Roxithromycin Attenuates Endoplasmic Reticulum Stress And Alveolar Epithelial Apoptosis In COPD Rats

Objective:To explore the intervention effects of roxithromycin (RXM) on endoplasmic reticulum stress (ERS) and alveolar epithelial cell apoptosis in rats model of COPD.Methods:48male SD rats were randomly divided into four groups:(1)Control group,(2)RXM group,(3)COPD group,(4)COPD+RXM group. Rats in COPD group received intratraeheal instillation of lipopolysaccharide (LPS)200μg/100μl (dayl, day31) and were exposed to cigarette smoke daily on day2to day31、day32to day60to set up COPD rat models, in addition to this, rats in the COPD+RXM group were treated with administered RXM at doses of35mg/kg daily during the second half of a60-day exposure period to assess the intervention effects, rats in RXM group and Control group received intratraeheal instillation of adequate saline, rats in the RXM group were also treated with administered RXM at doses of35mg/kg daily, in contrast, rats were gavaged with adequate saline. After the last exposure to cigarette smoke for24hours, pulmonary function of rats were conducted in all groups, and then all the rats were killed, lung pathological changes were observed by HE staining, the protein expression level of Caspase12and CHOP were detected by immunohistochemistry and western-blot, alveolar epithelial apoptosis were analyzed by Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL).Results:1. The FEV0.3/FVC (%) and dynamic lung compliance (Cdyn) of the COPD rats were significant lower than those of the Control group with the airway resistance (R1) increased obviously (P<0.05), with the RXM intervention, the FEV0.3/FVC (%) and Cdyn of the COPD+RXM group rats were significant improved compared with COPD group and R1decreased (P<0.05);2. In the COPD group, alveolar wall thinning、excessive bulge of the alveolar and more anastomosis alveolar were observed, lung tissue morphology changes moderately of rats in the COPD+RXM group, the Control group and RXM group show few above changes;3. In IHC, Caspase12stained mainly in cytoplasm and CHOP in nuclus, the rats lung tissue Integrated Optical Density (IOD) of Caspase12and CHOP increased significantly in the COPD group compared with the Control group (P＜0.05), while the IODs of COPD+RXM group decreased significantly compared with COPD group (P<0.05);4. Western-blot results show that the protein expressions of active-caspase12and CHOP increased in COPD group compared with Control group, the ratios of active-caspase12/β-actin、CHOP/β-actin were significantly higher than those of Control group (P<0.05), with RXM intervention, the ratios of the COPD+RXM group decreased significantly compared with the COPD group (P<0.05);5. Higher Apoptosis Index (AI) were seen in COPD group compared with the Control group (P<0.05), represented more alveolar epithelial apoptosis, the AI decreased in COPD+RXM group compared with the COPD group (P<0.05)Conclusions:RXM attenuates ERS and alveolar epithelial apoptosis in COPD rats exposed to cigarette smoke and lipopolysaccharide intratracheal instillation. This study supports the possibility that long term RXM treatment might provide a new therapeutic strategy for COPD.