Role of Mucin 5ac in Murine Airways

Abstract

Mucin is a highly glycosylated protein in epithelial lining of respiratory, gastrointestinal, and reproductive tracts. To determine the role of Muc5ac, the major secreted airway mucin, in respiratory pathogenesis, Muc5ac‐deficient mice (Muc5ac‐/‐), generated by deletion of exons 21‐31 encoding the glycosylation region, and wild type controls (Muc5ac+/+) were examined in models of respiratory syncytial virus (RSV) disease (intranasal infection, 106 plaque forming unit RSV/mouse) and pulmonary fibrosis (intratracheal instillation, 0.5 U bleomycin/Kg body weight). Phenotypes were assessed by histopathologic and bronchoalveolar lavage analyses. Reduced levels of intraepithelial mucus from nasal to bronchial airways, atrophic maxilloturbinates, and enriched nasal glands were manifest in Muc5ac‐/‐, compared to Muc5ac+/+. In Muc5ac‐/‐, RSV caused more severe nasal airway injuries including subepithelial congestion and gland secretion and compensatory increase of mucus secretion than in Muc5ac+/+ at 1‐5 d post‐infection. Bronchoepithelial injury and hyperplasia/hyperproliferation as well as pulmonary perivascular‐peribronchiolar edema and smooth muscle thickening were more evident in Muc5ac‐/‐ relative to Muc5ac+/+ at 1‐5 d post‐infection. Serum IgE level was also significantly higher in Muc5ac‐/‐ than in Muc5ac+/+ at 5 d after infection. Muc5ac‐/‐ exhibited significantly more severe pulmonary inflammation than Muc5ac+/+ at 7‐14 d post‐bleomycin. Overall, lack of epithelial barrier component Muc5ac impaired the airway defense against virus and fibrogen, and caused compensatory regulation of other secretory proteins. Supported by the NIEHS Intramural Program.