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Type-4 Phosphodiesterase (PDE4) Blockade Reduces NETosis in Cystic Fibrosis.

Licia Totani¹, Concetta Amore¹, Antonio Piccoli¹

¹Laboratory of Vascular Biology and Pharmacology, Fondazione Mario Negri Sud, Santa Maria Imbaro (CH), Mozzagrogna, Italy.

Frontiers in Pharmacology

|September 27, 2021

Summary

Phosphodiesterase type 4 (PDE4) inhibitors reduce neutrophil extracellular trap (NET) release in cystic fibrosis (CF) models. This suggests PDE4 blockade is a promising therapeutic strategy for CF lung disease.

Keywords:

PDE4 inhibition cystic fibrosis lung damage neutrophil neutrophil extracellular traps

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Published on: October 18, 2024

Area of Science:

Immunology
Pharmacology
Pulmonology

Background:

Neutrophilic inflammation and neutrophil extracellular traps (NETs) are implicated in cystic fibrosis (CF) lung disease progression.
NETs, composed of neutrophil-derived free DNA, correlate with reduced lung function in CF patients.
Targeting NETosis in lung neutrophils presents a potential therapeutic avenue for CF.

Purpose of the Study:

To investigate the efficacy of phosphodiesterase type 4 (PDE4) inhibitors in controlling NETosis.
To assess PDE4 inhibition's effects on neutrophils from healthy individuals and CF patients in vitro.
To evaluate PDE4 inhibition's impact on NET accumulation and lung inflammation in a mouse model of Pseudomonas aeruginosa infection.

Main Methods:

In vitro studies using neutrophils from healthy volunteers and CF patients challenged with endotoxin.
In vivo studies involving aerosol treatment with roflumilast (a selective PDE4 inhibitor) in Pseudomonas aeruginosa-infected mice.
Measurement of free DNA in bronchoalveolar lavage fluid (BALF), histone H3 citrullination, and weight recovery in mice.

Main Results:

PDE4 blockade inhibited endotoxin-induced NET production in vitro, preserving neutrophil integrity and apoptosis.
The effects of PDE4 inhibitors were more pronounced in neutrophils from CF patients.
Roflumilast treatment significantly reduced free DNA and histone H3 citrullination in infected mice, improving weight recovery.

Conclusions:

PDE4 blockade effectively controls NETosis in vitro and in vivo in CF-relevant models.
Selective PDE4 inhibitors demonstrate therapeutic potential for managing CF lung disease.
Results support clinical trials to test PDE4 inhibitors for CF treatment.