Effect of roflumilast on airway remodeling in a murine model of chronic asthma

Abstract

Roflumilast is a selective phosphodiesterase-4 inhibitor that has anti-inflammatory effect in chronic obstructive pulmonary disease. However, little is known regarding the effect of roflumilast in chronic asthma. This study is aimed to evaluate the effects of roflumilast on airway inflammation and remodeling in a murine model of chronic asthma. Female BALB/c mice, 6 weeks of age, were used. We developed a mouse model of airway remodeling in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Roflumilast was administered orally starting on the 38 th day and 5 days a week thereafter for 3 months during the intranasal OVA challenge. A lung fibroblast cell line was used in the proliferation assay. Compared with control mice, mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling. Administration of roflumilast significantly inhibited eosinophilic inflammation and AHR. The levels of interleukin (IL)-4, IL-5, and IL-13 in the bronchoalveolar lavage (BAL) fluids were significantly lower in the roflumilast group. The level of hydroxyproline was also significantly lower in the roflumilast group. In vitro, roflumilast significantly inhibited stem cell factor (SCF) induced cell proliferation of fibroblasts. SCF concentration and mRNA expression also significantly decreased with roflumilast treatment. These results suggest that roflumilast administration modulates the airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge. The beneficial effects from roflumilast may be related with SCF/c-kit pathway.