2025/11/20 by Naoya Tanabe · 1 voice
Medicine · #Chronic Obstructive Pulmonary Disease (COPD) Research #Cystic Fibrosis Research Advances #Respiratory and Cough-Related Research
paper · pdf · doi:10.1002/resp.70169
openalex publication_date 2025/11/20 · openalex created_date 2025/11/23 · openalex updated_date 2026/07/23
Airway mucus plays a critical role in protecting airways from external insults, including bacterial and viral pathogens, air pollutants, and occupational toxicants. It also facilitates mucociliary clearance and regulates the inflammatory responses [1]. However, mucus is overproduced and poorly cleared from the airways, leading to mucus plugging in chronic airway diseases such as chronic obstructive pulmonary disease (COPD). Hogg et al. demonstrated that inflammatory mucous exudates in the small airways on histology were associated with lower FEV1 and mortality in patients with COPD [2]. A recent study using micro-CT and histology suggested that mucus formation may play a critical role in the early stages of small airway disease [3]. Furthermore, clinical studies on COPD have shown that mucus plug scores on CT are associated with FEV1 and oxygen saturation, with patients exhibiting mucus plugs in three or more bronchopulmonary segments experiencing a higher frequency of exacerbations and poorer prognosis [4, 5]. A cohort study involving 4483 patients with COPD in the United States revealed that a high mucus plug score (≥ 3), observed in 18.9% of patients, was independently associated with increased mortality [4]. Similar results were reported in Japanese cohorts, where approximately 30% of patients had mucus plug scores ≥ 3 [6]. Notably, mucus plugs were identified on CT in 36% of patients without cough or phlegm, and those with silent mucus plugs (mucus plugs without cough or phlegm) were associated with a shorter 6-min walk distance, lower oxygen saturation, and a higher frequency of severe exacerbations in the past year than those without mucus plugs [7]. Subsequent studies have indicated that a higher mucus plug score is correlated with an increased risk of COPD exacerbations [8-10]. Moreover, a 5-year longitudinal analysis demonstrated that the presence of persistent mucus plugs on both baseline and five-year follow-up CT scans, as well as the emergence of new mucus plugs on follow-up CT scans, was associated with an accelerated decline in FEV1 over the corresponding 5 years in patients with COPD [11]. These findings suggest that persistence and dynamic alterations in airway mucus plugs may serve as markers of disease activity, reflecting the risk of lung function decline and exacerbations in patients with COPD. In clinical practice, identifying patients at a higher risk of mucus plugs and performing chest CT scans is crucial. A recent study introduced the Simple Index for predicting Mucus Plugs, which is calculated using factors such as age, sex, BMI, smoking status, GOLD grade, FEV1/FVC, chronic bronchitis, prior exacerbation, dyspnea, cough, and phlegm [12]. Once CT scans are obtained, it is advisable to analyse the mucus plugs automatically, as visual inspection can be time-consuming. In this context, another study used artificial intelligence to automatically quantify mucus plugs, revealing that mortality was higher in patients with COPD with ≥ 3 mucus-obstructed bronchial segments [13]. Furthermore, researchers have begun to evaluate multiple features of mucus plugs in vivo beyond volume and mucus score, by quantifying their length and density, which may sensitively reflect the mechanical and pathogenic properties of mucus plugs. Indeed, longer and denser mucus plugs are linked to airway eosinophilic inflammation in patients with asthma [14, 15]. This approach should be applied to patients with COPD to enhance our understanding of mucus in situ biology in clinical practice. Despite a deepened understanding of the clinical relevance of mucus plugs in patients with COPD, their pathogenesis remains poorly understood. MUC5AC is identified as the primary mucin component of mucus plugs and can be upregulated through two mechanisms, namely the interleukin (IL)-13 and epidermal growth factor receptor (EGFR) pathways [1]. The potential mechanism of mucus plug formation in COPD is shown in Figure 1. The IL-13 pathway is crucial for mucus plug formation in patients with type 2 high asthma, and biologics targeting type 2 inflammation have demonstrated efficacy in significantly reducing the mucus plug burden. Type 2 inflammation, characterised by elevated blood eosinophils and/or fractional exhaled nitric oxide (FeNO) levels, is observed in approximately 30% of COPD patients without a history of asthma [16]. Gene expression analysis of airway epithelium obtained via bronchoscopy revealed that IL-13 related gene expression was higher in patients with COPD with airway eosinophilic inflammation compared to those without eosinophilic inflammation [17]. Given the recently reported efficacy of dupilumab in reducing exacerbations in COPD patients with blood eosinophil counts ≥ 300/μL [18], the IL-13 pathway may play a role in mucus plug formation in a subset of patients with COPD. Factors other than IL-13 may also affect mucus plug formation in patients with COPD, especially those without type 2 inflammation. A CT study showed increased mucus plugs were associated with blood eosinophil count ≥ 300/μL and FeNO ≥ 25 ppb in asthma and asthma-COPD overlap but not in COPD [19]. Neutrophils and macrophages are the main inflammatory cells in COPD lungs. Neutrophil elastase stimulates mucus production, and neutrophilic inflammation links to neutrophil extracellular traps (NETs) and airway microbiome changes, including increases in the Proteobacteria phylum. A reduction in Actinobacteria was associated with higher mucus plug scores in COPD but not in asthma or their coexistence [20]. Airway epithelium damage facilitates IL-33 release, and oxidised IL-33 binds EGFR and activates MUC5AC production [21]. Smoking induces dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), leading to mucus dehydration [22]. When mucus plugs develop, mucus-obstructed airways become hypoxic, stimulating MUC5B production and fluid absorption through epithelial sodium channels (ENaC) [23]. Increased DNA concentration from NETs and mucus hyperconcentration from CFTR and ENaC dysfunction contribute to tenacious mucus plug formation. Once mucus plugs develop, affected bronchial regions may become hypoxic with epithelial dysfunction, microbiome alteration, and inflammation, increasing susceptibility to persistent mucus plugs. Research is needed to understand the mechanisms of mucus plug formation in COPD and provide personalised management strategies. A recent study has demonstrated that bronchial rheoplasty may reduce mucus plugs in patients with chronic bronchitis [24]. Furthermore, dupilumab is commercially available, and research on the effects of IL-33 targeting therapy is currently underway. Despite the increasing global burden of COPD, an enhanced understanding of the pathogenesis of mucus plugs will facilitate the identification of airway mucus plugs as treatable traits. This can be managed through existing and novel biologics in patients with COPD, and their potential should be tested in well-designed multi-regional studies, including in Asian countries. The authors have nothing to report. The author received research grants from FUJIFILM Co. Ltd. and Daiichi Sankyo, and lecture fees from Sanofi, GSK, and AstraZeneca, all outside the submitted work.