大鼠哮喘模型的改良与评价
|
摘要
目的
通过对大鼠肺的病理组织学检查、肺泡灌洗液(BALF)的细胞学分析、血清IgE、卵蛋白(OVA)特异性IgE检测以及气道阻力的测定,探讨泵雾化和超声雾化两种激发方式制备大鼠哮喘模型的优劣以及不同浓度的卵蛋白激发对大鼠哮喘模型的影响。为进一步改良大鼠哮喘模型使其更适于哮喘的发病机制研究提供实验依据。
方法
将40只SD大鼠分为5组：对照组(Control8只)、超声雾化组(Ultra组8只)和泵雾化组(Pump组),其中泵雾化组按照卵蛋白激发浓度的不同分为Pump1组(激发浓度为1%8只),Pump2组(激发浓度为2%8只),Pump3组(激发浓度为4%8只)。Control组予lml生理盐水腹腔注射,其余4组予10%OVA混合液lml(含OVA100mg、氢氧化铝100mg及灭活百日咳杆菌苗5×109个作为免疫佐剂)致敏。2周后再以OVA进行激发,Pump各组置于自制的透明密闭有机玻璃筒(3.52cm2×π×19.5 cm)内,用PARI BOY高频雾化器作为泵雾化器提供雾化动力,分别雾化吸入1%,2%,4%OVA进行激发,10 min／次,每天1次,每周3次,共6周。Ultra组用超声雾化器吸入2%OVA进行激发。30 min／次,每天1次,每周3次,共6周。Control组以生理盐水代替2% OVA泵入雾化进行激发,10 min／次,每天1次,每周3次,共6周。各组实验大鼠于末次激发24小时后(即第57天)腹腔注射10%水合氯醛5ml/kg麻醉,采用BUXCO测定气道阻力,测定后腹腔静脉采血lml,取血浆检测IgE、SIgE含量。腹主动脉放血处死,取右肺组织用于常规苏木精—伊红(HE)染色、Masson三色染色和AB-PAS染色检测,分析气道炎症和气道重塑情况；做左肺支气管肺泡灌洗,行BALF细胞学分析。
结果
1.各组动物的一般观察
激发过程中,Ultra组和Pump各组大鼠逐渐出现烦躁不安、抓耳挠腮、呼吸急促、呈点头状呼吸、活动进食减少或俯卧不动、出现竖毛、毛发失去光泽甚至脱毛、反应迟滞等哮喘样症状。激发过程结束时,Ultra组和Pump各组大鼠均出现呼吸急促、点头状呼吸、腹肌痉挛等表现,而Control组大鼠激发前后一般观察无明显变化,呼吸平稳,运动敏捷。
2.病理组织学检查
2.1病理切片
Control组肺组织病理学检测未见气道炎症改变,肺内支气管管壁无增厚、支气管管腔规则、粘膜上皮整齐,管腔内无炎性渗出物,气道周围未见明显炎性细胞浸润。Ultra与Pump各组支气管周围可见大量炎症细胞浸润,包括：EOS、中性粒细胞、巨噬细胞和淋巴细胞等；炎性细胞主要在支气管粘膜下层及粘膜外层、肺泡壁和小血管周围等处浸润,肺间质可见EOS,支气管内可见粘液栓；气道上皮有脱落、断裂和增生,杯状细胞和腺体增生,上皮下胶原和细胞外基质沉积,平滑肌肥大、平滑肌细胞聚集增多,基底膜增厚且形态不规则。
2.2各组大鼠肺组织病理学的比较
1)支气管周围炎性细胞浸润评分：与Control组相比较,Pump各组及Ultra组支气管周围炎性细胞浸润评分显著增高(P<0.01);Pump各组与Ultra组以及Pump各组之间支气管周围炎性细胞浸润评分无显著差异(P>0.05)。
2)支气管管壁周围EOS变化：与Control组比较,Pump各组及Ultra组支气管管壁周围EOS显著增高(P<0.01);Pump各组与Ultra组以及Pump各组之间支气管管壁周围EOS无显著差异(P>0.05)。
3)与Control组比较,Pump各组及Ultra组的气道平滑肌面积、杯状细胞占上皮细胞百分比、胶原沉积面积明显增高(P<0.01)；而与Ultra组比较,Pump各组的气道平滑肌面积、杯状细胞占上皮细胞百分比、胶原沉积面积增高(P<0.01)；而Pump各组之间比较差异无统计学意义(P>0.05)。
3各组大鼠BALF细胞数比较
1)BALF细胞细胞总数分析：相对于Control组,Pump各组及Ultra组BALF细胞总数显著增高(P<0.01)；但Pump各组与Ultra组以及Pump各组之间无显著差异(P>0.05)。
2)各细胞分类比较：与Control组相比,Pump各组及Ultra组各细胞分类中EOS,淋巴细胞、显著增高,尤以EOS为主(P<0.01)；巨噬细胞显著降低(P<0.01)；但Pump各组与Ultra组以及Pump各组之间无显著差异(P>0.05)。
4各组大鼠血清总IgE、SIgE比较
Ultra组和Pump各组血清总IgE和SIgE水平明显高于Control组(P<0.01); Pump各组血清总IgE和SIgE水平均高于Ultra组(P<0.01)；而Pump各组之间无显著差异(P>0.05)。
5各组大鼠气道阻力(Raw)的变化值比较
1)气雾吸入组胺激发能导致Ultra组及Pump各组的Raw值增加,气道阻力随着组胺用量的逐渐增加而逐渐增强。
2)Ultra组及Pump各组大鼠Raw值均大于Control组(P<0.01),提示Ultra组及Pump各组大鼠的气道反应性明显增高；Pump各组大鼠Raw值较Ultra组大鼠的气道反应性均明显增高(P<0.05)；而Pump各组之间无显著差异(P>0.05)。
结论
1)通过卵蛋白(OVA)与免疫佐剂氢氧化铝、灭活百日咳杆菌致敏,OVA超声雾化或泵雾化激发均能够成功复制哮喘大鼠模型。
2)使用改良后泵雾化激发的方式复制哮喘大鼠模型优于传统的超声雾化激发方式。
3)在一定范围下,卵蛋白泵雾化激发浓度对模型制作无明显影响。
Objective
To establish the rat asthma model through pump and ultrasonic atomization, and explore difference of two ways by lung histopathology, cytology analysis of bronchial alveolar lavage fluids (BALF), serum immunoglobulin E ovalbumin (OVA), specificity immunoglobulin E and airway resistance, investigate the influences of different concentration of OVA to rat asthma model. We provide laboratory evidences by improve the rat asthma model and make it more suitable to the research of pathogenesis of asthma
Methods
Male Sprague-Dawley (SD) rats (4 weeks) were given an intraperitoneal injection of 1 ml 10% OVA complexed with 10% aluminum hydroxide gel and the inactived Bacillus pertussis on days 0.Two weeks after sensitization, Forty male SD rats were randomly divided equally into five groups. The rats of control group inhaled 0.9% sodium chloride through Ultra method in the challenge stage. The rats in Ultra group inhaled 2% OVA 30 minutes by Ultra atomizer,three times a week,for 6 weeks to sensitize their airways; And The rats in the three Pump groups inhaled 1%,2%,4% OVA respectively 10 minutes by Pump Atomization,three times a week,for 6 weeks to sensitize their airways.All the rats of the different groups were anesthetized 24h afer the last challenge for assessment, to be detected by pulmonary function,then to be killed after obtaining blood from inferior vena cava. IgE and SIgE in blood plasma was analyzed by ELISA. The left lobe of the lung bronchoalveolar lavage(BAL) was performed to evaluate the airway inflammation. After BAL,the right lobe of the lung was removed for histological examination and were stained with HE, Masson and PAS.
Results
1. General observation of the animals
Rats in Ultra group and pump group appeared appeared visible respiratory distress signs (dysphoria, polypnea, contraction of accessory respiratory muscles and cyanosis). However, rats in control group were almost the same:breathing steadly, moving swiftly.
2 Lung histopathology
2.1 Pathological section
The lung histopathology of the control group, airway inflammation detected no significant changes, without bronchial wall thickening in the lungs, bronchial lumen regulation, epithelium mucosae well-arranged, non-infl ammatory exudate within the lumen.A large number of inflammatory cellular infiltration around the bronchial can be seen in the Ultra and Pump group, including:EOS, neutrophils, macrophages and lymphocytes, etc.; There can be seen EOS in the pulmonary mesenchymal and alveolar space,mucus plug in bronchus, injuries, fracture in the airway epithelium thickening of the basilar membrane with the irregular shape, hyperplasia of smooth muscle.
2.2 The comparation of each group on the lung histopathology
1) The score of inflammatory cell infiltration in ultra group and pump group were higher compared with control group (P<0.01);That was not statistically different in ultra group, pump group and each pump group (P>0.05).
2) EOS around bronchus wall in Ultra group and pump group was significantly more compared with control group (P<0.01); There was no significant difference in ultra group, pump group and each pump group (P>0.05).
3)Collagen deposition and goblet cells proliferation, mucus secretion were significantly increased in Ultra group and pump group compared with control;And these parameters in pump group were higher than those in ultra group; However, there was no significant difference in each pump group(P>0.05).
3. The comparation of each group on the number of BALF cells
1) The number of BALF cells in Ultra group and pump group was significantly increased compared with control group (P< 0.01);however,there was no statistically significant difference in ultra group, pump group and each pump group (P>0.05).
2) Cell percentage of EOS and lymphocyte in Ultra group and pump group were higher compared with control group(P<0.01), especially for EOS; There was no significant difference in ultra group, pump group and each pump group (P>0.05).
4. The comparation of each group on the level of IgE and SIgE
Total and special serum IgE level in Ultra group and pump group was markedly enhanced compared with control group(P<0.01); and those in pump group were much higher than those in Ultra group(P< 0.01);However,there was no significant difference in each pump group (P >0.05).
5. The comparation of each group on the airway resistance
1) Aerosol histamine induced airway hyperresponsiveness, with the increasing of the dose of the histamine,the Raw value is higher and higher.
2) Raw value in Ultra group and pump group was significantly increased compared with control group(P<0.01); And airway responsiveness in pump group higher than that of Ultra group(P<0.05); However,there was no significant difference in each pump group (P> 0.05).
Conclusions
1)OVA mixed with aluminum hydroxide gel and the inactivation Bacillus pertussis sensitized rats successfully, and inhaling OVA with pump and Ultra methods to challenge established the rat asthma model successfully.
2)The pump method is superior to the traditional Ultra method to challenge the rat asthma model.
3)In some range the challenge dose of OVA has no obviously difference to established the rat asthma model
通过对大鼠肺的病理组织学检查、肺泡灌洗液(BALF)的细胞学分析、血清IgE、卵蛋白(OVA)特异性IgE检测以及气道阻力的测定,探讨泵雾化和超声雾化两种激发方式制备大鼠哮喘模型的优劣以及不同浓度的卵蛋白激发对大鼠哮喘模型的影响。为进一步改良大鼠哮喘模型使其更适于哮喘的发病机制研究提供实验依据。
方法
将40只SD大鼠分为5组：对照组(Control8只)、超声雾化组(Ultra组8只)和泵雾化组(Pump组),其中泵雾化组按照卵蛋白激发浓度的不同分为Pump1组(激发浓度为1%8只),Pump2组(激发浓度为2%8只),Pump3组(激发浓度为4%8只)。Control组予lml生理盐水腹腔注射,其余4组予10%OVA混合液lml(含OVA100mg、氢氧化铝100mg及灭活百日咳杆菌苗5×109个作为免疫佐剂)致敏。2周后再以OVA进行激发,Pump各组置于自制的透明密闭有机玻璃筒(3.52cm2×π×19.5 cm)内,用PARI BOY高频雾化器作为泵雾化器提供雾化动力,分别雾化吸入1%,2%,4%OVA进行激发,10 min／次,每天1次,每周3次,共6周。Ultra组用超声雾化器吸入2%OVA进行激发。30 min／次,每天1次,每周3次,共6周。Control组以生理盐水代替2% OVA泵入雾化进行激发,10 min／次,每天1次,每周3次,共6周。各组实验大鼠于末次激发24小时后(即第57天)腹腔注射10%水合氯醛5ml/kg麻醉,采用BUXCO测定气道阻力,测定后腹腔静脉采血lml,取血浆检测IgE、SIgE含量。腹主动脉放血处死,取右肺组织用于常规苏木精—伊红(HE)染色、Masson三色染色和AB-PAS染色检测,分析气道炎症和气道重塑情况；做左肺支气管肺泡灌洗,行BALF细胞学分析。
结果
1.各组动物的一般观察
激发过程中,Ultra组和Pump各组大鼠逐渐出现烦躁不安、抓耳挠腮、呼吸急促、呈点头状呼吸、活动进食减少或俯卧不动、出现竖毛、毛发失去光泽甚至脱毛、反应迟滞等哮喘样症状。激发过程结束时,Ultra组和Pump各组大鼠均出现呼吸急促、点头状呼吸、腹肌痉挛等表现,而Control组大鼠激发前后一般观察无明显变化,呼吸平稳,运动敏捷。
2.病理组织学检查
2.1病理切片
Control组肺组织病理学检测未见气道炎症改变,肺内支气管管壁无增厚、支气管管腔规则、粘膜上皮整齐,管腔内无炎性渗出物,气道周围未见明显炎性细胞浸润。Ultra与Pump各组支气管周围可见大量炎症细胞浸润,包括：EOS、中性粒细胞、巨噬细胞和淋巴细胞等；炎性细胞主要在支气管粘膜下层及粘膜外层、肺泡壁和小血管周围等处浸润,肺间质可见EOS,支气管内可见粘液栓；气道上皮有脱落、断裂和增生,杯状细胞和腺体增生,上皮下胶原和细胞外基质沉积,平滑肌肥大、平滑肌细胞聚集增多,基底膜增厚且形态不规则。
2.2各组大鼠肺组织病理学的比较
1)支气管周围炎性细胞浸润评分：与Control组相比较,Pump各组及Ultra组支气管周围炎性细胞浸润评分显著增高(P<0.01);Pump各组与Ultra组以及Pump各组之间支气管周围炎性细胞浸润评分无显著差异(P>0.05)。
2)支气管管壁周围EOS变化：与Control组比较,Pump各组及Ultra组支气管管壁周围EOS显著增高(P<0.01);Pump各组与Ultra组以及Pump各组之间支气管管壁周围EOS无显著差异(P>0.05)。
3)与Control组比较,Pump各组及Ultra组的气道平滑肌面积、杯状细胞占上皮细胞百分比、胶原沉积面积明显增高(P<0.01)；而与Ultra组比较,Pump各组的气道平滑肌面积、杯状细胞占上皮细胞百分比、胶原沉积面积增高(P<0.01)；而Pump各组之间比较差异无统计学意义(P>0.05)。
3各组大鼠BALF细胞数比较
1)BALF细胞细胞总数分析：相对于Control组,Pump各组及Ultra组BALF细胞总数显著增高(P<0.01)；但Pump各组与Ultra组以及Pump各组之间无显著差异(P>0.05)。
2)各细胞分类比较：与Control组相比,Pump各组及Ultra组各细胞分类中EOS,淋巴细胞、显著增高,尤以EOS为主(P<0.01)；巨噬细胞显著降低(P<0.01)；但Pump各组与Ultra组以及Pump各组之间无显著差异(P>0.05)。
4各组大鼠血清总IgE、SIgE比较
Ultra组和Pump各组血清总IgE和SIgE水平明显高于Control组(P<0.01); Pump各组血清总IgE和SIgE水平均高于Ultra组(P<0.01)；而Pump各组之间无显著差异(P>0.05)。
5各组大鼠气道阻力(Raw)的变化值比较
1)气雾吸入组胺激发能导致Ultra组及Pump各组的Raw值增加,气道阻力随着组胺用量的逐渐增加而逐渐增强。
2)Ultra组及Pump各组大鼠Raw值均大于Control组(P<0.01),提示Ultra组及Pump各组大鼠的气道反应性明显增高；Pump各组大鼠Raw值较Ultra组大鼠的气道反应性均明显增高(P<0.05)；而Pump各组之间无显著差异(P>0.05)。
结论
1)通过卵蛋白(OVA)与免疫佐剂氢氧化铝、灭活百日咳杆菌致敏,OVA超声雾化或泵雾化激发均能够成功复制哮喘大鼠模型。
2)使用改良后泵雾化激发的方式复制哮喘大鼠模型优于传统的超声雾化激发方式。
3)在一定范围下,卵蛋白泵雾化激发浓度对模型制作无明显影响。
Objective
To establish the rat asthma model through pump and ultrasonic atomization, and explore difference of two ways by lung histopathology, cytology analysis of bronchial alveolar lavage fluids (BALF), serum immunoglobulin E ovalbumin (OVA), specificity immunoglobulin E and airway resistance, investigate the influences of different concentration of OVA to rat asthma model. We provide laboratory evidences by improve the rat asthma model and make it more suitable to the research of pathogenesis of asthma
Methods
Male Sprague-Dawley (SD) rats (4 weeks) were given an intraperitoneal injection of 1 ml 10% OVA complexed with 10% aluminum hydroxide gel and the inactived Bacillus pertussis on days 0.Two weeks after sensitization, Forty male SD rats were randomly divided equally into five groups. The rats of control group inhaled 0.9% sodium chloride through Ultra method in the challenge stage. The rats in Ultra group inhaled 2% OVA 30 minutes by Ultra atomizer,three times a week,for 6 weeks to sensitize their airways; And The rats in the three Pump groups inhaled 1%,2%,4% OVA respectively 10 minutes by Pump Atomization,three times a week,for 6 weeks to sensitize their airways.All the rats of the different groups were anesthetized 24h afer the last challenge for assessment, to be detected by pulmonary function,then to be killed after obtaining blood from inferior vena cava. IgE and SIgE in blood plasma was analyzed by ELISA. The left lobe of the lung bronchoalveolar lavage(BAL) was performed to evaluate the airway inflammation. After BAL,the right lobe of the lung was removed for histological examination and were stained with HE, Masson and PAS.
Results
1. General observation of the animals
Rats in Ultra group and pump group appeared appeared visible respiratory distress signs (dysphoria, polypnea, contraction of accessory respiratory muscles and cyanosis). However, rats in control group were almost the same:breathing steadly, moving swiftly.
2 Lung histopathology
2.1 Pathological section
The lung histopathology of the control group, airway inflammation detected no significant changes, without bronchial wall thickening in the lungs, bronchial lumen regulation, epithelium mucosae well-arranged, non-infl ammatory exudate within the lumen.A large number of inflammatory cellular infiltration around the bronchial can be seen in the Ultra and Pump group, including:EOS, neutrophils, macrophages and lymphocytes, etc.; There can be seen EOS in the pulmonary mesenchymal and alveolar space,mucus plug in bronchus, injuries, fracture in the airway epithelium thickening of the basilar membrane with the irregular shape, hyperplasia of smooth muscle.
2.2 The comparation of each group on the lung histopathology
1) The score of inflammatory cell infiltration in ultra group and pump group were higher compared with control group (P<0.01);That was not statistically different in ultra group, pump group and each pump group (P>0.05).
2) EOS around bronchus wall in Ultra group and pump group was significantly more compared with control group (P<0.01); There was no significant difference in ultra group, pump group and each pump group (P>0.05).
3)Collagen deposition and goblet cells proliferation, mucus secretion were significantly increased in Ultra group and pump group compared with control;And these parameters in pump group were higher than those in ultra group; However, there was no significant difference in each pump group(P>0.05).
3. The comparation of each group on the number of BALF cells
1) The number of BALF cells in Ultra group and pump group was significantly increased compared with control group (P< 0.01);however,there was no statistically significant difference in ultra group, pump group and each pump group (P>0.05).
2) Cell percentage of EOS and lymphocyte in Ultra group and pump group were higher compared with control group(P<0.01), especially for EOS; There was no significant difference in ultra group, pump group and each pump group (P>0.05).
4. The comparation of each group on the level of IgE and SIgE
Total and special serum IgE level in Ultra group and pump group was markedly enhanced compared with control group(P<0.01); and those in pump group were much higher than those in Ultra group(P< 0.01);However,there was no significant difference in each pump group (P >0.05).
5. The comparation of each group on the airway resistance
1) Aerosol histamine induced airway hyperresponsiveness, with the increasing of the dose of the histamine,the Raw value is higher and higher.
2) Raw value in Ultra group and pump group was significantly increased compared with control group(P<0.01); And airway responsiveness in pump group higher than that of Ultra group(P<0.05); However,there was no significant difference in each pump group (P> 0.05).
Conclusions
1)OVA mixed with aluminum hydroxide gel and the inactivation Bacillus pertussis sensitized rats successfully, and inhaling OVA with pump and Ultra methods to challenge established the rat asthma model successfully.
2)The pump method is superior to the traditional Ultra method to challenge the rat asthma model.
3)In some range the challenge dose of OVA has no obviously difference to established the rat asthma model
引文
[1]King CS, Moores LK. Clinical asthma syndromes and important asthma mimics[J]. Respir Care,2008,53(5):568-580.
[2]Downs SH, Marks GB, Sporik R, et al. Continued increase in the prevalence of asthma and atopy[J].Arch Dis Child,2001,84(1):20-23.
[3]沈华浩,王苹莉.如何评价哮喘动物模型[J].医学与哲学(临床决策论坛版)2007,28(8)：13-15.
[4]王妍,金先桥.支气管哮喘实验模型的研究进展[J].国际呼吸杂志,2006,26(1)：70-77.
[5]Temelcovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma:selective airway inflammation,epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J]. Thorax, 1998,53(10):849-856.
[6]Karol MH. Animal models of occupational asthma[J].Eur Respir J, 1994,7(3):555-568.
[7]Bergeron C,Boulet LP. Structural changes in airway diseases: characteristics,mechanisms,consequences,and pharmacologic modulation[J]. Chest, 2006,129(4):1068-1087.
[8]Schneider T, van VD, Moqbel R, et al. Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model[J]. Am J Respir Cell Mol Biol 1997,17(6):702-712.
[9]Underwood SL, Haddad E, Birrell MA, et al. Functional characterization and biomarker identification in the brown Norway model of allergic airway inflammation[J]. Br J Pharmacol,2002,137(2):263-275.
[10]Russo M,Mariano M,Jancar S.A new murine model of persistent lung eosinophilic inflammation[J]. Mem Inst Oswaldo Cruz,1997,92(2):215-218.
[11]Carvalho C, Jancar S, MariaaoM, et al. Aratmodel presenting eosinophilia in the airways, Lung eosinophil activation, and pulmonary h yperreactivity [J]. Exp Lung Res,1999,25 (4):303-316.
[12]Itami DM, Latinne D, Bazin H, et al. Immunogloblin E is not required for but enhances airway inflammation and hyperresponsiveness[J]. Allergy,2003,58(11): 1117-1124.
[13]崔龙苹,杨永清,陈汉平,等.过敏性哮喘大鼠模型的制备[J].上海实验动物科学，2000,20(2)：69-71.
[14]吉宁飞,卞涛,陈力,等.支气管哮喘大鼠模型的建立与气道反应性的测定[J].南京医科大学学报(自然科学版),2006,26(11)：1018-1021.
[15]吕国平,崔德健,郭英江,等.介绍一种建立大鼠哮喘模型的实验方法[J].中华结核和呼吸杂志,1995,18(6)：377-378.
[16]迟磊,符州,戴继宏,等.过敏性哮喘大鼠模型的建立[J].重庆医学,2003,32(4)：429-431.
[17]Santing RE, Olymulder CG, Zaagsma J, et al. Relationships among allergen-induced early late phase airway obstructions,bronchial hyperreactivity, and inflammation in consicious,unrcstrained guinca pigs[J].J Allergy Clin Immunol, 1994,93(6):1021-1030.
[18]Manzolli S, Macedo-Soares MF, Vianna EO, et al. Allergic inflammation in hypothyroid rats[J]. J Allergy Clinic Immunol,1999,104(3):595-600
[19]Mansoor JK, Decile KC, Giri SN, et al. Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma[J]. Pulm pharmacol Ther,2007,20(6):660-668.
[20]周妍,周新,王笑秋.1,25-二羟维生素D3对哮喘大鼠调节性T淋巴细胞和气道炎症的影响[J].上海交通大学学报,2008,28(7)：858-862.
[21]Palmans E, Kips JC,Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats[J].Am J Respir Crit Care Med,2000, 161(2):627-635.
[22]Werner KM, Goggel R, Westhof A, et al. Development and characterisation of a novel and rapid lung eosinophil influx model in the rat[J]. Pulm Pharmacol Ther,2008,21(4):648-656.
[23]袁转弟,谢丹宇,戴志辉.不同雾化吸入方式对哮喘婴幼儿血氧饱和度的影响[J].实用儿科临床杂志,2007,22(4)：273-274.
[24]徐璇,钟礼立,焦素敏,等.大鼠哮喘模型肺组织血红素氧合酶-1蛋白及基因表达[J].中国医师杂志,2008,8(10)：1021-1024.
[25]Palmans E, Vanacker NJ, Pauwels RA, et al. Effect of age on allergen-induced structural airway changes in brown Norwa rats[J]. Am J Respir Crit Care Med,2002,165(9):1280-1284.
[26]Gajewska BU, Swirski FK, Alvarez D, et al. Temporal-spatial analysis of the immune response in a murine model of ovalbumin-induced airways inflammation[J]. Am J Respir Cell MoBiol,2001,25(3):326-334.
[27]Chiba Y, Ueno A, Shinozaki K, et al. Involvement of RhoA-mediated Ca2+ sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice[J]. Respir Res,2005,8(6):4-7
[28]Reinhardt AK, Bottoms SE, Laurent GJ, et al. Quantification of collagen and proteoglycan deposition in a;murine model of airway remodelling[J]. Respir Res, 2005,8(6):30-34.
[29]Nigo YI, Yamashita M, Hirahara K, et al. Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function.Proc Natl Acad Sci USA,2006,103(7):2286-2291.
[30]Locke NR, Royce SG, Wainewright JS,et al. Comparison of Airway Remodeling in Acute, Subacute, and Chronic Models of Allergic Airways Disease[J]. Am J Respir Cell Mol Biol,2007,36(5):625-632.
[31]Trujillo Vargas CM, Werner Klein M, Wohlleben G et al. Helminth-derived products inhibit the development of allergic responses in mice[J]. Am J Respir Crit Care Med,2007,75(4):336-344.
[32]Renzi PM, Olivenstein R, Martin JG, et al. Inflammatory cell population in the airway and parenchyma after antigen challenge in rat[J]. Am Rev Respir Dis,1993,147(4):967-974.
[33]Deng YM, Xie QM, Chen JQ, et al. Coincidential increase of leukotrieneB4 between cerebral cortexand lungtissue of seneitized rats[J].Acta phar-macol sin,2003,24(10):1039-1044.
[34]Temelkovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma:selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J]. Thorax,1998,53(10):849-856.
[35]Shen H, O'Byrne PM, Ellis R, et al.The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice[J].Am J Respir Crit Care Med,2002,166(2):146-153.
[36]Hylkema MN, Hoekstra MO, Luinge M, et al. The strength of the OVA-induced airway inflammation in rats is strain dependent[J].Clin Exp Immunol,2002,129(3):390-396.
[37]Hayashi T, Adachi Y, Hasegawa K, et al. Less sensitivity for late airway inflammation in males than females in BALB/c mice[J].Scand J Immunol,2003,57(6):562-527.
[38]Bice DE, Seagrave JC, Green FH. Animal model of asthma:potential usefullness for study health effects of inhaled particles[J].Inhalation Toxicology, 2000,12(9):809-826.
[39]王宏伟,周丹,邵玉霞.吸入布地奈德对哮喘大鼠气道重构的影响[J].哈尔滨医科大学学报,2008,42(6)：574-577.
[40]吉宁飞,周玉婷,何畏.地塞米松对哮喘大鼠T-bet、GATA-3及气道炎症的作用机制[J].南京医科大学学报(自然科学板),2008,28(11)：1421-1425.
[41]Sugawa T, Fujiwara Y, Yamagami H, A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma[J]. Gut., 2008,57(5):575-581.
[42]Kucharewicz I, Mogielnicki A, Kasacka I. Plasmin system regulation in an ovalbumin-induced rat model of asthma[J]. Int Arch Allergy Immunol., 2008,147(3):190-196.
[43]Schuster M,Tschernig T,Krug N,et al.Lymphocytes migrate from the blood into the bronchoalveolar lavage and lung parenchyma in the asthma model of the brown-norway rat[J].Am J Respir Crit Care Med,2000,161(2):558-566,
[44]Eynott PR, Salmon M, Huang TJ, et al. Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats. Immunology,2003,109(3):461-467.
[45]Dong W, Selgrade MK, Gilmour MI. Systemic administration of Bordetella pertussis enhances pulmonary sensitization to house dust mite in juvenile rats[J]. Toxicol Sci,2003,72(1):113-121.
[46]周光炎.分子免疫学[M].上海：上海科学技术文献出版社,2002：71-191.
[47]Filosso PL,Turello D,Magnoni MS.Chronic inflammation and airway remodeling in asthma. Importance of an early treatment [J]. Minerva Pediatr,2003, 55(4):323-329.
[48]O'Byrne PM, Inman MD. Airway hyperresponsiveness[J]. Chest,2003, 123(3):411-416.
[49]Hamelmann E, Schwarze J, Takeda K,et al..Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography[J]. Am J Respir Crit Care Med,1997,156(3):766-775.
[50]Brownrh, Walters DM, Greenbergr S, et al. A method of endotracheal intubation and pulmonary functional assessment for repeated studies in mice[J]. J Appl Physiol,1999,87 (6):2362-2365.
[51]Hopfenspirger MT, Parr SK, Hopp RJ, et al. Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma. [J]. Int Immunopharmacol, 2001,1(9-10):1743-1751.
[52]Irvin C,Bates J. Measuring the lung function in the mouse:thechallenge of size[J]. Respir Res,2003,4(4):1-9.
[53]Zosky GR, von GarnierC, Stumbles PA, et al. The pattern of methacholine responsiveness in mice is dependent on antigen challenge dose[J]. Respir Res,2004, 5(1):15-25.
[54]Koarai A, Ichinose M, Sugiura H, et al. Allergic airway hyperresponsiveness and eosinophil infiltration is reduced by a selective NOS inhibitor,1400w, in mice[J].Pulm PharmacolTher,2000,13(6):267-275.
[55]龚非力.医学免疫学[M].北京：科学出版社,2000：286-288.
[56]王永午.哮喘患者必读[M].北京：人民军医出版社,1999：1-32.
[57]叶世泰.变态反应学[M].广州：广州科技出版社,1995：29-33.
[58]司小兵,陈淑彦,关东升等.“咳喘宁”贴膏对支气管哮喘模型大鼠血清IgE影响的研究[J].甘肃中医,2007,20(1)：51-52.
[59]Pauwels R,Bazin H,Platteau B,et al. The influence of different adjuvants on the production of IgD and IgE antibodies [J] Ann Immunol(Paris),1979,130(1):49-58.
[60]Zhang Y,Lamm WJ,Albert RK,et al.Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response[J]. Am J Respir Crit Care Med,1997,155(2):661-669.
[61]刘又宁.呼吸系统疾病治疗学[M].北京：科学出版社,2005：31-40.
[62]肖梅,胡雪,吴琳娜.老年患者使用不同雾化吸入器疗效对比[J].华西医学,2003,18(1)：73-73.
[63]黄如章,揭文球,胡敏红.三种雾化吸入方法治疗小儿中重度哮喘急性发作的疗效比较[J].中国医药,2007,2(1)56-57.
[64]Sakai K, Yokoyama A, Kohno N, et al. Effect of different sensitizing doses of antigen in a murine model of atopic asthma[J]. Clin Exp Immunol,1999,118(1):9-15.
[65]Smith N, Broadley KJ. Optimisation of the sensitisation conditions for an ovalbumin challenge model of asthma[J].Int Immunopharmacol,2007,7(2):183-190.
[1]Hoang BX, Levine SA, Graeme Shaw D, et al. Bronchial epilepsy or broncho-pumonary hyperexcitability as a model of asthma pathogenesis[J].Med Hypotheses,2006,67(5):1042-1051.
[2]Temelcovski J,Hogan SP,Shepherd DP,et al.An improved murine model of asthma:selective airway inflammation,epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J], Thorax, 1998,53(10):849-856.
[3]Ressmeyer AR,Larsson AK, Vollmer E,et al. Characterisation of guinea pig precision-cut lung slices:comparision with human tissue [J]. Eur J Respir,2006, 28(3):603-611.
[4]Masini E, Giannini L, Nistri S, et al. Ceramide:a key signaling molecule in a Guinea pig model of allergic asthmatic response and airway inflammation[J]. Pharmacol Exp Ther,2008,324(2):548-557.
[5]Canning BJ, Chou Y. Using guinea pigs in studies relevant to asthma and COPD[J]. Pulm Pharmacol Ther,2008,21(5):702-720.
[6]Long F, Wang Y, Qi HH et al. Rapid non-genomic effects of glucocorticoids on oxidative stress in a guinea pig model of asthma[J]. Respirology, 2008,13(2):227-232.
[7]Wagner JG, Jiang Q, Harkema JR et al. Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma[J]. Clin Exp Allergy,2008,38(3):501-511.
[8]Tamaoka M, Hassan M, McGovern T. The epidermal growth factor receptor mediates allergic airway remodelling in the rat[J]. Eur Respir J,2008,32 (5):1213-1223.
[9]贺建新,赵顺英，申昆玲,等.小剂量红霉素降低大鼠气道阻力的研究[J].中华结核和呼吸杂志,2008,31(3)：226-227.
[10]王小芳,洪建国,周小建维生素D对大鼠哮喘模型气道炎症的影响[J].上海医学,2008,31(1)：27-29.
[11]Elwood W, Lotvall JO, Barnes PJ, et al.Characterization of allergen-induced bronchial hyperresponsiveness and airway inflammation in actively sensitized brown-norway rats[J]. Allergy Clin Immunol,1991,88(6):951-960.
[12]唐艳,杨文思,黄瑾,等.小鼠实验性哮喘模型肺功能检测初步探讨[J].白求恩医科大学学报,1999,25(2)：131-132.
[13]Conejero L, Higaki Y, Baeza ML, et al. Pollen-induced airway inflammation, hyperresponsiveness and apoptosis in a murine model of allergy[J]. Clin Exp Allergy, 2007,37(3):331-338.
[14]Kung TT, Jones H, Adams GK, et al. Characterization of a murine model of allergic pulmonary inflammation[J]. Int Arch Allergy Immunol,1994,105(1):83-90.
[15]Simoes DC, Vassilakopoulos T, Toumpanakis D, et al. Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma [J]. Am J Respir Crit Care Med,2008,177(12):1314-1321.
[16]Padrid P,Snook S,FinucaneT,et al.Persistent airway hyperresp onsiveness and histologic alterations after chronic antigen chanllenge in cats[J]. Am J Respir Crit CareMed,1995,151(1):184-193.
[17]Wegner CD, Gundel RG, Abraham WM, et al.The role of 5-lipoxygenase products in preclinical models of asthma[J].J Allergy Clin Immunol,1993, 91(4):917-929.
[18]Karol MH.Animal models of occupational asthma[J].Eur Respir J,1994, 7(3):555-568.
[19]Deaton CM, Deaton L Jose-Cunilleras E,et al. Early onset airway obstructionin response to organic dust in the horse[J]. J Appl Physiol,2007, 102(3):1071-1077.
[20]Hylkema MN, Hoekstra MO, Luinge M, et al.The strength of theOVA-induced airway inflammation in rats is strain dependent[J].Clin Exp Immunol,2002,129(3):390-396,
[21]Pabst R. Animal models for asthma:controversial aspects and unsolved problems[J].Pathobiology,2003,70(5):260-265.
[22]Lee YL,Fu CL,Ye YL,et al.Administration of interleukin-12 prevents mite Der pl allergen-IgE antibody production and air-way eosinophil infiltration in an animal model of airway inflammation[J]. Scand J Immmunol,1999,49(3):229-236.
[23]Hayashi T,Adachi Y,Hasegawa K,et al. Less sensitivity for late airway inflammation in males than females in BALB/c mice[J].Scand J Immunol,2003,57(6):562-567.
[24]Oldham MJ, Phalen RF, Dosimetry implications of upper tracheobronchial airway anatomy in two mouse varieties[J]. Anat Rec,2002,268(1):59-65.
[25]Pabst R, Animal models for asthma:controversial aspects and unsolved problems[J]. Pathobiology,2002,70(5):252-254.
[26]Wang ZL, Walker BA, WeirTD, et al. Effect of chronic antigen and beat 2 anonist exposure on airway remodeling in guinea pigs [J]. Am J Respir Crit Care Med, 1995,152(6):2097-2104.
[27]Schmitz N,Kurrer M,Kopfl M,et al.The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model[J]. Eur J Immunol,2003,33 (4):991-1000.
[28]Smith JJ,Loveren HV,Maarten O,et al.Therapeutic treatment with heat-killed Mycobacterium vaccae (SRL172) in a mild and severe mouse model for allergic asthma[J]. Eur J Pharmacol,2003,470(3):193-199.
[29]Goldsmith CA, Ning Y, Qin G, et al. Combined air pollution particle and ozone exposure increases airway responsiveness in mice[J]. Inhal Toxicol,2002,14(4):325-347.
[30]Herz U,Gerhold K,Gruber C,et al.BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model[J]. Allergy Clin Immunol1998,102(5):867-874.
[31]Erb KJ, Holloway JW, Sobeck A, et al. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia[J]. J Exp Med,1998,187(4):561-569.
[32]Kumar RK, Herbert C, Ka sper M. Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma [J]. Clin Exp Allergy,2004,34(11):1796-1802.
[33]Smith N, Broadley KJ. Optimisation of the sensitisation conditions for an ovalbumin challenge model of asthma[J]. Int Immuno pharmacol, 2007,7(2):183-190.
[34]高光凯,刘又宁.氦氧混合气治疗支气管哮喘的实验研究与临床应用[J].军医进修学院学报,1998,19(2)：110-112.
[35]卢瑜,刘志刚,林雪怡,等.蛔虫变应原致喘豚鼠后外周血血液流变性的动态变化[J].中国血液流变学杂志,1999,9(4)：195-198.
[36]Tournoy KG, Kips JC, Schou C, et al. Airway eosinophilia is not a requirement for allergen induced airway hyperresponsiveness[J].Clin Exp Allergy,2000,30(1):79-85.
[37]Chang TT, Huang CC, Hsu CH. Inhibition of mite-induced im uno-globulin E synthesis, Airway inflammation, and hyperreactivi ty by herbal medicine TA-1[J]. Immunopharmacol Immunotoxicol,2006,28(4):683-695.
[38]John AE, Berlin AA,Lukacs NW.Respiratory syncytial virus induced CCL5/RANTES contributes to exacerbation of allergic airway inflammation[J]. Eur J Immunol,2003,33(6):1677-1685.
[39]Gore JC, Schal C. Cockroach allergen biology and mitigation in the indoorenviromnet [J]. Annu Rev Entomol,2007,52(1):439-463.
[40]Chapoval SP, David CS. CD28 costimulation is critical for experimental allergic asthma in HLA-DQ8 transgenic mice[J]. Clin Immunol,2003,106(2):83-94.
[41]Pauwels RA, Brusselle GJ, Kips JC. Cytokine manipulation in animal modeis of asthma [J]. Am J Respir Cirit Care Med,1997,156(4):78-81.
[42]Bianco A, Spiteri MA. A biological model to explain the association between human rhino virus respiratory infections and bronchial asthma [J]. Monaldi Arch chest Dis,1998,53(1):83-87.
[43]Michel O; Kips J, Duchateau J, et al. Severity of asthma is related to endotoxin in house dust [J]. Am J Respir Crit Care Med,1996,154(6):1641-1646.
[44]Herz U,Ruckert R,Wollwnhaupt K,et al. Airway expose to bacterial superantigen (SEB) induces lymphocyte dependent airway inflammation associated with increased airway responsiveness a model for non allergic asthma[J]. Eur J Immunol,1999,29(3):1021-1031.
[45]Rajagopalan Q Iijima K,Singh M, et al. Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class 11 transgenic mice [J]. Infect Immun,2006,74(2):1284-1296.
[46]Kurup VP, Grunig G. Animal models of allergic bronchopulmonary aspergillosis [J]. Mycopathologia,2002,153(4):165-177.
[47]Holtzman MJ, Morton JD, Shornick LP, et al. Immunity inflammation, and remodeling in the airway epithelial barrier:epithelial-viral-allergic paradigm [J]. Physiol Rev,2002,82(1):19-46.
[48]Garantziotis S, Brass DM, Savov J, et al. Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin[J]. Am J Respir Cell Mo 1 Biol,2006,35(6):662-667.
[49]Lee KS, Jin SM, Lee H, et al. Imbalance between matrixme talloproteinase-9 and tissue inhibitor of metalloproteinase-lin toluene diisocyanate-induced asthma[J].Clin Exp Allergy,2004,34(2):276-284.
[50]Vaniorbeek JA, Tarkowski M, Vanhooren HM, et al.Validation of a mouse model of chemical-indunced asthma using trimellitic anhydride,a respiratory sensitizer,and dinilrochlorobenzene, a dermol sensitizer[J].J Allergy Clin Immunol, 2006,117(5):1090-1097.
[51]Haczku A, Takeda K, Hamelmann E, et al. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperr esponsiveness[J].Am J Respir Crit Care Med,2000,161(3):952-960.
[52]Kimzey SL, Liu P, Green JM. Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation[J]. J Immunol,2004,173(1):632-640.
[53]ChapovalSP,DavidCS.CD28costimulationis critical for experimen tal allergic asthma in HLA-DQ8 transgenic mice. [J]Clin Immunol,2003,106(2):83-94.
[54]Kumar RK,Foster PS.Modeling allergic asthma in mice pitfalls and opportunities[J]. Am J Respir Cell Mol Biol,2002,27(3):267-272.
[55]Carey MA, Card JW, Bradbury JA, et al. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice[J].Am J Respir Crit Care Med,2007,175(2):126-135.
[56]Fulkerson PC, Fischetti CA, Rothenberg ME. Eosinophils andCCR3 regulate interleukn-13 transgene-induced pulmonary remodeling [J]. Am J Pathol, 2006,169(6):2117-2126.
[57]Nagase T, Dallaire MJ, Ludwing MS. Airway and tissre reponses during hyperpnae-inducedconstriction in guinea pigs,Am [J]. J Respir Crit Care Med,1994, 149(5):1342-1347.
[58]Nagai H, IwamaT, Mori H, et al. Increase in respiratory resistance after exercise in conscious guinea pigs. As a model for exercise induced asthma [J]. Bilo Pharm Bull,1995,18(1):37-41.
[2]Downs SH, Marks GB, Sporik R, et al. Continued increase in the prevalence of asthma and atopy[J].Arch Dis Child,2001,84(1):20-23.
[3]沈华浩,王苹莉.如何评价哮喘动物模型[J].医学与哲学(临床决策论坛版)2007,28(8)：13-15.
[4]王妍,金先桥.支气管哮喘实验模型的研究进展[J].国际呼吸杂志,2006,26(1)：70-77.
[5]Temelcovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma:selective airway inflammation,epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J]. Thorax, 1998,53(10):849-856.
[6]Karol MH. Animal models of occupational asthma[J].Eur Respir J, 1994,7(3):555-568.
[7]Bergeron C,Boulet LP. Structural changes in airway diseases: characteristics,mechanisms,consequences,and pharmacologic modulation[J]. Chest, 2006,129(4):1068-1087.
[8]Schneider T, van VD, Moqbel R, et al. Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model[J]. Am J Respir Cell Mol Biol 1997,17(6):702-712.
[9]Underwood SL, Haddad E, Birrell MA, et al. Functional characterization and biomarker identification in the brown Norway model of allergic airway inflammation[J]. Br J Pharmacol,2002,137(2):263-275.
[10]Russo M,Mariano M,Jancar S.A new murine model of persistent lung eosinophilic inflammation[J]. Mem Inst Oswaldo Cruz,1997,92(2):215-218.
[11]Carvalho C, Jancar S, MariaaoM, et al. Aratmodel presenting eosinophilia in the airways, Lung eosinophil activation, and pulmonary h yperreactivity [J]. Exp Lung Res,1999,25 (4):303-316.
[12]Itami DM, Latinne D, Bazin H, et al. Immunogloblin E is not required for but enhances airway inflammation and hyperresponsiveness[J]. Allergy,2003,58(11): 1117-1124.
[13]崔龙苹,杨永清,陈汉平,等.过敏性哮喘大鼠模型的制备[J].上海实验动物科学，2000,20(2)：69-71.
[14]吉宁飞,卞涛,陈力,等.支气管哮喘大鼠模型的建立与气道反应性的测定[J].南京医科大学学报(自然科学版),2006,26(11)：1018-1021.
[15]吕国平,崔德健,郭英江,等.介绍一种建立大鼠哮喘模型的实验方法[J].中华结核和呼吸杂志,1995,18(6)：377-378.
[16]迟磊,符州,戴继宏,等.过敏性哮喘大鼠模型的建立[J].重庆医学,2003,32(4)：429-431.
[17]Santing RE, Olymulder CG, Zaagsma J, et al. Relationships among allergen-induced early late phase airway obstructions,bronchial hyperreactivity, and inflammation in consicious,unrcstrained guinca pigs[J].J Allergy Clin Immunol, 1994,93(6):1021-1030.
[18]Manzolli S, Macedo-Soares MF, Vianna EO, et al. Allergic inflammation in hypothyroid rats[J]. J Allergy Clinic Immunol,1999,104(3):595-600
[19]Mansoor JK, Decile KC, Giri SN, et al. Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma[J]. Pulm pharmacol Ther,2007,20(6):660-668.
[20]周妍,周新,王笑秋.1,25-二羟维生素D3对哮喘大鼠调节性T淋巴细胞和气道炎症的影响[J].上海交通大学学报,2008,28(7)：858-862.
[21]Palmans E, Kips JC,Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats[J].Am J Respir Crit Care Med,2000, 161(2):627-635.
[22]Werner KM, Goggel R, Westhof A, et al. Development and characterisation of a novel and rapid lung eosinophil influx model in the rat[J]. Pulm Pharmacol Ther,2008,21(4):648-656.
[23]袁转弟,谢丹宇,戴志辉.不同雾化吸入方式对哮喘婴幼儿血氧饱和度的影响[J].实用儿科临床杂志,2007,22(4)：273-274.
[24]徐璇,钟礼立,焦素敏,等.大鼠哮喘模型肺组织血红素氧合酶-1蛋白及基因表达[J].中国医师杂志,2008,8(10)：1021-1024.
[25]Palmans E, Vanacker NJ, Pauwels RA, et al. Effect of age on allergen-induced structural airway changes in brown Norwa rats[J]. Am J Respir Crit Care Med,2002,165(9):1280-1284.
[26]Gajewska BU, Swirski FK, Alvarez D, et al. Temporal-spatial analysis of the immune response in a murine model of ovalbumin-induced airways inflammation[J]. Am J Respir Cell MoBiol,2001,25(3):326-334.
[27]Chiba Y, Ueno A, Shinozaki K, et al. Involvement of RhoA-mediated Ca2+ sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice[J]. Respir Res,2005,8(6):4-7
[28]Reinhardt AK, Bottoms SE, Laurent GJ, et al. Quantification of collagen and proteoglycan deposition in a;murine model of airway remodelling[J]. Respir Res, 2005,8(6):30-34.
[29]Nigo YI, Yamashita M, Hirahara K, et al. Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function.Proc Natl Acad Sci USA,2006,103(7):2286-2291.
[30]Locke NR, Royce SG, Wainewright JS,et al. Comparison of Airway Remodeling in Acute, Subacute, and Chronic Models of Allergic Airways Disease[J]. Am J Respir Cell Mol Biol,2007,36(5):625-632.
[31]Trujillo Vargas CM, Werner Klein M, Wohlleben G et al. Helminth-derived products inhibit the development of allergic responses in mice[J]. Am J Respir Crit Care Med,2007,75(4):336-344.
[32]Renzi PM, Olivenstein R, Martin JG, et al. Inflammatory cell population in the airway and parenchyma after antigen challenge in rat[J]. Am Rev Respir Dis,1993,147(4):967-974.
[33]Deng YM, Xie QM, Chen JQ, et al. Coincidential increase of leukotrieneB4 between cerebral cortexand lungtissue of seneitized rats[J].Acta phar-macol sin,2003,24(10):1039-1044.
[34]Temelkovski J, Hogan SP, Shepherd DP, et al. An improved murine model of asthma:selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J]. Thorax,1998,53(10):849-856.
[35]Shen H, O'Byrne PM, Ellis R, et al.The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice[J].Am J Respir Crit Care Med,2002,166(2):146-153.
[36]Hylkema MN, Hoekstra MO, Luinge M, et al. The strength of the OVA-induced airway inflammation in rats is strain dependent[J].Clin Exp Immunol,2002,129(3):390-396.
[37]Hayashi T, Adachi Y, Hasegawa K, et al. Less sensitivity for late airway inflammation in males than females in BALB/c mice[J].Scand J Immunol,2003,57(6):562-527.
[38]Bice DE, Seagrave JC, Green FH. Animal model of asthma:potential usefullness for study health effects of inhaled particles[J].Inhalation Toxicology, 2000,12(9):809-826.
[39]王宏伟,周丹,邵玉霞.吸入布地奈德对哮喘大鼠气道重构的影响[J].哈尔滨医科大学学报,2008,42(6)：574-577.
[40]吉宁飞,周玉婷,何畏.地塞米松对哮喘大鼠T-bet、GATA-3及气道炎症的作用机制[J].南京医科大学学报(自然科学板),2008,28(11)：1421-1425.
[41]Sugawa T, Fujiwara Y, Yamagami H, A novel rat model to determine interaction between reflux oesophagitis and bronchial asthma[J]. Gut., 2008,57(5):575-581.
[42]Kucharewicz I, Mogielnicki A, Kasacka I. Plasmin system regulation in an ovalbumin-induced rat model of asthma[J]. Int Arch Allergy Immunol., 2008,147(3):190-196.
[43]Schuster M,Tschernig T,Krug N,et al.Lymphocytes migrate from the blood into the bronchoalveolar lavage and lung parenchyma in the asthma model of the brown-norway rat[J].Am J Respir Crit Care Med,2000,161(2):558-566,
[44]Eynott PR, Salmon M, Huang TJ, et al. Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats. Immunology,2003,109(3):461-467.
[45]Dong W, Selgrade MK, Gilmour MI. Systemic administration of Bordetella pertussis enhances pulmonary sensitization to house dust mite in juvenile rats[J]. Toxicol Sci,2003,72(1):113-121.
[46]周光炎.分子免疫学[M].上海：上海科学技术文献出版社,2002：71-191.
[47]Filosso PL,Turello D,Magnoni MS.Chronic inflammation and airway remodeling in asthma. Importance of an early treatment [J]. Minerva Pediatr,2003, 55(4):323-329.
[48]O'Byrne PM, Inman MD. Airway hyperresponsiveness[J]. Chest,2003, 123(3):411-416.
[49]Hamelmann E, Schwarze J, Takeda K,et al..Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography[J]. Am J Respir Crit Care Med,1997,156(3):766-775.
[50]Brownrh, Walters DM, Greenbergr S, et al. A method of endotracheal intubation and pulmonary functional assessment for repeated studies in mice[J]. J Appl Physiol,1999,87 (6):2362-2365.
[51]Hopfenspirger MT, Parr SK, Hopp RJ, et al. Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma. [J]. Int Immunopharmacol, 2001,1(9-10):1743-1751.
[52]Irvin C,Bates J. Measuring the lung function in the mouse:thechallenge of size[J]. Respir Res,2003,4(4):1-9.
[53]Zosky GR, von GarnierC, Stumbles PA, et al. The pattern of methacholine responsiveness in mice is dependent on antigen challenge dose[J]. Respir Res,2004, 5(1):15-25.
[54]Koarai A, Ichinose M, Sugiura H, et al. Allergic airway hyperresponsiveness and eosinophil infiltration is reduced by a selective NOS inhibitor,1400w, in mice[J].Pulm PharmacolTher,2000,13(6):267-275.
[55]龚非力.医学免疫学[M].北京：科学出版社,2000：286-288.
[56]王永午.哮喘患者必读[M].北京：人民军医出版社,1999：1-32.
[57]叶世泰.变态反应学[M].广州：广州科技出版社,1995：29-33.
[58]司小兵,陈淑彦,关东升等.“咳喘宁”贴膏对支气管哮喘模型大鼠血清IgE影响的研究[J].甘肃中医,2007,20(1)：51-52.
[59]Pauwels R,Bazin H,Platteau B,et al. The influence of different adjuvants on the production of IgD and IgE antibodies [J] Ann Immunol(Paris),1979,130(1):49-58.
[60]Zhang Y,Lamm WJ,Albert RK,et al.Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response[J]. Am J Respir Crit Care Med,1997,155(2):661-669.
[61]刘又宁.呼吸系统疾病治疗学[M].北京：科学出版社,2005：31-40.
[62]肖梅,胡雪,吴琳娜.老年患者使用不同雾化吸入器疗效对比[J].华西医学,2003,18(1)：73-73.
[63]黄如章,揭文球,胡敏红.三种雾化吸入方法治疗小儿中重度哮喘急性发作的疗效比较[J].中国医药,2007,2(1)56-57.
[64]Sakai K, Yokoyama A, Kohno N, et al. Effect of different sensitizing doses of antigen in a murine model of atopic asthma[J]. Clin Exp Immunol,1999,118(1):9-15.
[65]Smith N, Broadley KJ. Optimisation of the sensitisation conditions for an ovalbumin challenge model of asthma[J].Int Immunopharmacol,2007,7(2):183-190.
[1]Hoang BX, Levine SA, Graeme Shaw D, et al. Bronchial epilepsy or broncho-pumonary hyperexcitability as a model of asthma pathogenesis[J].Med Hypotheses,2006,67(5):1042-1051.
[2]Temelcovski J,Hogan SP,Shepherd DP,et al.An improved murine model of asthma:selective airway inflammation,epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen[J], Thorax, 1998,53(10):849-856.
[3]Ressmeyer AR,Larsson AK, Vollmer E,et al. Characterisation of guinea pig precision-cut lung slices:comparision with human tissue [J]. Eur J Respir,2006, 28(3):603-611.
[4]Masini E, Giannini L, Nistri S, et al. Ceramide:a key signaling molecule in a Guinea pig model of allergic asthmatic response and airway inflammation[J]. Pharmacol Exp Ther,2008,324(2):548-557.
[5]Canning BJ, Chou Y. Using guinea pigs in studies relevant to asthma and COPD[J]. Pulm Pharmacol Ther,2008,21(5):702-720.
[6]Long F, Wang Y, Qi HH et al. Rapid non-genomic effects of glucocorticoids on oxidative stress in a guinea pig model of asthma[J]. Respirology, 2008,13(2):227-232.
[7]Wagner JG, Jiang Q, Harkema JR et al. Gamma-tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma[J]. Clin Exp Allergy,2008,38(3):501-511.
[8]Tamaoka M, Hassan M, McGovern T. The epidermal growth factor receptor mediates allergic airway remodelling in the rat[J]. Eur Respir J,2008,32 (5):1213-1223.
[9]贺建新,赵顺英，申昆玲,等.小剂量红霉素降低大鼠气道阻力的研究[J].中华结核和呼吸杂志,2008,31(3)：226-227.
[10]王小芳,洪建国,周小建维生素D对大鼠哮喘模型气道炎症的影响[J].上海医学,2008,31(1)：27-29.
[11]Elwood W, Lotvall JO, Barnes PJ, et al.Characterization of allergen-induced bronchial hyperresponsiveness and airway inflammation in actively sensitized brown-norway rats[J]. Allergy Clin Immunol,1991,88(6):951-960.
[12]唐艳,杨文思,黄瑾,等.小鼠实验性哮喘模型肺功能检测初步探讨[J].白求恩医科大学学报,1999,25(2)：131-132.
[13]Conejero L, Higaki Y, Baeza ML, et al. Pollen-induced airway inflammation, hyperresponsiveness and apoptosis in a murine model of allergy[J]. Clin Exp Allergy, 2007,37(3):331-338.
[14]Kung TT, Jones H, Adams GK, et al. Characterization of a murine model of allergic pulmonary inflammation[J]. Int Arch Allergy Immunol,1994,105(1):83-90.
[15]Simoes DC, Vassilakopoulos T, Toumpanakis D, et al. Angiopoietin-1 Protects against Airway Inflammation and Hyperreactivity in Asthma [J]. Am J Respir Crit Care Med,2008,177(12):1314-1321.
[16]Padrid P,Snook S,FinucaneT,et al.Persistent airway hyperresp onsiveness and histologic alterations after chronic antigen chanllenge in cats[J]. Am J Respir Crit CareMed,1995,151(1):184-193.
[17]Wegner CD, Gundel RG, Abraham WM, et al.The role of 5-lipoxygenase products in preclinical models of asthma[J].J Allergy Clin Immunol,1993, 91(4):917-929.
[18]Karol MH.Animal models of occupational asthma[J].Eur Respir J,1994, 7(3):555-568.
[19]Deaton CM, Deaton L Jose-Cunilleras E,et al. Early onset airway obstructionin response to organic dust in the horse[J]. J Appl Physiol,2007, 102(3):1071-1077.
[20]Hylkema MN, Hoekstra MO, Luinge M, et al.The strength of theOVA-induced airway inflammation in rats is strain dependent[J].Clin Exp Immunol,2002,129(3):390-396,
[21]Pabst R. Animal models for asthma:controversial aspects and unsolved problems[J].Pathobiology,2003,70(5):260-265.
[22]Lee YL,Fu CL,Ye YL,et al.Administration of interleukin-12 prevents mite Der pl allergen-IgE antibody production and air-way eosinophil infiltration in an animal model of airway inflammation[J]. Scand J Immmunol,1999,49(3):229-236.
[23]Hayashi T,Adachi Y,Hasegawa K,et al. Less sensitivity for late airway inflammation in males than females in BALB/c mice[J].Scand J Immunol,2003,57(6):562-567.
[24]Oldham MJ, Phalen RF, Dosimetry implications of upper tracheobronchial airway anatomy in two mouse varieties[J]. Anat Rec,2002,268(1):59-65.
[25]Pabst R, Animal models for asthma:controversial aspects and unsolved problems[J]. Pathobiology,2002,70(5):252-254.
[26]Wang ZL, Walker BA, WeirTD, et al. Effect of chronic antigen and beat 2 anonist exposure on airway remodeling in guinea pigs [J]. Am J Respir Crit Care Med, 1995,152(6):2097-2104.
[27]Schmitz N,Kurrer M,Kopfl M,et al.The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model[J]. Eur J Immunol,2003,33 (4):991-1000.
[28]Smith JJ,Loveren HV,Maarten O,et al.Therapeutic treatment with heat-killed Mycobacterium vaccae (SRL172) in a mild and severe mouse model for allergic asthma[J]. Eur J Pharmacol,2003,470(3):193-199.
[29]Goldsmith CA, Ning Y, Qin G, et al. Combined air pollution particle and ozone exposure increases airway responsiveness in mice[J]. Inhal Toxicol,2002,14(4):325-347.
[30]Herz U,Gerhold K,Gruber C,et al.BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model[J]. Allergy Clin Immunol1998,102(5):867-874.
[31]Erb KJ, Holloway JW, Sobeck A, et al. Infection of mice with Mycobacterium bovis-Bacillus Calmette-Guerin (BCG) suppresses allergen-induced airway eosinophilia[J]. J Exp Med,1998,187(4):561-569.
[32]Kumar RK, Herbert C, Ka sper M. Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma [J]. Clin Exp Allergy,2004,34(11):1796-1802.
[33]Smith N, Broadley KJ. Optimisation of the sensitisation conditions for an ovalbumin challenge model of asthma[J]. Int Immuno pharmacol, 2007,7(2):183-190.
[34]高光凯,刘又宁.氦氧混合气治疗支气管哮喘的实验研究与临床应用[J].军医进修学院学报,1998,19(2)：110-112.
[35]卢瑜,刘志刚,林雪怡,等.蛔虫变应原致喘豚鼠后外周血血液流变性的动态变化[J].中国血液流变学杂志,1999,9(4)：195-198.
[36]Tournoy KG, Kips JC, Schou C, et al. Airway eosinophilia is not a requirement for allergen induced airway hyperresponsiveness[J].Clin Exp Allergy,2000,30(1):79-85.
[37]Chang TT, Huang CC, Hsu CH. Inhibition of mite-induced im uno-globulin E synthesis, Airway inflammation, and hyperreactivi ty by herbal medicine TA-1[J]. Immunopharmacol Immunotoxicol,2006,28(4):683-695.
[38]John AE, Berlin AA,Lukacs NW.Respiratory syncytial virus induced CCL5/RANTES contributes to exacerbation of allergic airway inflammation[J]. Eur J Immunol,2003,33(6):1677-1685.
[39]Gore JC, Schal C. Cockroach allergen biology and mitigation in the indoorenviromnet [J]. Annu Rev Entomol,2007,52(1):439-463.
[40]Chapoval SP, David CS. CD28 costimulation is critical for experimental allergic asthma in HLA-DQ8 transgenic mice[J]. Clin Immunol,2003,106(2):83-94.
[41]Pauwels RA, Brusselle GJ, Kips JC. Cytokine manipulation in animal modeis of asthma [J]. Am J Respir Cirit Care Med,1997,156(4):78-81.
[42]Bianco A, Spiteri MA. A biological model to explain the association between human rhino virus respiratory infections and bronchial asthma [J]. Monaldi Arch chest Dis,1998,53(1):83-87.
[43]Michel O; Kips J, Duchateau J, et al. Severity of asthma is related to endotoxin in house dust [J]. Am J Respir Crit Care Med,1996,154(6):1641-1646.
[44]Herz U,Ruckert R,Wollwnhaupt K,et al. Airway expose to bacterial superantigen (SEB) induces lymphocyte dependent airway inflammation associated with increased airway responsiveness a model for non allergic asthma[J]. Eur J Immunol,1999,29(3):1021-1031.
[45]Rajagopalan Q Iijima K,Singh M, et al. Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class 11 transgenic mice [J]. Infect Immun,2006,74(2):1284-1296.
[46]Kurup VP, Grunig G. Animal models of allergic bronchopulmonary aspergillosis [J]. Mycopathologia,2002,153(4):165-177.
[47]Holtzman MJ, Morton JD, Shornick LP, et al. Immunity inflammation, and remodeling in the airway epithelial barrier:epithelial-viral-allergic paradigm [J]. Physiol Rev,2002,82(1):19-46.
[48]Garantziotis S, Brass DM, Savov J, et al. Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin[J]. Am J Respir Cell Mo 1 Biol,2006,35(6):662-667.
[49]Lee KS, Jin SM, Lee H, et al. Imbalance between matrixme talloproteinase-9 and tissue inhibitor of metalloproteinase-lin toluene diisocyanate-induced asthma[J].Clin Exp Allergy,2004,34(2):276-284.
[50]Vaniorbeek JA, Tarkowski M, Vanhooren HM, et al.Validation of a mouse model of chemical-indunced asthma using trimellitic anhydride,a respiratory sensitizer,and dinilrochlorobenzene, a dermol sensitizer[J].J Allergy Clin Immunol, 2006,117(5):1090-1097.
[51]Haczku A, Takeda K, Hamelmann E, et al. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperr esponsiveness[J].Am J Respir Crit Care Med,2000,161(3):952-960.
[52]Kimzey SL, Liu P, Green JM. Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation[J]. J Immunol,2004,173(1):632-640.
[53]ChapovalSP,DavidCS.CD28costimulationis critical for experimen tal allergic asthma in HLA-DQ8 transgenic mice. [J]Clin Immunol,2003,106(2):83-94.
[54]Kumar RK,Foster PS.Modeling allergic asthma in mice pitfalls and opportunities[J]. Am J Respir Cell Mol Biol,2002,27(3):267-272.
[55]Carey MA, Card JW, Bradbury JA, et al. Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice[J].Am J Respir Crit Care Med,2007,175(2):126-135.
[56]Fulkerson PC, Fischetti CA, Rothenberg ME. Eosinophils andCCR3 regulate interleukn-13 transgene-induced pulmonary remodeling [J]. Am J Pathol, 2006,169(6):2117-2126.
[57]Nagase T, Dallaire MJ, Ludwing MS. Airway and tissre reponses during hyperpnae-inducedconstriction in guinea pigs,Am [J]. J Respir Crit Care Med,1994, 149(5):1342-1347.
[58]Nagai H, IwamaT, Mori H, et al. Increase in respiratory resistance after exercise in conscious guinea pigs. As a model for exercise induced asthma [J]. Bilo Pharm Bull,1995,18(1):37-41.