Strategies to reduce excessive mucus secretion in airway inflammation

Pathologists have long felt that obstruction of small airways bymucus hypersecretion is a major cause of airflow obstruction leading to asphyxic death in asthma (1-3). Clinicians, in contrast, generally pay scant attention to this aspect of the asthma phenotype. The discrepancy in emphasis between clinicians and pathologists probably relates to the physical evidence witnessed by each: In the emergency room, the clinician observes a patient struggling to breathe but producing little or no sputum, while at autopsy, the pathologist grossly observes mucus plugs that protrude from airways of the sectioned lung and microscopically observes occlusion of small airways by secreted mucus (Fig. 1). For the clinician, the role of mucus hypersecretion in obstructed diseases of the airways is further confused by the weak relation between airflow obstruction and the volume of expectorated sputum in COPD patients (4-7). However, expectoratedsputum in COPD patients probably derives mostly from submucosal glands in the large airways. Excess mucus in large, central airways plays little role in airflow obstruction since it does not substantially reduce airway crosssectional area, and in any case it can be cleared by expectoration. Instead, airflow obstruction in COPD is generally felt to be due to a combination of dynamic small airway collapse (emphysema), fixed small airway narrowing due to inflammation and fibrosis (respiratory bronchiolitis), and small airway occlusion by mucus secreted from epithelial goblet cells (4-7). Thus, the mucus the clinician sees is not the mucus that causes airflow obstruction. In mouse models of airway inflammation, Evans et al.924.