[Resveratrol attenuates endoplasmic reticulum stress and alveolar epithelial apoptosis in a rat model of chronic obstructive pulmonary disease].
OBJECTIVE
To investigate alveolar epithelial cell apoptosis induced by endoplasmic reticulum stress in a rat model of chronic obstructive pulmonary disease (COPD) and the potential protective effect of resveratrol.


METHODS
The COPD rat model was established by intratracheal instillation of lipopolysaccharide (LPS) and exposure to cigarette smoke daily. Forty-eight male Sprague-Dawley rats were randomly divided into 4 groups (n = 12 each): a normal control group, a resveratrol control group (resveratrol 25 mg × kg⁻¹ × d⁻¹ gavage), a COPD group (COPD rat model established), and a resveratrol intervention group (COPD model rats receiving resveratrol 25 mg × kg⁻¹ × d⁻¹ gavage). Spirometry was conducted and the lung pathological changes were observed. The protein expression of CCAAT/enhancer binding protein homologous protein (CHOP) and caspase-12 were detected by immunohistochemistry and Western blot, and alveolar epithelial apoptosis was analyzed by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). Statistical analysis among groups were carried out by one way analysis of variance followed by LSD-t test between 2 groups.


RESULTS
Significant decrease of FEV0.3/FVC [(59 ± 4)%] and dynamic lung compliance [(0.154 ± 0.013) ml/cm H₂O, 1 cm H₂O = 0.098 kPa] and increase of airway resistance [(0.651 ± 0.046) cm H₂O × ml⁻¹× s⁻¹] were found in the COPD group when compared with the normal control group [(82 ± 4)%, (0.401 ± 0.033) ml/cm H₂O, (0.404 ± 0.033) cm H₂O × ml⁻¹ × s⁻¹] (t = -14.48, 16.48, P < 0.05). The FEV0.3/FVC [(71 ± 5)%] and dynamic lung compliance [(0.302 ± 0.023) ml/cm H₂O] of the resveratrol intervention group were significantly improved when compared with those of the COPD group, and the airway resistance [(0.442 ± 0.036) cm H₂O × ml⁻¹ × s⁻¹] also decreased (t = -10.02-10.37, P < 0.05). Significant small airway inflammation and emphysema were seen in the lung tissue of COPD group, while significant improvement was observed in the resveratrol intervention group when compared with COPD group. The lung tissue immunohistochemistry integrated optical density (IOD) of CHOP and caspase-12 (9 778 ± 217, 12 009 ± 346) of the COPD group increased significantly when compared with the normal control group (960 ± 94, 1 124 ± 112) (t = -100.43, - 90.43, P < 0.05), while the IODs of the resveratrol intervention group (5 799 ± 177, 6 720 ± 173) decreased significantly when compared with the COPD group (t = 45.32, 43.93, P < 0.05). Western blot results showed that the relative quantification of CHOP (0.910 ± 0.053) and caspase-12 (1.104 ± 0.026) increased in the COPD group when compared with the normal control group (0.204 ± 0.021, 0.133 ± 0.013, t = -36.04, -115.03, P < 0.05), while the ratios of the resveratrol intervention group (0.462 ± 0.037, 0.642 ± 0.011) decreased significantly when compared with COPD group (t = 24.22, 60.59, P < 0.05). Higher apoptosis index was seen in the COPD group [(39.8 ± 1.6)%] when compared with the resveratrol intervention group [(26.3 ± 1.5)%] and the normal control group [(6.4 ± 0.6)%] (t = 20.21, -49.94, P < 0.05).


CONCLUSIONS
Endoplasmic reticulum stress, which induced apoptosis of alveolar epithelial cells, was observed in this COPD model. Resveratrol was shown to alleviate endoplasmic reticulum stress and attenuate alveolar epithelial apoptosis.
Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China.
Yuping
Y
Li
Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China. Email: blluo181181@gmail.com.
Bailing
B
Luo
Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China.
Li
L
Zhang
Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China.
Miao
M
Ma
Department of Respiratory Medicine, Xiangya Hospital of Central South University, Changsha 410008, China.
Xianling
X
Guo
D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D008070:Lipopolysaccharides / Q000009:adverse effects; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D012906:Smoke / Q000009:adverse effects; D013267:Stilbenes / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000378:metabolism
D000975:Antioxidants; C497251:Ddit3 protein, rat; D008070:Lipopolysaccharides; D012906:Smoke; D013267:Stilbenes; D051742:Transcription Factor CHOP; C506443:Casp12 protein, rat; D053454:Caspase 12; D000077185:Resveratrol