Roflumilast N-oxide combined with PI3Kδ inhibitor improves the phenotype of early-onset COPD

Background: Severe, early-onset COPD (Chronic Obstructive Pulmonary Disease) is characterized by a rapid decline in lung function at an early age with neutrophil over-activation. Roflumilast is approved as treatment for moderate and severe COPD at risk of exacerbation as add on therapy. Recent evidence indicates that the combination of PDE4 and PI3Kδ inhibitors show synergic anti-inflammatory properties. Objectives: To explore the effects from adding a selective PI3Kδ inhibitor to roflumilast N-oxide (RNO) in neutrophils isolated from peripheral blood of severe, early-onset COPD patients in in vitro models. Methods: Neutrophils were isolated from peripheral blood of 20 severe, early-onset COPD patients and stimulated with fMLP. Neutrophils were pre-incubated with RNO (0.1nM-1µM) and PI3Kδ inhibitor (5nM and 50nM) alone or combination. Chemotaxis, superoxide anion generation, neutrophil elastase and IL-8 releases were. measured. Results: RNO at 100nM and 1µM (but not at lower concentrations) significantly inhibited fMLP-induced superoxide anion generation, chemotaxis, IL-8 and elastase released by neutrophils isolated from early-onset COPD. PI3Kδ inhibitor at 50nM significantly inhibited fMLP-induced the inflammatory parameters involved in COPD. The combination of RNO (0.1nM) and PI3Kδ inhibitor (5nM) at non-effective concentrations showed synergic properties inhibiting neutrophil activation parameters in early-onset COPD patients. Conclusions: The combination of RNO with PI3kδ inhibitor show synergic activity inhibiting the characteristic “overactive” neutrophil phenotype of early-onset COPD patients.