克拉霉素联合布地奈德对COPD大鼠糖皮质激素抵抗的影响

Effect of clarithromycin and budesonide on glucocorticoid resistance in COPD rats

目的:探讨克拉霉素联合布地奈德对慢性阻塞性肺疾病(COPD)大鼠糖皮质激素抵抗的影响。方法:对大鼠进行COPD造模,然后分4组处理,COPD组、克拉霉素组、布地奈德组和联合干预组(克拉霉素+布地奈德组),每组10只;以10只未处理未造模大鼠作空白对照(空白组)。留取各组大鼠肺组织和血清,HE染色,光镜下观察肺组织病理学改变,采用ELISA法测定血清中TNF-α水平,采用RT-PCR及Western blot检测肺组织糖皮质激素受体α(GRα)及GRβ的表达。结果:与空白组相比,COPD组大鼠气管及支气管黏膜上皮细胞脱落,炎性细胞浸润,支气管平滑肌增厚,肺泡壁变薄,甚至破裂融合成肺大泡,血清TNF-α水平升高,提示造模成功。对COPD组、克拉霉素组、布地奈德组和联合干预组的分析表明,克拉霉素和布地奈德均可降低COPD大鼠血清TNF-α水平和肺组织GRβ mRNA和蛋白的表达水平,升高肺组织GRα mRNA和蛋白的表达水平,且二者联用有协同作用(P<0.05)。结论:克拉霉素、布地奈德均可在不同程度上调节GRα/GRβ失衡,从而改善COPD大鼠糖皮质激素抵抗,二者联用抗炎效果更佳。

Aim： To explore the effect of clarithromycin and budesonide on chronic obstructive pulmonary disease（ COPD） rat glucocorticoid resistance and its mechanism. Methods： Rats were randomly allocated into 5 groups,blank group,COPD group,clarithromycin group,budesonide group,and combined intervention group; 10 rats in each group. The rats in the latter 4 groups were made COPD model. The pathological changes of lung tissue were observed by HE staining.Level of TNF-α in serum was determined by ELISA. The expressions of glucocorticoid receptor α（ GRα） and GRβ mRNA and protein in lung tissue were detected by RT-PCR and Western blot. Results： Compared with blank group,there were tracheal and bronchial epithelial cells shedding,inflammatory cell infiltration,thickening of bronchial smooth muscle,alveolar wall thinning or even ruptured and fused into bullae of lung,and the level of serum TNF-α increased in COPD group（ P 〈 0. 05）. Compared with COPD group,the level of serum TNF-α and the expressions of GRβ mRNA and protein decreased in clarithromycin group and budesonide group,while those of GRα mRNA and protein increased（ P 〈 0. 05）,and the 2 drugs had synergistic effects（ P 〈 0. 05）. Conclusion： Clarithromycin or budesonide could adjust GRα/GRβ imbalance,reverse glucocorticoid resistance in COPD rats,and the antiinflammatory effect is synergistic when they are combined.