Abstract
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac–/–) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.
Highlights
Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disorder punctuated by acute exacerbations that are frequently precipitated by rhinoviruses (RVs) [1, 2]
We initially evaluated the expression of the major mucin glycoproteins mucin 5AC (MUC5AC) and MUC5B in sputum samples obtained from patients with COPD during virus-associated, naturally occurring exacerbations in our community-based cohort study (Figure 1A)
Given that ELISA-based quantification of sputum mucins may be influenced by proteases present in sputum samples [14], we measured mucin expression by quantitative PCR in RNA extracted from sputum cells from the same individuals
Summary
Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disorder punctuated by acute exacerbations that are frequently precipitated by rhinoviruses (RVs) [1, 2]. Abnormalities in mucus secretion, including increased expression of the major airway mucins MUC5AC and MUC5B, are a cardinal feature of inflammatory airway diseases such as COPD [5–7]. The complexity of interactions between mucins and pathogens and how the perturbations in mucin expression that occur in COPD affect susceptibility to infection and subsequent exacerbations are poorly understood. Nor is it known whether inhibition of mucus production would be beneficial or harmful in the context of exacerbations
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