噻托溴铵联合布地奈德福莫特罗对中度哮喘患者β2受体的调节作用

Tiotropium combined with budesonide formoterol regulates β2 receptor in moderate asthma patients:report of 84 cases

目的观察联合应用吸入性糖皮质激素/长效β2受体激动剂(inhaled corticosteroid/long-actingβ2agonist,ICS/LABA)和长效抗胆碱能拮抗剂(long-acting antimuscarinic agent,LAMA)对中度哮喘患者外周血淋巴细胞β2R的调节作用及意义。方法将初治中度持续性哮喘患者分为ICS/LABA组和ICS/LABA+LAMA组,给药前后测定肺功能、ACT评分及AQLQ评分,Western blot检测外周血淋巴细胞β2受体、M3受体、PLCβ1水平。结果84例患者给药24周时2组FEV1值、ACT评分、AQLQ评分均有明显提高,且ICS/LABA+LAMA组较ICS/LABA组改善更为显著(P<0.05)。Western blot检测结果显示,治疗24周后ICS/LABA组外周血淋巴细胞较治疗前β2AR水平略有下降(P>0.05);ICS/LABA+LAMA组外周血淋巴细胞β2AR水平较治疗前变化不大(P>0.05);ICS/LABA组外周血淋巴细胞M3R、PLCβ1蛋白表达水平较治疗前逐渐升高(P<0.05);ICS/LABA+LAMA组M3R、PLCβ1蛋白表达水平较治疗前明显降低(P<0.05)。结论β2受体激动剂的长期使用使哮喘患者出现气道高反应性增高、支气管保护效应下降、急性发作次数增加和病死率上升的现象,可能与M3R及其通路的活化/表达上调和β2受体出现脱敏有关,联合LAMA通过拮抗M3R有可能恢复对β2受体激动剂的敏感性,从而抵消由于β2受体脱敏和M3R及其通路活化引起的不良反应。

Objective To investigate the role of the combination of inhaled corticosteroid/long-acting β2 agonist （ICS/LABA） and long-acting anti-cholinergic drugs （LAMA） in regulation of peripheral blood lymphocytes from patients with moderate asthma. Methods A total of 84 moderate persistent asthma outpatients （with asthma over 1 year, 40%≤FEV1%≤60%） in the department of respiratory diseases, West China Hospital during November 2010 to December 2011 were randomly and equally divided into ICS/LABA group and ICS/LABA＋LAMA group. Pulmonary function, asthma control test （ACT） score and asthma quality of life questionnaire （AQLQ） score were measured before and after administration. Western blotting was used to analyze β2 receptor, M3 receptor and PLCβ1 in peripheral blood lymphocytes. Results The FEV1 value, ACT score, and AQLQ score of the 84 patients were significantly improved after 24 weeks’ administering in both groups. Meanwhile, ICS/LABA/LAMA group improved more significantly （P〈0.05 in all）. β2AR decreasing trend in ICS/LABA group was not obvious, the protein expression of M3R and PLCβ1 was increased, and in ICS/LABA/LAMA group, β2AR level was unchanged the M3R was significantly decreased, and PLCβ1 was noticeably increased. Long-term administration of β2 agonists may lead to the increased airway hyper-responsiveness, reduce bronchial protection effect, increase risks for acute exacerbation, and higher incidence of mortality. This phenomenon may be related to the activation or up-regulation of M3R and its pathway and desensitization of β2 receptors. Combining with LAMA, the sensitivity of β2 agonists might restore the antagonizing M3R, which therefore offset the adverse reactions caused by the desensitization of β2 receptor, as well as activation of M3R and its pathway.