Abstract
Background and Purpose: Neutrophilic inflammation is a key determinant
of cystic fibrosis (CF) lung disease. Neutrophil-derived free DNA,
released in form of extracellular trap (NETs), significantly correlates
with impaired lung function in patients with CF, underlying their
pathogenetic role in CF lung disease. Thus, specific approaches to
control NETosis of neutrophils migrated into the lungs may be clinically
relevant in CF. Experimental Approach: We investigated the efficacy of
phosphodiesterase (PDE) type-4 inhibitors, in vitro, on NETs release by
neutrophils from healthy volunteers and individuals with CF, and in
vivo, on NETs accumulation and lung inflammation in mice infected with
Pseudomonas aeruginosa. Key Results: PDE4 blockade curbed
endotoxin-induced NETs production and preserved cellular integrity and
apoptosis in neutrophils, from healthy subjects and patients with CF,
challenged with endotoxin, in vitro. The pharmacological effects of PDE4
inhibitors were significantly more evident on CF neutrophils. In a mouse
model of Pseudomonas aeruginosa chronic infection, aerosol treatment
with roflumilast, a selective PDE4 inhibitor, gave a significant
reduction in free-DNA in BALF. This was accompanied by reduced
citrullination of Histone H3 in neutrophils migrated into the airways.
Roflumilast-treated mice showed a significant improvement in weight
recovery. Conclusions and Implications: Our study provides the first
evidence that PDE4 blockade controls NETosis in vitro and in vivo, in CF
relevant models. Since selective PDE4 inhibitors have been recently
approved for the treatment of COPD and psoriasis, our present results
encourage clinical trials to test the efficacy of this class of drugs in
CF.