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

Frontiers in Pharmacology

Paolo Moretti¹  Alessandra Bragonzi²  Ida De Fino²  Alice Rossi²  Serena Ranucci²  Romina Pecce³  Mario Romano³  Roberto Plebani³  Licia Totani⁴  Antonio Piccoli⁴  Virgilio Evangelista⁴  Giuseppe Dell’Elba⁴  Nicola Martelli⁴  Concetta Amore⁴  Angelo Di Santo⁴ 

[1] Cystic Fibrosis Centre, S. Liberatore Hospital, Atri, Italy;Infection and Cystic Fibrosis Unit, Division of Immunology Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy;Laboratory of Molecular Medicine, Centre for Advanced Studies and Technology (CAST), Department of Medical Oral and Biotechnological Sciences, G. D’Annunzio University of Chieti-Pescara, Chieti, Italy;Laboratory of Vascular Biology and Pharmacology, Fondazione Mario Negri Sud, Santa Maria Imbaro (CH), Mozzagrogna, Italy;

关键词: cystic fibrosis;    neutrophil;    neutrophil extracellular traps;    lung damage;    PDE4 inhibition;   

DOI  :  10.3389/fphar.2021.702677

来源: DOAJ

【 摘 要 】

Neutrophilic inflammation is a key determinant of cystic fibrosis (CF) lung disease. Neutrophil-derived free DNA, released in the form of extracellular traps (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. We investigated the efficacy of phosphodiesterase (PDE) type-4 inhibitors, in vitro, on NET release by neutrophils from healthy volunteers and individuals with CF, and in vivo, on NET accumulation and lung inflammation in mice infected with Pseudomonas aeruginosa. PDE4 blockade curbed endotoxin-induced NET 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 the 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. 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.

【 授权许可】

Unknown