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      Carbocisteine inhibits the expression of Muc5b in COPD mouse model

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          Abstract

          Background

          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.

          Methods

          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.

          Results

          High-dose carbocisteine significantly decreased the overproduction of Muc5b ( P<0.01) and Muc5ac ( P<0.001), and restored Muc5b/Muc5ac ratio in COPD model group ( P<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.

          Conclusions

          These findings suggest that carbocisteine attenuated Muc5b and Muc5ac secretion and restored Muc5b protein levels, which may improve mucus clearance in COPD.

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          Most cited references 35

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          Airway mucus function and dysfunction.

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            Structure and function of the polymeric mucins in airways mucus.

            The airways mucus gel performs a critical function in defending the respiratory tract against pathogenic and environmental challenges. In normal physiology, the secreted mucins, in particular the polymeric mucins MUC5AC and MUC5B, provide the organizing framework of the airways mucus gel and are major contributors to its rheological properties. However, overproduction of mucins is an important factor in the morbidity and mortality of chronic airways disease (e.g., asthma, cystic fibrosis, and chronic obstructive pulmonary disease). The roles of these enormous, multifunctional, O-linked glycoproteins in health and disease are discussed.
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              Muc5b is required for airway defence.

              Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                16 September 2019
                2019
                : 13
                : 3259-3268
                Affiliations
                [1 ]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
                [2 ]Drug Research Institute of Guangzhou BaiYunShan Pharmaceutical General Factory , Guangzhou, 510515, People’s Republic of China
                Author notes
                Correspondence: Jinping Zheng First Affiliated Hospital of Guangzhou Medical University , No 151 Yanjiang Road, Guangzhou510120, People’s Republic of ChinaTel +86 208 306 2869Fax +86 208 306 2729Email jpzhenggy@163.com
                Article
                198874
                10.2147/DDDT.S198874
                6754527
                © 2019 Song et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 1, References: 43, Pages: 10
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                carbocisteine, copd, muc5ac, muc5b, cigarette smoke

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