Major Airway Gel-Forming Mucin MUC5AC May Serve as COPD Biomarker

An increased concentration of MUC5AC in the airways of lungs may play an important pathobiological role in the initiation and progression of chronic obstructive pulmonary disease (COPD), and may also be a disease-associated biomarker, according to study results published in The Lancet Respiratory Medicine.

In healthy individuals, MUC5B is the major gel-forming mucin in the lungs required for mucociliary clearance; however, MUC5AC is not as present and may not be required for mechanical clearance of mucus in the lungs. Conversely, in muco-obstructive diseases, MUC5AC concentrations disproportionately increase and may play a role in pathobiological mechanisms.

A team of investigators proposed that a hyperconcentration of MUC5AC may be an early and sensitive biomarker for smokers at risk of developing COPD. The researchers conducted a multicenter, observational study (SPIROMICS; ClinicalTrials.gov Identifier: NCT01969344) to determine the relative contribution of MUC5AC and MUC5B in COPD initiation, progression, and early diagnosis. The mucins were quantified using stable isotope-labelled mass spectrometry from collected sputum samples from healthy individuals who had never smoked, individuals who had ever smoked who were at risk for COPD, and individuals who had ever smoked who had COPD.

A total of 331 people (mean age, 63 years) were included in the study: 40 patients were healthy participants who never smoked, 90 participants were ever smokers who were at risk for COPD, and 201 participants were ever smokers with COPD.

In healthy never smokers, the mean concentration of MUC5B was about 8 times greater than the concentration of MUC5AC. The calculated ratio of MUC5AC to MUC5B was 0.14. Compared with healthy never smokers, ever-smokers with COPD had an average concentration of MUC5AC approximately 6 times higher, an average concentration of MUC5B was about 5 times higher, and the ratio of MUC5AC to MUC5B was 0.6.

Following multivariate analysis, the researchers found that MUC5AC concentration (P <.0001), MUC5B concentration (P =.038), and the ratio of MUC5AC to MUC5B (P =.0002) were all significantly associated with smoking status and COPD status; however, age, sex, BMI, chronic bronchitis, emphysema, and asthma status were not significantly associated with these mucin concentrations.

In testing lung function, participants were divided into MUC5AC to MUC5B terciles. It was observed that participants in the MUC5AC high tercile group had significantly lower mean forced expiratory volume at 1 second (FEV₁) compared with participants in low (P =.008) and mid (P =.017) tercile groups. The ratio of FEV₁ to forced vital capacity (FVC) was similarly low in patients in the high MUC5AC tercile group; however no significant changes were observed in the MUC5B terciles. 

Current smokers who were at risk for COPD had elevated concentrations of MUC5AC at their initial visits with decreasing lung function at 3-year follow-up; however, former smokers who were at risk for COPD had normal MUC5AC concentrations at their initial visit and preserved lung function over the 3-year follow-up.

“The greater dynamic range of MUC5AC concentrations in response to cigarette smoke and chronic bronchitic symptoms compared with MUC5B suggests that MUC5AC could provide a novel and disease-associated biomarker to detect at-risk and pre-COPD individuals,” wrote the study authors. “Increased MUC5AC concentrations may also add an important pathobiological component to COPD initiation and progression over and above increased total mucin or MUC5B concentrations.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Radicioni G, Ceppe A, Ford AA, et al. Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort. Lancet Respir Med. Published online May 28, 2021. doi:10.1016/S2213-2600(21)00079-5