Tanshinone IIA\xa0sulfonate protects against cigarette smoke-induced COPD and down-regulation of CFTR in mice

Defu Li,Xue Liang,Hua Jiang,Zhen Long,Nanshan Zhong,Yiguan Chen,Xuefang Gong,Liang Yuan,Jiaze Shu,Hongwei Yao,Wenju Lu,Zili Zhang,Ziying Li,Ziyi Wang,Jian Wang,Ruijuan Guan,Dejun Sun

doi:10.1038/s41598-017-18745-5

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by abnormal inflammation, persistent and progressive lung function decline. The anti-inflammatory actions of tanshinone IIA, which is the most important active component from Chinese herbal medicine Danshen, have been well studied. However, it remains unknown whether sodium tanshinone IIA sulfonate (STS) protects against the development of COPD. Here we found that STS inhalation (5 mg/kg, 30 min per session, twice a day) significantly attenuated lung function decline, airspace enlargement, mucus production, bronchial collagen deposition, inflammatory responses and oxidative stress caused by cigarette smoke (CS) and lipopolysaccharide (LPS) exposures in mice. Moreover, treatment with STS (10 μg/ml) reduced CS extract (CSE)-induced IL-6 and IL-8 secretion in human bronchial epithelial (16HBE) cells. The anti-inflammatory actions of STS were associated with inhibition of ERK1/2 and NF-κB activations. Interestingly, STS inhibited CS-induced reduction of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse lungs and in 16HBE cells. Treatment with a specific CFTR inhibitor CFTR-Inh172 augmented CSE-induced ERK1/2 and NF-κB-dependent inflammatory responses, but abolished the inhibitory action of STS on IL-6 and IL-8 secretion in 16HBE cells. These results demonstrate that CS-induced COPD and down-regulation of CFTR are prevented by STS.

Highlights

Chronic obstructive pulmonary disease (COPD), currently the fourth predominant cause of death in the world, is predicted to be the third one by 20301
Lung function decline was reflected by an increase in functional residual capacity (FRC) (Fig. 2A), total lung capacity (TLC) (Fig. 2B), chord compliance (Cchord) (Fig. 2C), forced vital capacity (FVC) (Fig. 2D) and lung resistance index (RI) (Fig. 2E), as well as a decrease in forced expiratory volume at 50 ms (FEV50)/FVC (Fig. 2F)
All these manifestations were attenuated in mice administered with Sodium tanshinone IIA sulfonate (STS) compared to vehicle-treated mice exposed to cigarette smoke (CS) and LPS (FRC: CS group: 163.85 ± 11.08%, CS + STS group: 112.54 ± 7.06%; TLC: CS group: 130.06 ± 4.47%, CS + STS group: 110.89 ± 4.57%; Cchord: CS group: 142.6 ± 2.95%, CS + STS group: 116.54 ± 2.56%; FVC: CS group: 131 ± 3.27%, CS + STS group: 113.33 ± 5.09%; RI: CS group: 137.97 ± 9.66%, CS + STS group: 107.88 ± 4.42%; FEV50/FVC: CS group: 81.67 ± 3.33%, CS + STS group: 97.24 ± 2.05%, percentage of the CTL group, Fig. 2A–F)

Summary

Introduction

Chronic obstructive pulmonary disease (COPD), currently the fourth predominant cause of death in the world, is predicted to be the third one by 20301. STS and TIIA have been found to be anti-inflammatory in experimental lung and cardiac diseases[10,11,12]. In these experiments, STS or TIIA was administered via intraperitoneal injection. Excess STS will be administered intraperitoneally so as to reach effective concentration in lungs, which inevitably limits its clinical use. It is not known whether STS attenuates CS-induced inflammatory responses and subsequent COPD. To the best of our knowledge, this is the first report regarding the effects of STS inhalation on CS-induced COPD and underlying mechanisms

Methods

Results

Conclusion