Pharmacy Unit, Hospital Clínico Universitario, Valencia, Spain.
Health Research Institute INCLIVA, Valencia, Spain.
PLoS One. 2019 Jan 4;14(1):e0210188. doi: 10.1371/journal.pone.0210188. eCollection 2019.
Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and β2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and β2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and COPD patients were incubated with AZD8999 and fluticasone propionate, individually or in combination, for 1h followed by lipopolysaccharide (LPS) stimulation for 6h. The IL-8, MMP9, IL-1β, and GM-CSF release was measured in cell culture supernatants. AZD8999 shows ~ 50% maximum inhibitory effect and similar potency inhibiting the released cytokines in neutrophils from healthy and COPD patients. However, while fluticasone propionate suppresses mediator release in neutrophils from healthy patients, COPD neutrophils are less sensitive. The combination of non-effective concentrations of AZD8999 (0.01nM) with non-effective concentrations of fluticasone propionate (0.1nM) shows synergistic anti-inflammatory effects. The studied mechanisms that may be involved in the synergistic anti-inflammatory effects of this combination include the increase of glucocorticoid receptor (GR)α and MKP1 expression, the induction of glucocorticoid response element (GRE) activation and the decrease of ERK1/2, P38 and GR-Ser226 phosphorylations compared with monotherapies. In summary, AZD8999 shows anti-inflammatory effects in neutrophils from COPD patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate, supporting the use of MABA/ICS combination therapy in COPD.
最近的证据表明，AZD8999（LAS190792）是一种新型的毒蕈碱乙酰胆碱受体拮抗剂和β2-肾上腺素能受体激动剂（MABA），用于治疗慢性呼吸道疾病，通过作用于毒蕈碱乙酰胆碱受体和β2-肾上腺素能受体，对人支气管产生强大而持久的舒张作用。然而，AZD8999 单药治疗或与皮质类固醇联合治疗的抗炎作用尚不清楚。本研究旨在探讨 AZD8999 单药治疗和联合丙酸氟替卡松治疗对健康人和慢性阻塞性肺疾病（COPD）患者中性粒细胞的抗炎作用。健康人和 COPD 患者的外周血中性粒细胞分别与 AZD8999 和丙酸氟替卡松单独或联合孵育 1 小时，然后用脂多糖（LPS）刺激 6 小时。在细胞培养上清液中测量白细胞介素-8（IL-8）、基质金属蛋白酶 9（MMP9）、白细胞介素-1β（IL-1β）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的释放。AZD8999 对健康人和 COPD 患者中性粒细胞释放的细胞因子表现出约 50%的最大抑制作用和相似的抑制作用。然而，虽然丙酸氟替卡松能抑制健康患者中性粒细胞中介质的释放，但 COPD 患者的中性粒细胞敏感性较低。非有效浓度的 AZD8999（0.01nM）与非有效浓度的丙酸氟替卡松（0.1nM）联合使用具有协同抗炎作用。这种组合协同抗炎作用的研究机制可能包括增加糖皮质激素受体（GR）α和 MKP1 的表达，诱导糖皮质激素反应元件（GRE）的激活以及减少 ERK1/2、P38 和 GR-Ser226 的磷酸化，与单药治疗相比。总之，AZD8999 对 COPD 患者中性粒细胞具有抗炎作用，与丙酸氟替卡松联合使用时可诱导协同抗炎作用，支持在 COPD 中使用 MABA/ICS 联合治疗。
