Phosphodiesterase 4 (PDE4) inhibitors may be useful for treating cystic fibrosis (CF) and other respiratory diseases, according to a review article recently published in Cureus.

“The previous conclusion that PDE inhibitors are ineffective in restoring [cystic fibrosis transmembrane conductance regulator (CFTR)]-dependent ion transport in cystic fibrosis mutated cells was challenged by a recent study that demonstrated selective PDE4 inhibitor-associated amplification in the CFTR correctors and/or CFTR potentiators,” the authors explained.

Moreover, despite previous findings, research on roflumilast, the only currently approved second-generation PDE4 inhibitor, demonstrated its ability to activate CFTR channels in the epithelial cells of the human respiratory tract, implying a beneficial effect for patients with CF.

This systematic review included 11 articles regarding the therapeutic uses of PDE4 inhibitors in diseases related to the respiratory system other than chronic obstructive pulmonary disease. The authors reviewed articles published between 2017 and 2022, which were found using 4 different databases and included 8 literature reviews, 2 randomized controlled trials, and 1 systematic review and meta-analysis.

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The findings were especially favorable for asthma. For example, a selective PDE4 inhibitor, tanimilast, administered via inhalation, and a nonselective PDE4 and PDE3 inhibitor, ensifentrine, exhibited encouraging results. Similar outcomes could potentially occur in patients with CF and other respiratory diseases such as chronic cough and allergic rhinitis.

“The pathogenic role of neutrophil-derived free DNA, which is released in the form of extracellular traps (NETs), causing impaired lung function in CF, was the target mechanism in this study, and PDE4 inhibitors demonstrated significant control of NETosis of neutrophils migrated into the lungs,” the authors wrote.

These promising results should promote future studies assessing the effectiveness and safety of PDE4 inhibitors in patients with CF, the researchers wrote. Because CF is a chronic disease with challenging optimal treatment, developing new agents to aid in the prevention of complications associated with CF would be of great impact.


Goonathilake MR, Waqar S, George S, et al. Can phosphodiesterase 4 inhibitor therapy be used in respiratory diseases other than chronic obstructive pulmonary disease? Cureus. 2022;14(7):e27132. doi:10.7759/cureus.27132