The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

Abstract

In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucus occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma

“…We conducted the PAS staining for mucin after BAL and after methacholine challenge. In this context, it was previously demonstrated, using quantitative morphometry, that there is an acute decrease in mucin content in the epithelium that represents the release of mucin from the epithelium (38). We found that there was a significant decrease in mucin staining relative to the epithelial area in the Pla2r1 2/2 mice relative to WT controls (P = 0.01, Figure 6A).…”

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…Goblet cell hyperplasia and mucus hypersecretion are important features in the conducting airways during allergic asthma, and extensive mucus plugging is associated with fatal asthma episodes (41). Animal models of allergic asthma support the critical role of the mucin gene Muc5ac in the development of mucus obstruction and airway hyperreactivity (42). The process of mucus hypersecretion during allergic asthma involves a complex multistep process, including mucin gene induction, mucus packaging in storage granules, mucus secretion, and changes in extracellular mucus viscosity.…”

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

“…Such a scenario could explain attenuation of AHR in Glrx1 2/2 mice, despite the apparent similar extent of overall mucus metaplasia. Previous studies have suggested that inflammation-triggered airway smooth muscle contraction alone is not sufficient for airway hyperreactivity to methacholine, and that noncontractile factors, such as mucus, are essential for AHR (29)(30)(31).…”