A recent study of mucus plugs in COPD, Mucus Plugs-Associated Gene Expression Identifies Pathophysiology Shared With Chronic Bronchitis, identified dysregulated biologic pathways that could become useful therapeutic targets.1 Gene expression profiles associated with mucus plugs reflect pathogenesis in ciliary, mucus, and immune pathways.
“We tend to think of mucus plugs as just a radiographic finding, but they are a fairly strong and reproducible marker of morbidity in obstructive lung disease,” said investigator Ehab Billatos, MD, Assistant Professor of Pulmonary, Allergy, Sleep & Critical Care Medicine at Boston University Chobanian & Avedisian School of Medicine, who was not involved in the study. “In COPD, mucus plugs correlate with worsening lung function, more frequent exacerbations, faster decline in FEV1, and increased mortality. Mucus plugging is treatable, reversible, and potentially a prognostically meaningful target.”
The study assessed 290 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP) 2 study for both mucus plugs prevalence and RNA sequencing of samples collected by mainstem bronchial brush.1–2 Participants were divided into discovery (204 participants) and validation (86 participants) cohorts.
In the discovery cohort, 191 had COPD and 37% had mucus plugs in at least one bronchopulmonary segment. In the validation set, 33% of participants had mucus plugs.
The study identified gene expression signatures associated with mucus plugs, Dr. Billatos said. The genes the researchers identified overlap pathways that have previously been identified in chronic bronchitis. Hypersecretion of mucin, epithelial modeling, and immune system activation are common to both mucus plugs and chronic bronchitis. There is also a transcriptomic fingerprint that matches radiologic evidence of mucus plugs, he said.
Data showed that expression of four mucus plug epithelial gene clusters is highly associated with chronic bronchitis symptoms such as chronic cough and phlegm production, suggesting common pathways across different phenotypes of mucus pathology. A fifth gene cluster is seen only in mucus plugs and may represent a specific mucus plug pathway.
Dr. Billatos said these distinct gene clusters may underly the clinical heterogeneity of mucus pathology that leave some patients with mucus plug and chronic bronchitis symptoms while other patients have predominant symptoms from one condition.
Changes in expression in specific gene clusters may suggest multiple pathophysiologic pathways in both mucus plugs and chronic bronchitis, Dr. Billatos said. Decreased expression of some clusters appears to represent cilia dysfunction, which results in impaired mucus clearance.
As cilia dysfunction increases, the likelihood of mucus plugs may likewise increase. Lower levels of cilia dysfunction may be insufficient to cause mucus plugs and could result in chronic bronchitis symptoms without mucus plugging.
One cluster includes genes related to epithelial maintenance and protection, and the research showed increased expression of these genes in participants with mucus plugs and chronic bronchitis. Dr. Billatos said these genes are involved in the production of lipid signaling mediators, barrier integrity and defense, and surface liquid homeostasis. He said at least one gene has been shown to alter airway surface hydration.
Additionally, some genes have been linked to cystic fibrosis while others are involved in response to airway injury and inflammation. Inflammation, infection, environmental triggers, and other airway insults can alter mucus production, hydration, and clearance. Local heterogeneity may play a role in mucus plug formation within the airway, Dr. Billatos said.
He said it was not clear whether increased mucus levels inhibit ciliary movement or alter ciliary signaling pathways to worsen mucus status or whether ciliary dysfunction impairs mucus clearance, leading to a positive feedback loop of mucus secretion. The molecular consequences of cough and phlegm may also play a role in mucus clearance or accumulation.
Dr. Billatos said the findings could help close clinical knowledge gaps in the mechanisms of mucus production and the biological processes that lead to mucus plugging.
“The goal is to develop therapeutic targets for pathways we’ve identified, whether it’s goblet cell hyperplasia, regulation of mucus production and clearance, or immune signaling,” he explained. “We can think more creatively about therapies that might address these different aspects of mucus secretion and mucus plugging. This doesn’t change anything at the moment, but it does set the foundation for future studies and identifying drug targets.”
References
1. Souery WN, Billatos E, Elalami R, et al. Mucus plugs-associated gene expression identifies pathophysiology shared with chronic bronchitis. Am J Respir Crit Care Med. Published online October 10, 2025. doi:10.1164/rccm.202501-0262OC
2. DECAMP-2: Screening of patients with early stage lung cancer or at high risk for developing lung cancer (DECAMP-2). ClinicalTrials.gov. NCT02504697. https://clinicaltrials.gov/study/NCT02504697
