Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
Autoimmunity and Vascular Inflammation Unit, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy.
Int J Mol Sci. 2022 Apr 29;23(9):4982. doi: 10.3390/ijms23094982.
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.
中性粒细胞是血液中最丰富的白细胞亚群，在宿主抵御入侵病原体的反应中发挥着关键作用。然而，在呼吸道疾病中，中性粒细胞的过度浸润和激活可导致组织损伤。替米司他（CHF6001 的国际非专利名）是一种新型的磷酸二酯酶 4（PDE4）抑制剂，目前处于临床开发的后期阶段，用于治疗慢性阻塞性肺疾病（COPD）。COPD 是一种慢性炎症性肺部疾病，中性粒细胞炎症在其中起着关键的病理作用。本研究采用健康供者的中性粒细胞，在存在或不存在替米司他和布地奈德（一种典型的吸入性皮质类固醇药物）的情况下，暴露于促炎刺激物中，以研究其对效应功能（包括与内皮细胞的黏附、颗粒蛋白胞吐、细胞外 DNA 陷阱释放、细胞因子分泌和细胞存活）的调节作用。替米司他可显著降低中性粒细胞-内皮细胞黏附、脱颗粒、细胞外 DNA 陷阱形成和细胞因子分泌。相反，它通过减少存活因子存在时的自发凋亡和细胞死亡，促进中性粒细胞存活。本研究提示，替米司他可减轻 COPD 等炎症性疾病中大量募集和激活中性粒细胞引起的严重组织损伤。
