title: Inhalation of ambroxol inhibits cigarette smoke-induced acute lung injury in a mouse model by inhibiting the Erk pathway.
abstract: 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 5 AC (MUC5AC) and proinflammatory cytokines in NCI-H292 cells stimulated with cigarette smoke extract (CSE). Four days of daily inhalation of ambroxol at 3.75 or 7.5mg/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)-α, CCL-2 and KC, but not interleukin (IL)-1β in the CS-exposed mice. Moreover, ambroxol at 3.75 or 7.5mg/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 7.5mg/ml was comparable to that of ambroxol at 20mg/kg i.v. and dexamethasone at 0.5mg/kg i.p. Using cultured lung epithelial cells, we demonstrated that pretreatment with ambroxol at 2 or 20 μM inhibited the CSE-induced up-regulation of MUC5AC, TNF-α, IL-1β 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.
authors.affiliation: Medical College of Yangzhou University, 11 Huaihai Road, Yangzhou 225001, China; Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Ling-tian
authors.initials: LT
authors.lastname: Ge
authors.affiliation: Medical College of Yangzhou University, 11 Huaihai Road, Yangzhou 225001, China; Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Ya-nan
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Xi-xi
authors.initials: XX
authors.lastname: Lin
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Hui-juan
authors.initials: HJ
authors.lastname: Shen
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Yong-liang
authors.initials: YL
authors.lastname: Jia
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China.
authors.forename: Xin-wei
authors.initials: XW
authors.lastname: Dong
authors.affiliation: Medical College of Yangzhou University, 11 Huaihai Road, Yangzhou 225001, China. Electronic address: jgz7718@sina.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of China Food and Drug Administration, Medical Science College of Zhejiang University, Hangzhou 310058, China; Laboratory Animal Center of Zhejiang University, Hangzhou 310058, China. Electronic address: xieqm@zju.edu.cn.
authors.forename: Qiang-min
authors.initials: QM
authors.lastname: Xie
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000280:Administration, Inhalation; D000551:Ambroxol / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005100:Expectorants / Q000627:therapeutic use*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009079:Mucociliary Clearance / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D012907:Smoking / Q000009:adverse effects
chemical_list: D016207:Cytokines; D005100:Expectorants; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D000551:Ambroxol
keywords: Airway inflammation; Ambroxol; Drug delivery; Mucokinetic activity