SDF-1/CXCR4轴在实验性变应性鼻炎鼻粘膜中的表达和意义
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摘要
目的:1.成功建立大鼠变应性鼻炎(Allergic rhinitis,AR)动物模型
2.提供变应性鼻炎模型的鼻粘膜组织形态学特征
3.确定SDF-1和CXCR4在大鼠变应性鼻炎时鼻粘膜上的表达情况
4.观察地塞米松及非那根对大鼠变应性鼻炎时SDF-1和CXCR4表达的影响。
方法:健康清洁级SD大鼠64只,体重250～300g,随机分成空白组(C1),假处理组(C2),模型组(M),干预一组(D1,D2),干预二组(HR1,HR2),模型组16只,其他每组8只。AR模型建立方法:以卵清蛋白(OVA)经全身致敏,5天后强化致敏,自第14天开始以1mg/mlOVA,20ul每天滴鼻,直至大鼠打喷嚏,搔鼻,鼻涕的症状评分达到标准;干预组则在模型成功的基础上给予地塞米松1mg/kg及非那根2mg/kg肌肉注射,每天一次,分别干预一周、两周;假处理组则以生理盐水代替OVA,其余与模型组相同;空白组不作任何处理。用组织化学方法观察变应性鼻炎的组织形态学特征,运用免疫组织化学方法(SP法)检测各组动物鼻粘膜SDF-1和CXCR4的表达和变化。并与地塞米松及非那根干预后进行比较。本实验的数据应用SPSS11.5统计软件包进行统计学处理,实验各组间的显著性检验采用方差分析及重复测量,以P<0.05作为有显著性差异意义。
结果:AR模型时鼻分泌物涂片显示大量中性粒细胞和嗜酸性粒细胞。粘膜中嗜酸性粒细胞在M组明显增多,经地塞米松或非那根作用后减少。形态学改变:HE染色见正常鼻粘膜上皮为假复层纤毛柱状上皮和复层扁平上皮,由纤毛柱状上皮细胞,杯状细胞、扁平细胞等组成,粘膜下纤维结缔组织很薄,血管数量很少,无炎性细胞浸润及血管改变;模型组较C1,C2组粘膜增厚显著,小血管增生扩张明显,上皮分泌细胞增多,上皮下大量炎性细胞浸润,粘膜下腺体数量明显增加,腺体扩张;经地塞米松或非那根处理后,粘膜厚度变薄,血管扩张及腺体增生及炎性细胞浸润程度减轻。免疫组化:1.SDF-1表达于鼻粘膜上皮层细胞(包括假复层纤毛柱状上皮细胞纤毛面及复层扁平细胞)、固有层炎性细胞(单核细胞多见)、上皮内腺细胞、毛细血管及血窦内皮细胞,其表达部位主要在细胞质。2.CXCR4表达于鼻粘膜上皮层细胞(包括假复层纤毛柱状上皮纤毛面及复层扁平上皮细胞)、固有层炎性细胞(单核细胞多见)、上皮内腺细胞。在细胞膜和细胞质均有表达。3.AR模型时,SDF-1和CXCR4表达增加(P<0.05);经地塞米松及非那根干预1周后,SDF-1和CXCR4蛋白表达较AR模型时均有减少(P<0.05);地塞米松及非那根干预2周与干预1周时比较,SDF-1和CXCR4蛋白表达减少(P<0.05)。而地塞米松与非那根的治疗疗效之间没有明显差异(P>0.05)。
结论:通过OVA多次致敏,局部激发能够成功的建立大鼠变应性鼻炎的动物模型。病理形态学上的改变:变应性鼻炎时,上皮分泌细胞明显增多,粘膜增厚,炎性细胞浸润及嗜酸性粒细胞明显增多,腺体扩张增多,小血管的增加,充血。经地塞米松或非那根处理后,粘膜厚度变薄,血管扩张及腺体增生及炎性细胞浸润程度减轻。免疫组组织化学结果显示:变应性鼻炎时,SDF-1和CXCR4表达强度发生改变,推测SDF-1和CXCR4在AR时起着重要作用;地塞米松及非那根的干预可能是通过减少SDF-1和CXCR4在粘膜上的表达从而影响AR的转归。
Objectives
1. To establish the model of allergic rhinitis (AR) in SD rat.
2. To present the character of morphology in allergic rhinitis of rat.
3. To determine the expression of SDF-1/CXCR4 in nasal mucosa of AR.
4. To observe the effect of dexamethasone (DEX) and diprazine on the expression of SDF-1/CXCR in the allergic rhinitis.
Methods: Sixty-four healthy adult rats whose weight were 250～300g were randomly divided into the blank group (C1), control group (C2), model group(M), hormone-intervention group(D1,D2),histamine receptor antagonist–intervention group(HR1, HR2).Model group had 16 rats, the others had 8 rats each. The methods of establishing the model : Group M and group D1,D2,HR1, HR2 were sensitized by injection of 1ml of physiological saline containing ovalbumin (1mg) and alum (2mg) into the four footpads . Five days later, they were boosted by subcutaneous injection of 1ml of physiological saline containing ovalbumin (0.5mg) in 10 sites on the back. Then local sensitization was performed every day by dripping the ovalbumin in physiological saline (1mg/ml, 20ul) into the bilateral nasal cavities using a micropipette from the 14th day to the establishment which was defined by the symptom score. After the establishment of model, dexamethasone (1mg/kg) and diprazine (2mg/kg)were administered to group D1,D2, HR1 and HR2 by intramuscular injection once a day, group D1, HR1 were treated for one week, group D2, HR2 were treated for two weeks respectively. While group C2 were treated with physiological saline replacing ovalbumin, the others steps were the same as group M. The group C1 remains virgin. Applying with history chemistry staining, we observed the histomorphologic character of AR. The expression and changes of SDF-1/CXCR4 in nasal mucosa in each group were investigated with immunohistochemical technique (SP method). All the data are represented as means±SEM. Statistical analysis was performed using one-way ANOVA and Repeated measures with SPSS11.5 statistical package. A probability value of less than 0.05 was considered significant.
Results :(1)A large number of neutrophil and eosinophile granulocyte were present in nasal smear of group M. In nasal mucosa, EOS got increase obviously in group M, and then, decreased after DEX and DIP treatment. In group C1 and C2, epithelium mucosa was composed of ciliated columnar epithelia ,goblet cell and pavement cells etc. by hemotoxylineosin (HE) staining, and submucosa without inflammatory cell infiltrated and few vessels was compact fibrous connective tissue adjacent to the surface of cartilage. While, group M showed a significant increase of mucosa thickness, vessels and glands, epithelium secretive cells, inflammatory cells, compared to group C1 and C2. After the treatment of DEX and DIP, mucosa recovered slowly, and all of vessels expanding, glands hyperplasted and inflammatory cell infiltrated did lighten. (2)Applying with immunohistochemistry method, SDF-1 expressed in nasal cellular epithelium mucosae cells (including the cilium-side of cellular columnoepithelialis and stratified pinacocyte). Phlegmonosis cellular (mostly histoleucocyte). Cellular endoepithelial gland ; capillary cell and cellular sinusoidal endothelial that mostly present in cytoplasm.CRCR4 expresses in nasal cellular epithelium mucosae cells (including the cilium-side of cellular columnoepithelialis and stratified pinacocyte). Phlegmonosis cellular (mostly histoleucocyte). Cellular endoepithelial gland .It presents in both cytomembrane and cytoplasm,but mostly in cytomembrane. ( 3 ) Computer-assissted gray scale date showed that in group M.the expreession of SDF-1 and CXCR4 increased.compared to group C1(P<0.05).The expreession in groupD1,HR1 significantly decreased versus in group M(P<0.05).Compared to groupD1,HR1,the expression in groupD2,HR2 also decreased(P<0.05).Butthere are no difference either in groupD1,HR1 or in group D2,HR2.
Conclusion: According to stimulating in nasal cavity repeatedly, we established the allergic rhinitis model in rat after the system sensibilization. Group M showed a significant increase in mucosa thickness, vessels and glands, epithelium secretive cells, inflammatory cells, including eosinophile granulocytes. Applying with immunohistochemistry method, we observed that SDF-1and CXCR4 presented at same sites. We concluded that in circumstance of allergic rhinitis, the expression change of SDF-1 and CXCR4 played an important role. The possible reason that the treatment of DEX or DIP had an effect on the proceeding of allergic rhinitis was to regulate the expression of SDF-1and CXCR4 in nasal mucosa.
2.提供变应性鼻炎模型的鼻粘膜组织形态学特征
3.确定SDF-1和CXCR4在大鼠变应性鼻炎时鼻粘膜上的表达情况
4.观察地塞米松及非那根对大鼠变应性鼻炎时SDF-1和CXCR4表达的影响。
方法:健康清洁级SD大鼠64只,体重250～300g,随机分成空白组(C1),假处理组(C2),模型组(M),干预一组(D1,D2),干预二组(HR1,HR2),模型组16只,其他每组8只。AR模型建立方法:以卵清蛋白(OVA)经全身致敏,5天后强化致敏,自第14天开始以1mg/mlOVA,20ul每天滴鼻,直至大鼠打喷嚏,搔鼻,鼻涕的症状评分达到标准;干预组则在模型成功的基础上给予地塞米松1mg/kg及非那根2mg/kg肌肉注射,每天一次,分别干预一周、两周;假处理组则以生理盐水代替OVA,其余与模型组相同;空白组不作任何处理。用组织化学方法观察变应性鼻炎的组织形态学特征,运用免疫组织化学方法(SP法)检测各组动物鼻粘膜SDF-1和CXCR4的表达和变化。并与地塞米松及非那根干预后进行比较。本实验的数据应用SPSS11.5统计软件包进行统计学处理,实验各组间的显著性检验采用方差分析及重复测量,以P<0.05作为有显著性差异意义。
结果:AR模型时鼻分泌物涂片显示大量中性粒细胞和嗜酸性粒细胞。粘膜中嗜酸性粒细胞在M组明显增多,经地塞米松或非那根作用后减少。形态学改变:HE染色见正常鼻粘膜上皮为假复层纤毛柱状上皮和复层扁平上皮,由纤毛柱状上皮细胞,杯状细胞、扁平细胞等组成,粘膜下纤维结缔组织很薄,血管数量很少,无炎性细胞浸润及血管改变;模型组较C1,C2组粘膜增厚显著,小血管增生扩张明显,上皮分泌细胞增多,上皮下大量炎性细胞浸润,粘膜下腺体数量明显增加,腺体扩张;经地塞米松或非那根处理后,粘膜厚度变薄,血管扩张及腺体增生及炎性细胞浸润程度减轻。免疫组化:1.SDF-1表达于鼻粘膜上皮层细胞(包括假复层纤毛柱状上皮细胞纤毛面及复层扁平细胞)、固有层炎性细胞(单核细胞多见)、上皮内腺细胞、毛细血管及血窦内皮细胞,其表达部位主要在细胞质。2.CXCR4表达于鼻粘膜上皮层细胞(包括假复层纤毛柱状上皮纤毛面及复层扁平上皮细胞)、固有层炎性细胞(单核细胞多见)、上皮内腺细胞。在细胞膜和细胞质均有表达。3.AR模型时,SDF-1和CXCR4表达增加(P<0.05);经地塞米松及非那根干预1周后,SDF-1和CXCR4蛋白表达较AR模型时均有减少(P<0.05);地塞米松及非那根干预2周与干预1周时比较,SDF-1和CXCR4蛋白表达减少(P<0.05)。而地塞米松与非那根的治疗疗效之间没有明显差异(P>0.05)。
结论:通过OVA多次致敏,局部激发能够成功的建立大鼠变应性鼻炎的动物模型。病理形态学上的改变:变应性鼻炎时,上皮分泌细胞明显增多,粘膜增厚,炎性细胞浸润及嗜酸性粒细胞明显增多,腺体扩张增多,小血管的增加,充血。经地塞米松或非那根处理后,粘膜厚度变薄,血管扩张及腺体增生及炎性细胞浸润程度减轻。免疫组组织化学结果显示:变应性鼻炎时,SDF-1和CXCR4表达强度发生改变,推测SDF-1和CXCR4在AR时起着重要作用;地塞米松及非那根的干预可能是通过减少SDF-1和CXCR4在粘膜上的表达从而影响AR的转归。
Objectives
1. To establish the model of allergic rhinitis (AR) in SD rat.
2. To present the character of morphology in allergic rhinitis of rat.
3. To determine the expression of SDF-1/CXCR4 in nasal mucosa of AR.
4. To observe the effect of dexamethasone (DEX) and diprazine on the expression of SDF-1/CXCR in the allergic rhinitis.
Methods: Sixty-four healthy adult rats whose weight were 250～300g were randomly divided into the blank group (C1), control group (C2), model group(M), hormone-intervention group(D1,D2),histamine receptor antagonist–intervention group(HR1, HR2).Model group had 16 rats, the others had 8 rats each. The methods of establishing the model : Group M and group D1,D2,HR1, HR2 were sensitized by injection of 1ml of physiological saline containing ovalbumin (1mg) and alum (2mg) into the four footpads . Five days later, they were boosted by subcutaneous injection of 1ml of physiological saline containing ovalbumin (0.5mg) in 10 sites on the back. Then local sensitization was performed every day by dripping the ovalbumin in physiological saline (1mg/ml, 20ul) into the bilateral nasal cavities using a micropipette from the 14th day to the establishment which was defined by the symptom score. After the establishment of model, dexamethasone (1mg/kg) and diprazine (2mg/kg)were administered to group D1,D2, HR1 and HR2 by intramuscular injection once a day, group D1, HR1 were treated for one week, group D2, HR2 were treated for two weeks respectively. While group C2 were treated with physiological saline replacing ovalbumin, the others steps were the same as group M. The group C1 remains virgin. Applying with history chemistry staining, we observed the histomorphologic character of AR. The expression and changes of SDF-1/CXCR4 in nasal mucosa in each group were investigated with immunohistochemical technique (SP method). All the data are represented as means±SEM. Statistical analysis was performed using one-way ANOVA and Repeated measures with SPSS11.5 statistical package. A probability value of less than 0.05 was considered significant.
Results :(1)A large number of neutrophil and eosinophile granulocyte were present in nasal smear of group M. In nasal mucosa, EOS got increase obviously in group M, and then, decreased after DEX and DIP treatment. In group C1 and C2, epithelium mucosa was composed of ciliated columnar epithelia ,goblet cell and pavement cells etc. by hemotoxylineosin (HE) staining, and submucosa without inflammatory cell infiltrated and few vessels was compact fibrous connective tissue adjacent to the surface of cartilage. While, group M showed a significant increase of mucosa thickness, vessels and glands, epithelium secretive cells, inflammatory cells, compared to group C1 and C2. After the treatment of DEX and DIP, mucosa recovered slowly, and all of vessels expanding, glands hyperplasted and inflammatory cell infiltrated did lighten. (2)Applying with immunohistochemistry method, SDF-1 expressed in nasal cellular epithelium mucosae cells (including the cilium-side of cellular columnoepithelialis and stratified pinacocyte). Phlegmonosis cellular (mostly histoleucocyte). Cellular endoepithelial gland ; capillary cell and cellular sinusoidal endothelial that mostly present in cytoplasm.CRCR4 expresses in nasal cellular epithelium mucosae cells (including the cilium-side of cellular columnoepithelialis and stratified pinacocyte). Phlegmonosis cellular (mostly histoleucocyte). Cellular endoepithelial gland .It presents in both cytomembrane and cytoplasm,but mostly in cytomembrane. ( 3 ) Computer-assissted gray scale date showed that in group M.the expreession of SDF-1 and CXCR4 increased.compared to group C1(P<0.05).The expreession in groupD1,HR1 significantly decreased versus in group M(P<0.05).Compared to groupD1,HR1,the expression in groupD2,HR2 also decreased(P<0.05).Butthere are no difference either in groupD1,HR1 or in group D2,HR2.
Conclusion: According to stimulating in nasal cavity repeatedly, we established the allergic rhinitis model in rat after the system sensibilization. Group M showed a significant increase in mucosa thickness, vessels and glands, epithelium secretive cells, inflammatory cells, including eosinophile granulocytes. Applying with immunohistochemistry method, we observed that SDF-1and CXCR4 presented at same sites. We concluded that in circumstance of allergic rhinitis, the expression change of SDF-1 and CXCR4 played an important role. The possible reason that the treatment of DEX or DIP had an effect on the proceeding of allergic rhinitis was to regulate the expression of SDF-1and CXCR4 in nasal mucosa.
引文
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