Cyclic nucleotide phosphodiesterase inhibitors as therapeutic interventions for cystic fibrosis.

Cystic Fibrosis (CF) lung disease results from mutations in the CFTR anion channel that reduce anion and fluid secretion by airway epithelia. Impaired secretion compromises airway innate defence mechanisms and leads to bacterial colonization, excessive inflammation and tissue damage; thus, restoration of CFTR function is the goal of many CF therapies. CFTR channels are activated by cyclic nucleotide-dependent protein kinases. The second messengers 3'5'-cAMP and 3'5'-cGMP are hydrolysed by a large family of cyclic nucleotide phosphodiesterases that provide subcellular spatial and temporal control of cyclic nucleotide-dependent signalling. Selective inhibition of these enzymes elevates cyclic nucleotide levels, leading to activation of CFTR and other downstream effectors. Here we examine members of the PDE family that are likely to regulate CFTR-dependent ion and fluid secretion in the airways and discuss other actions of PDE inhibitors that can influence cyclic nucleotide-regulated mucociliary transport, inflammation and bronchodilation. Finally, we review PDE inhibitors and the potential benefits they could provide as CF therapeutics.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest M.J.T. previously received salary support from Verona Pharma plc, which is evaluating Ensifentrine as a first-in-class, inhaled, dual inhibitor of PDE3 and PDE4 for the treatment of COPD, asthma and CF. K. A.-B. was previously employed by Verona Pharma and holds shares in the company and is currently Discovery Medicine Scientist Director, Discovery Medicine, GlaxoSmithKline plc. J.W.H. has received research funding from Verona Pharma. K.A.-B., D.Y.T. and J.W.H. are co-inventors on patent WO2015173551A1. None of the views expressed in this review were influenced by Verona Pharma plc or GSK plc.