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 andin 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.