Role for Mucin-5AC in Upper and Lower Airway Pathogenesis in Mice

Mucin-5AC (MUC5AC) is a major secreted mucin in pathogenic airways. To determine its role in mucus-related airway disorders, Muc5ac-deficient (Muc5ac^-/-) and wild-type (Muc5ac^+/+) mice were compared in bleomycin-induced pulmonary fibrosis, respiratory syncytial virus (RSV) disease, and ozone toxicity. Significantly greater inflammation and fibrosis by bleomycin were developed in Muc5ac^-/- lungs compared to Muc5ac^+/+ lungs. More severe mucous cell metaplasia in fibrotic Muc5ac^-/- lungs coincided with bronchial Muc2, Muc4, and Muc5b overexpression. Airway RSV replication was higher in Muc5ac^-/- than in Muc5ac^+/+ during early infection. RSV-caused pulmonary epithelial death, bronchial smooth muscle thickening, and syncytia formation were more severe in Muc5ac^-/- compared to Muc5ac^+/+. Nasal septal damage and subepithelial mucoserous gland enrichment by RSV were greater in Muc5ac^-/- than in Muc5ac^+/+. Ozone exposure developed more severe nasal airway injury accompanying submucosal gland hyperplasia and pulmonary proliferation in Muc5ac^-/- than in Muc5ac^+/+. Ozone caused periodic acid-Schiff-positive secretion only in Muc5ac^-/- nasal airways. Lung E-cadherin level was relatively lower in Muc5ac^-/- than in Muc5ac^+/+ basally and after bleomycin, RSV, and ozone exposure. Results indicate that MUC5AC is an essential mucosal component in acute phase airway injury protection. Subepithelial gland hyperplasia and adaptive increase of other epithelial mucins may compensate airway defense in Muc5ac^-/- mice.