Wang Meijia, Gao Pengfei, Wu Xiaojie, Chen Yuetao, Feng Yikuan, Yang Qun, Xu Yongjian, Zhao Jianping, Xie Jungang
Department of Respiratory and Critical Care Medicine, National Clinical Research Center of Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Respiratory, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Respir Res. 2016 Nov 16;17(1):153. doi: 10.1186/s12931-016-0462-0.
Steroid resistant (SR) asthma is characterized by persistent airway inflammation that fails to resolve despite treatment with high doses of corticosteroids. Furthermore, SR patient airways show increased numbers neutrophils, which are less responsive to glucocorticoid. The present study seeks to determine whether dexamethasone (DEX) has different effect on neutrophils from steroid sensitive (SS) asthmatics compared to SR asthmatics.
Adults with asthma (n = 38) were classified as SR or SS based on changes in lung FEV1% following a one-month inhaled corticosteroid (ICS) treatment. Blood samples were collected from all patients during their first visit of the study. Neutrophils isolated from the blood were cultured with dexamethasone and/or atopic asthmatic serum for 18 h. The mRNA expression of mitogen-activated protein kinase phosphatase-1 (MKP-1), a glucocorticoid transactivation target, and glucocorticoid-induced transcript 1 (GLCCI1), an early marker of glucocorticoid-induced apoptosis whose expression was associated with the response to inhaled glucocorticoids in asthma , was determined by real-time PCR, and ELISA was used to assess the pro-inflammatory cytokine IL-8 levels in the supernatant. Constitutive neutrophil apoptosis was detected by flow cytometry.
DEX significantly induced MKP-1 expression in both patients with SS and SR patients in a concentration-dependent manner, but greater induction was observed for SS patients at a low concentration (10 M). Asthmatic serum alone showed no MKP-1expression, and there was impaired induction of MKP-1 by DEX in SR asthma patients. The expression of GLCCI1 was not induced in neutrophils with DEX or DEX/atopic asthmatic serum combination. Greater inhibition of IL-8 production was observed in neutrophils from patients with SS asthma treated with DEX/atopic asthmatic serum combination compared with SR asthma patients, though DEX alone showed the same effect on neutrophils from SS and SR asthma patients. Meanwhile, DEX dependent inhibition of constitutive neutrophil apoptosis was similar between SS asthma and SR asthma patients.
DEX exerted different effects on neutrophils from patients with SS asthma and SR asthma, which may contribute to glucocorticoid insensitivity.
激素抵抗（SR）性哮喘的特征是尽管使用高剂量皮质类固醇进行治疗，但气道炎症仍持续存在。此外，SR患者气道中的中性粒细胞数量增加，且对糖皮质激素的反应性较低。本研究旨在确定与SR哮喘患者相比，地塞米松（DEX）对激素敏感（SS）哮喘患者的中性粒细胞是否有不同影响。
根据吸入皮质类固醇（ICS）治疗1个月后肺功能FEV1%的变化，将38例成年哮喘患者分为SR组或SS组。在研究的首次就诊时采集所有患者的血样。从血液中分离出的中性粒细胞与地塞米松和/或特应性哮喘血清一起培养18小时。通过实时PCR测定糖皮质激素反式激活靶点丝裂原活化蛋白激酶磷酸酶-1（MKP-1）和糖皮质激素诱导凋亡早期标志物糖皮质激素诱导转录物1（GLCCI1）的mRNA表达，GLCCI1的表达与哮喘患者对吸入糖皮质激素的反应相关，并用ELISA法评估上清液中促炎细胞因子IL-8水平。通过流式细胞术检测组成性中性粒细胞凋亡。
DEX以浓度依赖性方式显著诱导SS患者和SR患者中性粒细胞中MKP-1的表达，但在低浓度（10 μM）时，SS患者的诱导作用更强。单独的哮喘血清未显示MKP-1表达，且SR哮喘患者中DEX对MKP-1的诱导受损。DEX或DEX/特应性哮喘血清联合处理均未诱导中性粒细胞中GLCCI1的表达。与SR哮喘患者相比，DEX/特应性哮喘血清联合处理的SS哮喘患者中性粒细胞中IL-8产生的抑制作用更强，尽管单独的DEX对SS和SR哮喘患者的中性粒细胞显示出相同的作用。同时，SS哮喘和SR哮喘患者中DEX依赖性组成性中性粒细胞凋亡抑制作用相似。
DEX对SS哮喘患者和SR哮喘患者的中性粒细胞产生不同影响，这可能导致糖皮质激素不敏感。
