Inhalation of ambroxol inhibits cigarette smoke-induced acute lung injury in a mouse model by inhibiting the Erk pathway
Inhalation of ambroxol inhibits cigarette smoke-induced acute lung injury in a mouse model by inhibiting the Erk pathway
复制标题
吸入氨溴索通过抑制 Erk 通路抑制小鼠模型中香烟烟雾引起的急性肺损伤
DOI：
10.1016/j.intimp.2016.02.004
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发表时间：
2016-04-01
影响因子：
5.6
通讯作者：
Xie, Qiang-min
中科院分区：
文献类型：
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作者：
Ge, Ling-tian;Liu, Ya-nan;Xie, Qiang-min
口服和注射氨溴索已在临床上用于治疗气道疾病。然而，人们对其在吸入治疗中的潜力知之甚少。在本研究中，我们测试了氨溴索经静脉吸入的作用，并探讨了其潜在的工作机制。小鼠每天接触10支香烟，持续4天。吸入氨溴索溶液于香烟烟雾暴露前20分钟雾化。氨溴索对香烟烟雾提取物刺激NCI-H292细胞MUC5AC和促炎细胞因子表达的影响每天吸入氨溴索4天，剂量为3.75或7.5 mg/ml，持续20分钟，可抑制支气管肺泡灌洗液（BALF）和肺组织中中性粒细胞和巨噬细胞的积累，抑制肿瘤坏死因子(TNF)- α、CCL-2和ICC mRNA和蛋白水平的升高，但对白细胞介素(IL)-1 β无抑制作用。此外，3.75或7.5 mg/ml氨溴索促进气道黏膜纤毛清除，降低肺组织中BALF中的糖胺聚糖水平和MUC5AC mRNA水平。吸入氨溴索7.5 mg/ml的效果与氨溴索20 mg/kg静脉滴注和地塞米松0.5 mg/kg静脉滴注的效果相当。通过培养的肺上皮细胞，我们发现氨溴索2或20 μ M预处理可以抑制se诱导的MUC5AC、tnf - α、IL-1 β mRNA水平的上调，这是通过抑制Erk信号通路实现的。我们的研究结果表明，氨溴索作为吸入替代全身给药治疗COPD的有益效果。(C) 2016 Elsevier B.V.版权所有
Oral and injection administration of ambroxol has been clinically used to treat airway disease. However, little is known about its potentials in inhalation therapy. In present studies, we tested the effects of ambroxol by inhalation with intravenous administration, and explored the underlying working mechanism. The mice received 10 cigarettes exposure every day for 4 days. Inhaled solution of ambroxol was aerosolized 20 min before the exposure of cigarette smoke (CS). The effect of ambroxol on the expression of mucoprotein 5AC (MUC5AC) and pro-inflammatory cytokines in NCI-H292 cells stimulated with cigarette smoke extract (CSE). Four days of daily inhalation of ambroxol at 3.75 or 7.5 mg/ml for 20 min suppressed the accumulation of neutrophils and macrophages in the bronchoalveolar lavage fluid (BALF) and lung tissues, and inhibited increases in the mRNA and protein levels of tumor necrosis factor (TNF)-alpha, CCL-2 and ICC, but not interleukin (IL)-1 beta in the CS-exposed mice. Moreover, ambroxol at 3.75 or 7.5 mg/ml facilitated airway mucosa cilia clearance, reduced glycosaminoglycans level in BALF and MUC5AC mRNA levels in lung tissues. The effects of ambroxol by inhalation at 7.5 mg/ml was comparable to that of ambroxol at 20 mg/kg i.v. and dexamethasone at 0.5 mg/kg i.p. Using cultured lung epithelial cells, we demonstrated that pretreatment with ambroxol at 2 or 20 mu M inhibited the CSE-induced up-regulation of MUC5AC, TNF-alpha, IL-1 beta mRNA levels, which was through inhibiting Erk signaling pathway. Our results demonstrate the beneficial effects of ambroxol as an inhalation replace systemic administration for COPD therapy. (C) 2016 Elsevier B.V. All rights reserved.