Abstract
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [nuclear factor-κB (NF-κB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by high mortality and morbidity globally
Retention of small airway mucus and even formation of mucus plugs have been observed in the lung tissue of patients who have succumbed to COPD [57,58]
Lam and colleagues showed that elevated autophagy in primary cultured epithelial cells under cigarette smoke (CS) exposure was accompanied by cilia shortening and increased localization of ciliary proteins, including Ift88, Arl13, centrin 1, and pericentrin, to autophagosomes in mouse airways demonstrating that autophagy is increased in COPD cells under CS exposure, and that cilia shortening is caused by increased autophagic degradation of ciliogenic proteins
Summary
COPD is characterized by high mortality and morbidity globally. The World Health Organization (WHO) predicts that COPD will become the third among the top causes of deaths by 2030 [1]. COPD is considered a treatable and preventable disease which often presents with unyielding airflow limitation It is often driven by chronic inflammatory response of the airways and lung tissue. The 2018 China pulmonary health [CPH] epidemiological survey found that a smoking rate exceeding 20 pack-years increases the prevalence of COPD by 2-fold. Treatment of patients with stable COPD include long-term oxygen therapy, pulmonary rehabilitation, and smoking cessation. Lung volume reduction surgery, oxygen inhalation, and drug therapy improve pulmonary function to an extent, reduce the frequency of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and enhance quality of life, they do not halt COPD progression [16]. Multiple studies indicate that airway mucus hypersecretion contributes to the rapid deterioration of lung function and progression of COPD, including hospitalization and mortality. We discuss MUC5AC function, regulatory mechanisms, pathophysiological effects, and clinical significance in COPD
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