Vardenafil reduces macrophage pro-inflammatory overresponses in Cystic Fibrosis through PDE5- and CFTR-dependent mechanisms
(2017) Clinical Science — Vol. 131, n° 11, p. 1107-1121 (2017)
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- 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 immunomodulatory 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 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 CFTR and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil downregulated overresponses of the M1 markers, tumor 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.
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Noël, S., Panin, N., Beka, M., Dhooghe, B., Huaux, F., & Leal, T. (2017). Vardenafil reduces macrophage pro-inflammatory overresponses in Cystic Fibrosis through PDE5- and CFTR-dependent mechanisms. Clinical Science, 131(11), 1107-1121. https://doi.org/10.1042/CS20160749 (Original work published 2017)