Roflumilast ameliorates obesity-induced airway hyper-responsiveness and pulmonary fibrosis in a murine model

Abstract

Background: Obese asthma patients respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various cytokines and reactive oxygen species (ROS) which are implicated in obese asthmatics, may be effective to treat obese asthmatics.

Objectives: We evaluated the potential of roflumilast as a novel therapeutic agent for obese asthmatics.

Methods: We designed three models (diet-induced obesity [DIO], DIO with ovalbumin [OVA], and OVA). We fed C57BL/6J mice a high-fat (60%) diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally thrice at 2-day intervals at the last experimental week. Airway hyper-responsiveness (AHR), bronchoalveolar fluid (BALF), lung pathology, mRNA and protein levels of cytokines and adipokines, ROS levels, and T cell activation were evaluated.

Results: AHR resulting from DIO significantly improved in the roflumilast-treated group, compared with dexamethasone-treated groups. Although DIO did not affect the cell proliferation in BALF, increased fibrosis was seen in the DIO group, which significantly improved by the treatment of roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, while dexamethasone aggravated them. Messenger RNA levels and proteins of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-1β, and interferon (IFN)- γ increased in the DIO group, and decreased by roflumilast. The ROS levels was also increased in the DIO group, and decreased by roflumilast. In the DIO-with-OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone.

Conclusions: Roflumilast is significantly more effective than dexamethasone against AHR and fibrosis caused by DIO in the murine model, as roflumilast treatment led to improved levels of adiponectin, leptin, TNF-α, TGF-β, IL-1β, IFN- γ and ROS. Roflumilast may represent a promising therapeutic agent for the treatment of obese asthma patients.