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The PDE4 Inhibitor Tanimilast Restrains the Tissue-Damaging Properties of Human Neutrophils

2022; Multidisciplinary Digital Publishing Institute; Volume: 23; Issue: 9 Linguagem: Inglês

10.3390/ijms23094982

1661-6596

Tiziana Schioppa, Hoang Oanh Nguyen, Valentina Salvi, Norma Maugeri, Fabrizio Facchinetti, Gino Villetti, Maurizio Civelli, Carolina Gaudenzi, Mauro Passari, Francesca Sozio, Ilaria Barbazza, Nicola Tamassia, Marco A. Cassatella, Annalisa Del Prete, Daniela Bosisio, Laura Tiberio,

S100 Proteins and Annexins

Neutrophils, the most abundant subset of leukocytes in the blood, play a pivotal role in host response against invading pathogens. However, in respiratory diseases, excessive infiltration and activation of neutrophils can lead to tissue damage. Tanimilast-international non-proprietary name of CHF6001-is a novel inhaled phosphodiesterase 4 (PDE4) inhibitor in advanced clinical development for the treatment of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease where neutrophilic inflammation plays a key pathological role. Human neutrophils from healthy donors were exposed to pro-inflammatory stimuli in the presence or absence of tanimilast and budesonide-a typical inhaled corticosteroid drug-to investigate the modulation of effector functions including adherence to endothelial cells, granule protein exocytosis, release of extracellular DNA traps, cytokine secretion, and cell survival. Tanimilast significantly decreased neutrophil-endothelium adhesion, degranulation, extracellular DNA traps casting, and cytokine secretion. In contrast, it promoted neutrophil survival by decreasing both spontaneous apoptosis and cell death in the presence of pro-survival factors. The present work suggests that tanimilast can alleviate the severe tissue damage caused by massive recruitment and activation of neutrophils in inflammatory diseases such as COPD.