Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
Pharmacy Unit, Consorcio Hospital General Universitario, Avenida tres cruces s/n, 46014, Valencia, Spain.
Sci Rep. 2022 Mar 24;12(1):5132. doi: 10.1038/s41598-022-09241-6.
Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM-1 µM), fluticasone propionate (0.1 nM-1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate.
非 T2 严重哮喘和慢性阻塞性肺疾病（COPD）是气道慢性炎症性疾病，对皮质类固醇反应不佳。LAS194046 是一种新型的泛 Janus 激酶（JAK）抑制剂，对大鼠 T2 过敏性肺炎症具有抑制作用。在这项工作中，我们分析了 LAS194046、丙酸氟替卡松及其组合在非 T2 严重哮喘和 COPD 患者体外中性粒细胞中的作用。将来自 23 名健康受试者、23 名 COPD 和 21 名非 T2 严重哮喘患者的中性粒细胞与 LAS194046（0.01 nM-1 μM）、丙酸氟替卡松（0.1 nM-1 μM）或其组合孵育，并刺激用脂多糖（LPS 1 μM）。LAS194046 在来自健康、COPD 和哮喘的中性粒细胞中显示出相似的最大 %抑制作用和抑制白细胞介素-8、MMP-9 和超氧阴离子释放的效力。丙酸氟替卡松仅抑制来自健康患者中性粒细胞的介质释放。LAS194046 与丙酸氟替卡松的组合显示出协同的抗炎和抗氧化作用。这种组合协同作用的机制包括增加 MKP1 表达、减少 PI3Kδ、诱导糖皮质激素反应元件以及减少 ERK1/2、P38 和 JAK2/STAT3 磷酸化，与单药治疗相比。总之，LAS194046 对 COPD 和非 T2 严重哮喘患者的中性粒细胞具有抗炎作用，并与丙酸氟替卡松联合使用时诱导协同抗炎作用。
