodies and inhibitors Protein.[J]Science,1994,3:1687-1689.
[54]Ohuchi M, Asaoka N etal Roles of neuram inidase in the initial stage influenza Virus infection.[J] Microbes and infection 2006,8:1287-1293.
[55]Calfee DP, Hayden FG. New approaches to influenza chemotherapy Neuraminidase inhibitors.[J] Drugs,1998,56:537-553.
[56]Jung,T.E.&Brownlee,G.G.A new prooter-binding site in the PBI subunit of the influenza A vitus polymerase.[J]Gen. Virol 2006,87,679-688.
[57]Kawaguchi,A,Naito,T. Nagata, K.Involvement of influenza vitus PA subunit in assembly of functional RNA polymerase complexes.[J]Virol.2005,79,732-744.
[58]Matsukura S, Kokubu F,Noda H,et al.Expression of IL-6 IL-8 and RANTES on human bronchial epithelial cells induced by influenza virus A.[J] Allergy Clin Immunol,1996,98:1080-1087.
[59]Adachi M.Matsukura S.Tokunaga H et al. Expression of cytokines on human bronchial epithelial cells induced by influenza virus A.[J]Arch Allergy Immunol,1997,113:307-311.
[60]Gern JE, French DA, Grindle KA, et al. Double-stranded RNA induces the synthesis of specific chemokines by bronchialepithelial cells.[J]Respir Cell Mol Biol,2003,28:731-737.
[61]Kaufmann A, Salentin R, Meyer RG,et al. Defense against influenza A virus infectionessential role of the chemokine system.[J]Immunobiology,2001,204(5):603-613.
[62]Tong HH, Long JP, Shannon PA,et al. Expression of cytokine and chemokine genes by human middle ear epithelial cells induced by influenza A virus and Streptococcus pneumoniae opacity variants. [J]Infect Immun,2003,71(8):4289-4296.
[63]Hayden FG, Fritz R, Lobo MC, and et al. Local and systemic cytokine responses during experimental human influenza A virus infection:Relation to symptom formation and host defense.[J]Clin Invest, 1998,101(3):643-649.
[64]Skoner DP,Gentile DA,Patel A,et al. Evidence for cytokine mediation of disease expression in adults experimentally infected with influenza A virus.[J] Infect Dis,1999180(1):10-14.
[65]Kaiser L, Fritz RS, Straus SE,et al. Symptom pathogenesis during acute influenza interleukin-6 and other cytokine responses.[J] Med Virol,2001,64(3):262-268.
[66]Houde M,D.J.Arora Stimulation of tumor necrosis factor secretion by purified influenza virus neuraminidase.[J]Cell Immunol,1990,129:104-111.
[67]Matsukura,Kokubu S,Noda FH,et al.Expression of IL-6、IL-8 and RANTES on human bronchial epithelial cells,NCI-H292, induced by influenza virus A.[J]Allergy Clin Immunol,1996,98:1080-1087.
[68]Lehmann C, Sprenger H, Nain M et al. Infection of macrophages by influenza A virus:characteristics of tumor necrosis factor-alpha (TNF-alpha) gene expression.[J]Res Virol,1996,147:123-130.
[69]Hussell T, Pennycook A, Openshaw PJ. Inhibition of tumor necrosis factor reduces the severity of virus-specific lungimmunopathology.[J]Eur Immunol,2001,31(9):2566-2573.
[70]Julkunen I,Sareneva T,Pirhonen J,et al. Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression.[J]Cytokin Growth FactorRev,2001,12(2-3): 171-180.
[71]SarenevaT,MatikainenS,KurimotoM,etal.Influenza Avirus induced IFN-alpha/beta and IL-18 synergistically enhance IFN-gamma gene expression in human T cells.[J] Immunol,1998,160(12): 6032-6038.
[72]Liu B,Mori I,Hossain MJ,Dong L,et al.Interleukin-18 improves the early defence system against influenza virus infection by augmenting natural killer cell-mediated ytotoxicity.[J]Gen Virol,2004, 85(Pt2):423-428.
[73]Seo SH,Webster RG.Tumor necrosis factor alpha exerts powerful anti-fluenza virus affects in lung epithelial cells.[J] Virol,2002,76(3):1071-1076.
[74]Bironca Activation and function of natural killer cell rsponses during viral infections[J]Immunol 1997, 9 (Ⅰ):24-34
[75]BROBERO E K, NYGARDAS M, SALMI A A, et al.Low copy numberdetection of herpes simplex virus type Ⅰ mRNA and mouse Thl type cytokine mRNAs by night cycler quantitative Real-time PCR.[J]Viral Methods 2003 112(1-2):53-65
[76]MOSMANNTR, SADS The expanding universe of T-cell subsets Thl Th2 and more cytokine.[J] Iruruuuol Todat 1996 17(3):138-146.
[77]TRINCH IERI G Biology of natural killer cells.[J] Adv Iruruuuol 1989 47 (Ⅰ):187-376.
[78]IWASHIROM, PE ERSON K, MESSER R.etal CD4(+) T cells and gamma interferon in the long-term control of persistent friend retrovims infections. [J] Viro j 2001,75 (Ⅰ):52-60.
[79]LIL,SAD S KAGID et al CD8 Tc1 and Tc2 cells secrte distinct cytokine patterns in vitra and inviuo but induce similar inflammatory reactions.[J].Jmmunoj1997,158(9):4152-4161,158(9):4152-4161.
[80]Abraham L.Brass, I-Chueh Huang, et al The IFITM Proteins Mediate Cellular Resistance to Influenza A H1N1 Virus,West Nile Virus, and Dengue Virus.[J]Cell,2009,139,1243-1254.
[81]Van Campen H. Influenza A virus replication is inhibited by tumor necrosis factor-invitro.[J]Arch Virol,1994,136:439-446.
[82]金奇主编.医学分子病毒学.[M]北京：科学出版社,2001,117.
[83]Nicole Schmitz, Michael Kurrer, Martin F etal. Interleukin-1Is Responsible for Acute Lung Immunopathology but Increases Survival of Respiratory Influenza Virus. [J]Infection Journal of Virology,2005,29(10):6441-6448.
[84]OdaT,AkaikeT,HamamotoT,etal.Oxygen radical sinpolymer conjugated influenza induced pathogenesis and treatment with pyran SOD.[J]Science,1989,244:974-976.
[85]Kinnula VL,Adler KB,Ackley NJ,et al. Release of reactive oxygen species by guinea pig tracheal epithelial cells in vitro.[J] Physiol Lung Cell Mol Physiol,1992,262:708-712.
[86]Ischiropoulos H, Zhu L, Beckman JS. Peroxynitrite formation from macrophage-derived nitricoxide. [J]Arch Biochem Biophys,1992,298:446-451.
[87]Akaike T, Noguchi Y, Ijiri S et al. Pathogenesis of influenza virus-induced pneumonia:involvement of both nitricoxide and oxygen radicals.[J]Proc Natl Acad Sci,1996,93:2448-2453.
[88]Knobil K,Choi AM,Weigand GW, et al. Role of oxidants in influenza virus induced gene expression. [J]Physiol Lung Cell Mol Physiol,1998,274:134-142.
[89]叶苓,杨守京,刘彦仿,等.流行性出血热尸检组织中热休克蛋白70mRNA的定位及分布.[J]中国病毒学,1998,19(4)：327-331.
[90]叶苓,杨守京,刘彦仿.汉滩病毒感染诱导热休克蛋白70表达.[J]中国病毒学,2000,15(2)：106-110.
[91]谭淼,邱仞之,蔡俊杰.热应激与热休克诱导兔肝、肺、心和肾热休克蛋白70合成的研究.[J]工业卫生与职业病,1996,22(1)：29-31.
[92]Medzhitov R,Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. [J]Nature,1997,388(6640):394-397.
[93]Takizawa T, Matsukawa S, Higuchi Y et al. Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells. [J] Gen Virol,1993,74:2347-2355.
[94]Mori I,Komatsu T,Takeuchi K,and et al. Invivo induction of apoptosis by influenza virus.[J]Gen Virol,1995,76 (Pt 11):2869-2873.
[95]Schultz-Cherry S,Krug RM,Hinshaw VS.Intruction of apoptosis by influenza virus.[J]Semin Virol, 1998,8:495-501.
[96]Ohta S,Yanaguhara K,Nagata K. Mechanism of apoptotic cell death of human gastric carcinoma cells mediated by transforming growth factor.[J]beta.Biochem,1997,324 (Pt3):777-782.
[97]Stacey Schultz-Cherry,Naomi Dybdahl-Sissoko, Gabriele Neumann, et al.Influenza Virus NS1 Protein Induces Apoptosis in Cultured Cells. [J]Journal of Virology,2001,75(17):7875-7881.
[98]Wang J.H, Devalia JL,Xia C.R,et al. Expression of RANTES by human bronchial epithelial cells in vitro and in vivo and the effect f corticosteroids. [J] Respir Cell Mol Biol,1996,14:27-35.
[99]Stasakova J, Ferko B,Kittel C, et al. A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages resulting in fast apoptosis and release of high levels of interleukins 1{beta} and 18.[J]Gen Virol,2005,86 (Pt 1):185-195.
[100]Stellato C,Beck LA,Gorgone GA,et al. Expression of the chemokine RANTES by a human bronchial epithelial cell line.[J] Immunol,1995,155:410-418.
[101]Salom D,Hill B R,Lear JD,Degrado W F,Ph-Dependent Tetramerization and Amantadine Binding of the T ransmembrane Helix of M2 From the Influenza a Virus.[J]Biochemistry,2000,39 (46):14160-14170.
[102]Jefferson T, Deeks J J, Demicheli V, Rivetti D, Rudin M, Amantadine and Rimantadine for Preventing and Treating Influenza a in Adults.[J] Cochrane DatabaseSyst Rev,2004,(3):D1169.
[103]Saito R, Sakai T, Sato I, Sano Y,Oshitani H, Sato M, Suzuki H,Frequency of Amantadine-Resistant Influenza a Viruses During Two Seasons Featuring Cocirculation of H1N1 and H3N2.[J]Journal Of Clinical Microbiology,2003,41 (5):2164-2165.
[104]Astrahan P,KassI,Cooper MA,Arkin IT,A Novel Method of Resistance for Influenza Against a Channel Blocking Antiviral Drug.[J]Proteins-Structure Function And Genetics,2004,55(2):251-257.
[105]Gubareva LV, Molecular Mechanisms of Influenza Virus Resistance to Neuraminidase Inhibitors.[J]Virus Research,2004,103 (1-2):199-203.
[106]Matrosovich M, Klenk H D, Natural and Synthetic Sialic Acid-Containing Inhibitors of Influenza Virus Receptor Binding.[J]Reviews In Medical Virology,2003,13 (2):85-97.
[107]Reuter J D,Myc A,Hayes M M,Gan Z,Roy R, Qin D,Yin R,Piehler L T, Esfand R, Tomalia D A,Jr Baker J R, Inhibition of Viral Adhesion and Infection by Sialic-Acid-Conjugated Dendritic Polymers. [J] Bioconjug Chem,1999,10 (2):271-278.
[108]Yoshimoto J, Kakui M, Iwasaki H, Fujiwara T, Sugimoto H, Hattori N, Identification of a Novel Ha Conformational Change Inhibitor of Human Influenza Virus.[J]Archives Of Virology,1999,144(5): 865-878.
[109]Wong J P, Christopher M E, Salazar A M, e al. Nucleic acidbased antiviral drugs against seasonal and avian influenza viruses.[J]Vaccine,2007,25(16):3175-3178.
[110]CooperN J, Sutton A J, Abrans K R, et al. Effectiveness of neuramini2 dase inhibitors in treatment and prevention of influenza A and B:sys2tematic review and meta2analyses of randomized controlled trials.[J]BHJ,2003,326 (7401):1235-1239.
[111]Fodor E, Brownlee G G. Influenza virus replication M Potter CW.[J]Influenza. Amsterdam Elsevier,2002:1229.
[112]Naffakh N, Massin P, Escriou N, et al. Genetic analysis of the compati bility between polymerase protein from human and avian strains of influenza A virus.[J]JGen Virol,2000,81:1283-1291.
[113]HaraK,Schmidt FI,CrowM,et al.Aminoacid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability,endonuclease activity cap binding and virus RNA promoter binding. [J] Virol,2006,80:7789-7798.
[114]Maier H J,Kashiwag T,Hara K, et al.Differential role of the influenza A virus polymerase PA subunit for VRNA and CRNA promoter biding.[J] Virology,2008,370:194-204.
[115]DiasA, BouvierD, Crepin T, et al. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. [J] N ature,2009,10:1038.
[116]张丽玲,梁卫,张丽萍,万筱荣,马建芳,扶正固本法预防感冒的临床与实验研究.[J]临床军医条志,2001,9(4)：14-15.
[117]李建生,任汉阳.培元解表方治疗老年人感冒综合征临床观察.[J]河南中医,1995,15(2)：26-27.
[118]张韧闻,刘福礼等益气清解法治疗流行性感冒.[J]山东中医志,2000,29(8)：460-461.
[119]金飏.注重守气解毒治疗流感高热临床观察.[J]新疆中医药,1998,16(1)：18.
[120]梁瑞明.感冒不可尽发表.[J]河南中医药学刊,2001,16(2)：74-75.
[123]耿荣安,衰志敏,宋宗良.固表祛毒退热治疗感冒200例.[J]陕西中医学院学报,2003,26(4)：12-13
[124]孟杰,程红.中医药治疗时行感冒78例.[J]河南中医,2002,22(5)：69-70.
[125]黄斌,谢秋芳.清凉涤暑法治湿热感冒97例.[J]江西中医药,1998,29(5)：18.
[126]李英杰.中西医治疗流感高热疗效分析.[J]现代中西医结合杂志,2001,10(3)：214.
[127]牛延献,史智勇.中药增强机体免疫功能研究进展.[J]中国兽医杂志,1998,3,38-40.
[128]杨占秋,余宏.临床病毒学[M].北京：中国医药科技出版社,2000,第1版,188.
[129]常曼丽,李洪源,刘电力,等.抗病毒1号中药有效部位抗流感病毒FM1的实验研究.[J]疾病控制杂志,2003,7(3)：201-203.
[130]彭慧琴,蔡卫民,项哨.茶多酚体外抗流感病毒A3的作用.[J]茶叶科学,2003,23(1)：80-81.
[131]杨子峰,徐活腾,刘妮,等.贯叶金丝桃醇提物抗流感病毒作用的研究.[J]现代中西医结合杂志,13(6)：712-713.
[132]朱明,夏瑶宾,白音夫,等.双解口服液抗流感病毒实验研究.[J]内蒙古中医药,2002(2)：38.
[133]张国红.中药抗病毒研究进展.[J]中外技术情报,1996,10：7-8.
[134]张宏秀,闻良珍,凌霞珍,等.中药金叶败毒制剂抑制巨细胞病毒感染ERK/MAPK信号通路的研究.[J]现代生物医学进展,2006,6(11)：1-3.
[135]左丽,陈力,唐晓敏等.黄芪A6组分对流感病毒感染小鼠的防治作用.[J]中国病毒学,1997,12(4)：342-345.
[136]胡兴昌,郑伟强,板蓝根粗提液抑制流感病毒的实验研究.[J]上海师范大学学报(自然科学版),2003,10(1)：62-64.
[137]TakizawaT Matsukawa S,HiguchiY,etal.Induction of programmed cell death by influenza virus infection in tissue culture cells.[J]Gen Virol,1993,74:2347-2355.
[138]Mori I,KomatsuT,Takeuchi K,etal.Invivo induction of apoptosis by influenza virus.[J]Gen Virol.1995,76 (Pt 11):2869-2873.
[139]Ippei Fujimoto, Jiehong Pan, Takenori Takizawa, et al.Virus Clearance through Apoptosis Dependent Phagocytosis of Influenza A Virus-Infected Cells by Macrophages.[J]Virology,2000, 74(7):3399-3403.
[140]陈志敏,邵洁,张群卫,等.穿孔素缺陷小鼠对流感病毒感染及其免疫功能的影响.[J]中华微生物学和免疫学杂志,2002,22(1)：49-52.
[141]孙坚,王农荣,陈世件,等.穿琥宁抑制流感病毒诱导狗肾传代细胞凋亡.[J]中国医院药学杂志,2003,7：405-407.
[142]郭惠,姚灿,何士勤.鱼腥草抗流感病毒诱导细胞凋亡的研究.[J]赣南医学院学报,2003,6：615-616.
[143]俞晶华,严红.清气凉营注射液作用机理的研究.[J]辽宁中医杂志,1999,26(9)：427-428.
[144]刘培民.升降散抗流感病毒实验研究.[J]山东中医药大学学报,2001,25(1)：43-45.
[145]欧敏,董建华,段蕴铀.清肺饮对流感病毒感染小鼠免疫功能的调节作用.[J]北京中医药大学学报,1998,21(6)：19-21.
[146]顾丽贞,王彦云,王勒渝,等.克感利咽口服液对流感性肺炎小鼠免疫功能的若干调节作用.[J]云南中医中药杂志,2001,22(2)：37-39.
[147]陈达,张永萍.天然药物中抗流感成分的研究.[J]医学导刊2008 4(4)103.
[148]史利卿,邱全瑛,吕燕宁,等.宣肺解毒颗粒剂对流感病毒肺炎小鼠血浆中细胞因子水平的影响.[J]北京中医药大学学报,1998,21(4)：23-25.
[149]欧敏,杜怀棠,段蕴铀.清肺饮对呼吸道病毒感染及其对NK、IFN-γ、IL-2的影响.[J]北京中医药大学学报,2002,25(4)：56-58.
[150]胡旭,邱全瑛,姜良铎.胚芽滋养胶囊对流感病毒感染小鼠血清IL-2和TNF-α水平的影响.[J]中国中医急症,2004,13(5)：306-307.
[151]张晓梅,姜良择,史利卿,等.灵丹草颗粒剂对上呼吸道感染患者IL-1、IL-6、TNF-α的影响.[J]中国医药学报,2001,16(4)：25-27.
[152]陈奇,中药药理研究方法学[M].北京：人民卫生出版社,1993,251-256.
[153]萨姆布鲁克,DW.拉塞尔著.分子克隆[M]上册3版.黄培堂等译.北京：科学出版社,2002.607-608.
[154]张国萍,吴丁兰,党华,等两种不同胞内pH敏感染料在激光扫描共聚焦显微镜中的应用.[J]细胞与分子免疫学杂志2009,25(6)：559-561.
[155]流感病毒更易攻击免疫低下人群[EB/OL].http://news.ifeng.com/mainland/171165061.stml.
[156]赵戈清,罗辉,陈东辉.不同剂量环磷酰胺诱导正常小鼠免疫抑制的研究.[J]免疫学杂志,2005,(3)：122-124.
[157]杨颖,蔡玟,黄志彪,等环磷酰胺致小鼠免疫功能低下模型建立与评价.[J]中国公共卫生2008(5)：581-583.