目的 探讨维甲酸相关孤儿核受体C (retinoic acid receptor related orphan C,RORC)抑制剂(SR1001)对变应性鼻炎(AR)模型小鼠鼻黏膜中缺氧诱导因子(hypoxia inducible factor,HIF)-1α及血管内皮生长因子(VEGF)蛋白表达的影响.方法 将30只BALB/c小鼠按数字表法随机分为正常对照组、AR模型组和RORC抑制剂组,每组10只.采用卵清蛋白(OVA)致敏法建立小鼠AR模型,RORC抑制剂组腹腔注射SR1001 (25 mg/kg),AR模型组用0.9％生理盐水给予相同处理.给药期间每周末次给药后,对小鼠进行行为学评分测定,随后麻醉小鼠取鼻黏膜组织,于光镜下观察组织病理学变化;免疫组织化学法观察HIF-1α及VEGF的蛋白表达情况.ELISA法测定小鼠血清中干扰素(IFN)-γ、白细胞介素(IL)-17、特异性IgE(sIgE)的含量.Western blot法检测鼻黏膜组织中HIF-1α及VEGF的表达情况.组间比较采用单因素方差分析,方差齐用LSD法进行组间两两比较,不齐则用Dunnett T3法进行组间两两比较.设P＜0.05为差异有统计学意义.结果 小鼠AR模型建立成功.与AR模型组比较,RORC抑制剂组AR小鼠的行为学评分明显降低[(4.02±0.97)分比(8.50±1.76)分,t=7.050,P＜0.01];已损伤的黏膜上皮出现好转,腺体和扩张的腺管趋于正常,肥大的杯状细胞明显减少,黏膜固有层浸润的炎性细胞减少.与AR模型组比较,RORC抑制剂组小鼠的血清IL-17、sIgE的含量显著降低[(25.10±4.11) ng/ml比(42.56±5.98) ng/ml,(0.875±0.244) ng/ml比(1.982±0.365) ng/ml,t值分别为14.141、10.275,P值均＜0.01],IFN-γ含量显著升高[(61.32±8.83) pg/ml比(38.94±5.97) pg/ml,t=8.133,P＜0.01];HIF-1α及VEGF蛋白表达量显著降低[(0.92±0.08)比(1.67±0.31),(1.12±0.21)比(2.54±0.46),t值分别为7.408、8.880,P值均＜0.01].结论 RORC抑制剂可能通过改变AR小鼠体内炎性因子的含量、降低鼻黏膜组织中HIF-1α及VEGF表达水平的方式,达到治疗AR的效果.%Objective To investigate the effects of the retinoic acid receptor related orphan C (RORC) inhibitor (SR1001) on the expression changes of proteins of hypoxia induced factor (HIF-1α) and vascular endothelial growth factor (VEGF) in the nasal mucosa of mice with allergic rhinitis (AR) model.Methods Thirty BALB/c were randomly divided into normal group,AR model group and RORC inhibitor group,10 mice each group.AR model of mice was established by ovalbumin (OVA) sensitization method.RORC inhibitor group was given intraperitoneal injection of SR1001 (25 mg/kg),while AR model group intraperitoneal injection of the same volume of 0.9％ normal saline.The symptom score of the mice was determined every weekend after administration.The pathological morphological changes in the nasal mucosa tissue obtained from anesthetized mice were observed by light microscope.The expression of HIF-1α and VEGF protein were detected by immunohistochemistry.IFN-γ,IL-17,and sIgE in the serum were detected by ELISA and the expression of HIF-1α and VEGF in the nasal mucosal tissue of the mice were measured by Western blot.One-way ANOVA was used for inter-group comparison.LSD method was used for inter-group comparison with equal variance,and Dunnett T3 method for inter-group comparison with unequal variance.P ＜ 0.05 was considered statistically significant.Results The AR model was successfully established.Compared with the model group,the RORC inhibitor group significantly reduced the symptom score of AR mice (4.02 ±0.97 vs 8.50 ± 1.76,t =7.050,P ＜0.01).The damaged mucosal epithelium appeared to be improved,the glands and dilated ducts tended to be normal,the mast goblet cells significantly reduced,and the infiltration of inflammatory cells in the inherent mucosa reduced.Meanwhile,the content of IL-17 and sIgE in serum decreased [(25.10 ± 4.11) ng/ml vs (42.56 ± 5.98) ng/ml,(0.875 ±0.244) ng/ml vs (1.982 ± 0.365) ng/ml,t value was 14.141,10.275,respectively,all P ＜ 0.01] and the content of IFN-γincreased [(61.32 ± 8.83) pg/ml vs (38.94 ± 5.97) pg/ml,t =8.133,P＜0.01].The expression of HIF-1α and VEGF protein in the nasal mucosal tissues of AR mice significantly reduced (0.92 ±0.08 vs 1.67 ±0.31,1.12 ±0.21 vs 2.54 ±0.46,t value was 7.408,8.880,respectively,all P ＜ 0.01).Conclusion The RORC inhibitor has the therapeutic effect on AR by changing the content of inflammatory factors in AR mice and reducing the expression level of HIF-1α and VEGF in the nasal mucosa.
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