Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria.
Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed, Graz, Austria.
Biochem Pharmacol. 2021 Oct;192:114690. doi: 10.1016/j.bcp.2021.114690. Epub 2021 Jul 16.
Eosinophilic asthma is increasingly recognized as one of the most severe and difficult-to-treat asthma subtypes. The JAK/STAT pathway is the principal signaling mechanism for a variety of cytokines and growth factors involved in asthma. However, the direct effect of JAK inhibitors on eosinophil effector function has not been addressed thus far.
Here we compared the effects of the JAK1/2 inhibitor baricitinib and the JAK3 inhibitor tofacitinib on eosinophil effector function in vitro and in vivo.
Differentiation of murine bone marrow-derived eosinophils. Migratory responsiveness, respiratory burst, phagocytosis and apoptosis of human peripheral blood eosinophils were assessed in vitro. In vivo effects were investigated in a mouse model of acute house dust mite-induced airway inflammation in BALB/c mice.
Baricitinib more potently induced apoptosis and inhibited eosinophil chemotaxis and respiratory burst, while baricitinib and tofacitinib similarly affected eosinophil differentiation and phagocytosis. Of the JAK inhibitors, oral application of baricitinib more potently prevented lung eosinophilia in mice following allergen challenge. However, both JAK inhibitors neither affected airway resistance nor compliance.
Our data suggest that the JAK1/2 inhibitor baricitinib is even more potent than the JAK3 inhibitor tofacitinib in suppressing eosinophil effector function. Thus, targeting the JAK1/2 pathway represents a promising therapeutic strategy for eosinophilic inflammation as observed in severe eosinophilic asthma.
嗜酸性粒细胞性哮喘越来越被认为是最严重和最难治疗的哮喘亚型之一。JAK/STAT 通路是参与哮喘的多种细胞因子和生长因子的主要信号转导机制。然而，迄今为止，尚未研究 JAK 抑制剂对嗜酸性粒细胞效应功能的直接影响。
本研究比较了 JAK1/2 抑制剂巴瑞替尼和 JAK3 抑制剂托法替尼对体外和体内嗜酸性粒细胞效应功能的影响。
鼠骨髓来源嗜酸性粒细胞的分化。体外评估人外周血嗜酸性粒细胞的迁移反应性、呼吸爆发、吞噬作用和凋亡。在 BALB/c 小鼠急性屋尘螨诱导的气道炎症模型中研究体内作用。
巴瑞替尼更有效地诱导凋亡，并抑制嗜酸性粒细胞趋化性和呼吸爆发，而巴瑞替尼和托法替尼对嗜酸性粒细胞分化和吞噬作用的影响相似。在 JAK 抑制剂中，巴瑞替尼口服给药在过敏原攻击后更有效地预防小鼠肺部嗜酸性粒细胞增多。然而，两种 JAK 抑制剂均不影响气道阻力或顺应性。
我们的数据表明，JAK1/2 抑制剂巴瑞替尼在抑制嗜酸性粒细胞效应功能方面甚至比 JAK3 抑制剂托法替尼更有效。因此，靶向 JAK1/2 通路可能是治疗严重嗜酸性粒细胞性哮喘中观察到的嗜酸性粒细胞炎症的一种有前途的治疗策略。
