NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells.

RATIONALE: Goblet cell hyperplasia (GCH) is one of the cardinal features of chronic obstructive pulmonary disease (COPD) and contributes to airways obstruction. Rhinovirus (RV), which causes acute exacerbations in patients with COPD, also causes prolonged airways obstruction. Previously, we showed that RV enhances mucin gene expression and increases goblet cell number in a COPD mouse model. This study examines whether RV causes sustained GCH in relevant models of COPD. METHODS: Mucociliary-differentiated COPD and normal airway epithelial cell cultures and mice with normal or COPD phenotype were infected with RV or sham and examined for GCH by immunofluorescence and/or mucin gene expression. In some experiments, RV-infected COPD cells and mice with COPD phenotype were treated with γ-secretase inhibitor or interleukin-13 neutralising antibody and assessed for GCH. To determine the contribution of NOTCH1/3 in RV-induced GCH, COPD cells transduced with NOTCH1/3 shRNA were used. RESULTS: RV-infected COPD, but not normal cell cultures, showed sustained GCH and increased mucin genes expression. Microarray analysis indicated increased expression of NOTCH1, NOTCH3 and HEY1 only in RV-infected COPD cells. Blocking NOTCH3, but not NOTCH1, attenuated RV-induced GCH in vitro. Inhibition of NOTCH signalling by γ-secretase inhibitor, but not neutralising antibody to IL-13, abrogated RV-induced GCH and mucin gene expression. CONCLUSIONS: RV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD.

Rhinovirus and COPD airway epithelium.

Chronic Obstructive Pulmonary Disease (COPD) is characterized by irreversible airflow limitation. It is a global disease and expected to be the third leading cause of death. Respiratory exacerbations are associated with increased mortality and morbidity in this patient population. Respiratory viruses were isolated from at least 30 to 50% of the infectious respiratory COPD exacerbations with rhinovirus being most commonly isolated pathogen. Although rhinovirus does not cause airway epithelial damage like influenza and other respiratory viruses, it may further impair innate immunity of airway epithelium, which is the first line of defense in the lungs. This may increase susceptibility to secondary bacterial infections leading to progression of lung disease. Currently, there arc no therapies available to treat rhinovirus infection in COPD and therefore understanding the mechanisms underlying RV pathogenesis in COPD is essential to identify molecular target to develop new therapeutic strategies. Quercetin, a plant polyphenol, which modulates innate immunity and effectively blocks viral replication may be useful in treating rhinovirus associated COPD exacerbations.