Song Yan, Wang Wei, Xie Yanqing, Xiang Bin, Huang Xuan, Guan Weijie, Zheng Jinping
State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, People's Republic of China.
Drug Research Institute of Guangzhou BaiYunShan Pharmaceutical General Factory, Guangzhou, 510515, People's Republic of China.
Drug Des Devel Ther. 2019 Sep 16;13:3259-3268. doi: 10.2147/DDDT.S198874. eCollection 2019.
Cigarette smoke (CS) results in chronic mucus hypersecretion and airway inflammation, contributing to COPD pathogenesis. Mucin 5B (MUC5B) and mucin 5 AC (MUC5AC) are major mucins implicated in COPD pathogenesis. Carbocisteine can reduce mucus viscosity and elasticity. Although carbocisteine decreased human elastase-induced MUC5AC expression in vitro and reduced MUC5AC expression that alleviated bacteria adhesion and improved mucus clearance in vivo, the roles of carbocisteine in inducing MUC5B expression in COPD remain unclear.
To investigate the Muc5b/Muc5ac ratio and the gene and protein levels of Muc5b in COPD and carbocisteine intervention models. C57B6J mice were used to develop COPD model by instilling intratracheally with lipopolysaccharide on days 1 and 14 and were exposed to CS for 2 hr twice a day for 12 weeks. Low and high doses of carbocisteine 112.5 and 225 mg/kg/d, respectively, given by gavage administration were applied for the treatment in COPD models for the same duration, and carboxymethylcellulose was used as control. Carbocisteine significantly attenuated inflammation in bronchoalveolar lavage fluid and pulmonary tissue, improved pulmonary function and protected against emphysema.
High-dose carbocisteine significantly decreased the overproduction of Muc5b (<0.01) and Muc5ac (<0.001), and restored Muc5b/Muc5ac ratio in COPD model group (<0.001). Moreover, the Muc5b/Muc5ac ratio negatively correlated with pro-inflammatory cytokines such as IL-6 and keratinocyte-derived cytokine, mean linear intercept, functional residual capacity and airway resistance, but positively correlated with dynamic compliance.
These findings suggest that carbocisteine attenuated Muc5b and Muc5ac secretion and restored Muc5b protein levels, which may improve mucus clearance in COPD.
香烟烟雾（CS）可导致慢性黏液高分泌和气道炎症，这是慢性阻塞性肺疾病（COPD）发病机制的一部分。黏蛋白5B（MUC5B）和黏蛋白5AC（MUC5AC）是与COPD发病机制相关的主要黏蛋白。羧甲司坦可降低黏液的黏度和弹性。虽然羧甲司坦在体外可降低人弹性蛋白酶诱导的MUC5AC表达，并在体内降低MUC5AC表达，从而减轻细菌黏附并改善黏液清除，但羧甲司坦在COPD中诱导MUC5B表达的作用仍不清楚。
研究COPD和羧甲司坦干预模型中Muc5b/Muc5ac比值以及Muc5b的基因和蛋白水平。采用C57B6J小鼠，于第1天和第14天经气管内滴注脂多糖建立COPD模型，并每天两次暴露于香烟烟雾中，每次2小时，持续12周。分别以低剂量和高剂量羧甲司坦112.5和225mg/kg/d灌胃给药，对COPD模型进行相同疗程的治疗，以羧甲基纤维素作为对照。羧甲司坦可显著减轻支气管肺泡灌洗液和肺组织中的炎症，改善肺功能并预防肺气肿。
高剂量羧甲司坦可显著降低COPD模型组中Muc5b（<0.01）和Muc5ac（<0.001）的过量产生，并恢复Muc5b/Muc5ac比值（<0.001）。此外，Muc5b/Muc5ac比值与白细胞介素-6和角质形成细胞衍生细胞因子等促炎细胞因子、平均线性截距、功能残气量和气道阻力呈负相关，但与动态顺应性呈正相关。
这些发现表明，羧甲司坦可减少Muc5b和Muc5ac的分泌，并恢复Muc5b蛋白水平，这可能改善COPD中的黏液清除。
