Increase, Mucin production leads to Decreased lung function

Physiological response to stressors that increase mucin production often is resolved after stressor exposure is eliminated, and the normal function of the airway is restored. For this KER to occur, sustained mucin production should ensue. Moreover, the KER is based on assumption that increased mucin production logically leads to mucin hypersecretion. However, when mucin secretion is inhibited (e.g. through MANS peptide (Singer et al. 2004)), increase in mucin production might not translate into mucin hypersecretion. A study of endobronchial biopsies from patients with mild and moderate asthma showed an increase in stored mucin compared with healthy controls. Stored mucin levels were similar in mild and moderate asthma patients, however secreted mucin was significantly lower in mild asthma patients than in moderate asthma patients (28.4 ± 6.3 versus 73.5 ± 47.5 µg/ml). These data add uncertainty to the KER by signifying the role of mucin secretion which is needed for downstream KE to occur (Ordoñez et al. 2001).  

The evidences below are correlative and are not sufficient to conclude on causality of the KER. 

• COPD patients with decreased lung function had increased mucin expression. MUC5AC protein levels detected by immunohistochemistry were significantly higher (0.27%±0.09%) in COPD group compared with non-COPD group (0.20%±0.10%) Similarly, histopathological analysis of goblet cells with AB/PAS staining (detection of mucus glycoconjugates) revealed significantly higher amount of goblet cells (0.20%±0.10%) in COPD group than in the non-COPD group (0.13%±0.06%). Lung function tests operated on patients indicated significantly lower FEV1/FVC ratio and FEV1% in COPD group (FEV1/FVC: 63.78% ±6.60%, FEV1%: 77.56%±12.74%) compared to non-COPD group (FEV1/FVC:  79.80%±4.47%, FEV1%: 92.05%±15.17%). (Ma et al. 2005). 

• The area occupied by AB/PAS stained cells in the bronchial submucosal glands was significantly increased in COPD patients [20% (5.5–31.7%) gland area] in comparison to smokers with normal lung function [9.5% (2.5–17.5%)] and non-smokers [2% (0.4–6.2%)]. The area occupied by MUC5AC stained cells in the bronchial epithelium was also increased in smokers (with ⁄ without COPD) [73.5% (25–92%) epithelial area] compared with non-smokers [15% (2.7–32%)]. MUC5AC expression inversely correlated with FEV1 (% of predicted), indicating a potential role of MUC5AC in the pathogenesis of airflow obstruction in COPD (Caramori et al. 2009). 

• Following exposure to smoke from 3R4F research cigarettes for 1 h twice daily for 6 months, ferrets showed increased mucin production, increased number of goblet cells and chronic mucus hypersecretion (histology, PAS staining, MUC5AC and MUC5B staining). Mucus expression measured by PAS-positive goblet cell area, normalized by the size of the airway lumen to account for cell variation due to airway diameter, was 60% higher in smoke-exposed than in air-exposed animals (0.042% ± 0.025% smoke vs. 0.025% ± 0.013% air control). Inspiratory capacity, a sensitive marker of airway obstruction, was significantly reduced in smoke-exposed ferrets (79.5 ± 9.4 mL vs. 85.9 ± 5.9 mL air control) (Raju et al. 2016). 

• Increased MUC5AC concentration in sputum was associated with lung function decrease parameters such as decreased FEV1, FEF25-75%, RV/TLC. Statistical modelling of 3-year longitudinal data indicated that baseline MUC5AC (but not MUC5B) concentration is a significant predictor for lung function decrease (FEV1 (p=0.010), FEV1/FVC (p=0.013), FEF25–75% (p=0.0005), FVC (p=0.14), CAT (COPD assessment test) score decline (p<0.0001)). Current smokers at-risk for COPD with raised baseline visit MUC5AC concentrations showed decline in lung function over 4 years whereas former smokers at-risk for COPD with normal baseline MUC5AC concentrations did not show lung function decline during the same observational period (Radicioni et al. 2021). 

• AECOPD rat model showed declines in lung function parameters such as forced expiratory volume in 0.3 second (FEV0.3), FEV0.3/FVC% and maximal voluntary ventilation MVV (P < 0.01) measured with pulmonary functionality test machine AniRes2005. AB/PAS-staining in rat airway epithelium was 18.73 ± 2.38% compared to 0.02 ± 0.02% in control animals. Similarly, MUC5AC mRNA and protein levels were increased in AECOPD rats. Administration of LQZS to AECOPD rats decreased AB/PAS staining to 1.49 ± 1.18%, abolished AECOPD-related MUC5AC mRNA and protein upregulation, and resulted in improved MVV parameter (Feng et al. 2019). 

An observational longitudinal study showed that raised MUC5AC concentrations at initial monitoring visit of smokers at-risk for COPD resulted in significant lung function decline (FEV1) over 4 years (Radicioni et al. 2021). 

In longitudinal follow-up studies of patients with chronic mucus hypersecretion an excess decline in FEV1 was recognized throughout years, suggesting that mucus hypersecretion may lead to progressive lung function decline in time (Sherman et al. 1992; Vestbo, Prescott, and Lange 1996). An analysis of the National Survey of Health and Development (NSHD) data indicated that chronic mucus hypersecretion was associated with smoking status, and that the longer it was present, the faster was the decline in FEV1, corresponding to an additional decrement of 3.6 ± 2.5 ml/yr per occasion (Allinson et al. 2016). 

Generally, it is observed that the prevalence of chronic mucus hypersecretion increases with age (Viegi et al. 2007) indicating that long-term exposures are needed for the stressor-induced increase in mucin production to develop into chronic mucus hypersecretion with an eventual risk of lung function decline.