Roflumilast Ameliorates Airway Hyperresponsiveness Caused by Diet-Induced Obesity in a Murine Model

Abstract

Obese patients with asthma respond poorly to conventional asthma medications, resulting in severe symptoms and poor prognosis. Roflumilast, a phosphodiesterase-4 inhibitor that lowers the levels of various substances that are implicated in obese subjects with asthma, may be effective in the treatment of those subjects. We evaluated the potential of roflumilast as a novel therapeutic agent for obese subjects with asthma. We designed three models: diet-induced obesity (DIO); DIO with ovalbumin (OVA); and OVA. We fed C57BL/6J mice a high-fat diet for 3 months with or without OVA sensitization and challenge. Roflumilast or dexamethasone was administered orally three times at 2-day intervals in the last experimental week. Airway hyperresponsiveness resulting from DIO significantly improved in the roflumilast-treated group compared with the dexamethasone-treated groups. Although DIO did not affect the cell proliferation in bronchoalveolar lavage fluid, increased fibrosis was seen in the DIO group, which significantly improved from treatment with roflumilast. DIO-induced changes in adiponectin and leptin levels were improved by roflumilast, whereas dexamethasone aggravated them. mRNA levels and proteins of TNF-α, transforming growth factor-β, IL-1β, and IFN-γ increased in the DIO group and decreased with roflumilast. The reactive oxygen species levels were also increased in the DIO group and decreased by roflumilast. In the DIO plus OVA and OVA models, roflumilast improved Th1 and Th2 cell activation to a greater extent than dexamethasone. Roflumilast is significantly more effective than dexamethasone against airway hyperresponsiveness caused by DIO in the murine model. Roflumilast may represent a promising therapeutic agent for the treatment of obese patients with asthma.

Short‐term high‐fat diet feeding protects from the development of experimental allergic asthma in mice

“…Our study demonstrates that short‐term HFD feeding leads to a marked reduction of AHR in HFD/OVA compared to CD/OVA mice. However, PBS controls in both feeding groups did not augment AHR upon methacholine provocation indicating that short‐term HFD feeding and mild body weight gain alone are not sufficient to induce a non‐allergic form of asthma as opposed to obesity . While hyperinsulinaemia can aggravate the severity of AHR in obesity models, we found a decreased maximal response to methacholine upon HFD as compared with CD.…”

“…In the late‐onset non‐allergic phenotype of obesity‐associated asthma (LONA), airway hyperresponsiveness (AHR) is considered a consequence of lung compression and structural lung modifications due to increased body weight . Furthermore, animal models show that LONA is associated with T helper (Th)1‐ and Th17 aberrant immune responses . However, next to LONA, an early‐onset allergic form of obesity‐associated asthma has been described (EOA), which is characterized by a more classical allergen‐driven eosinophilia and Th2 differentiation without body weight‐induced modulations .…”

Hyperinsulinemia promotes heterologous desensitization of β2adrenergic receptor in airway smooth muscle in obesity

“…Other experimental models of lung diseases have shown that Roflu significantly attenuates lung fibrosis, ROS production, and adipokine and cytokine levels. These factors may also contribute to the amelioration of airway hyperresponsiveness during chronic therapy with Roflu . Another intriguing beneficial side effect clinically, is that Roflu may also provide relief of obesity‐associated asthma by inducing weight loss .…”

“…also reported that prostaglandin E 2 (PGE 2 )‐induced heterologous β 2 AR desensitization in ASM is mediated by upregulated phosphodiesterase (PDE4) expression . Furthermore, it has been recently reported that roflumilast (Roflu), a PDE4 inhibitor, ameliorates airway hyperresponsiveness caused by diet‐induced obesity in a murine model …”

Efficacy and safety of phosphodiesterase 4 inhibitors in patients with asthma: A systematic review and meta‐analysis

“…In our analysis, we also found that PDE4 inhibitors could improve AHR to different allergen provocations, but it did not attenuate methacholine PC 20 from baseline without allergen challenge, even if lung function improved. This might result from two possible causes: (i) the variable relationship between AHR and lung function and AHR often persisting, even when lung function returns to normal; or (ii) different asthma phenotypes such as obese patients with asthma in whom AHR was ameliorated after roflumilast treatment …”