Vardenafil reduces macrophage pro-inflammatory overresponses in cystic fibrosis through PDE5- and CFTR-dependent mechanisms.

Chronic inflammation that progressively disrupts the lung tissue is a hallmark of cystic fibrosis (CF). In mice, vardenafil, an inhibitor of phosphodiesterase type 5 (PDE5), restores transepithelial ion transport and corrects mislocalization of the most common CF mutation, F508del-CFTR. It also reduces lung pro-inflammatory responses in mice and in patients with CF. To test the hypothesis that macrophages are target effector cells of the immunomo-dulatory effect of vardenafil, we isolated lung macrophages from mice homozygous for the F508del mutation or invalidated for the cftr gene and from their corresponding wild-type (WT) littermates. We then evaluated the effect of vardenafil on the classical M1 polarization, mirroring release of pro-inflammatory cytokines. We confirmed that macrophages from different body compartments express CF transmembrane conductance regulator (CFTR) and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil down-regulated overresponses of the M1 markers, tumour necrosis factor (TNF)-α and inducible nitric oxide synthase (NOS)-2. Our study identifies lung macrophages as target cells of the anti-inflammatory effect of vardenafil in CF and supports the view that the drug is potentially beneficial for treating CF as it combines rescue of CFTR protein and anti-inflammatory properties.