title: Ambroxol inhalation ameliorates LPS-induced airway inflammation and mucus secretion through the extracellular signal-regulated kinase 1/2 signaling pathway.
abstract: Ambroxol, a metabolite of bromhexine, is shown to exert several pharmacological activities, including secretolytic, anti-inflammatory and antioxidant actions. Oral and intravenous administration of ambroxol is useful for the airway inflammatory diseases. However, little is known about its potential in inhalation therapy for lipopolysaccharide (LPS)-induced mucous hypersecretion and inflammatory response. In the present study, we compared the pharmacological effects of ambroxol by inhalation with intravenous administration and preliminarily explored its mechanism of action. Our results demonstrated that ambroxol administered by inhalation inhibited MUC5AC expression, reduced glycosaminoglycan levels, enhanced the function of mucociliary clearance and promoted sputum excretion, suggesting that ambroxol increases expectoration of sputum by reducing its viscosity. Moreover, ambroxol significantly alleviated LPS-induced the influx of inflammatory cells and the extracellular signal-regulated kinase 1/2 (Erk 1/2) expression in lung tissues, and inhibited increases in the mRNA expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, CCL-2 (monocyte chemotactic protein-1), KC (keratinocyte cell protein) and interleukin (IL)-1β in lung tissues. The secretolytic and anti-inflammatory effects of inhaled ambroxol at a dose of 7.5 mg/ml was comparable to that of ambroxol at 20 mg/ml i.v. and dexamethasone at 0.5 mg/kg i.p. In addition, we found that ambroxol dose-dependently inhibited LPS-induced increases in the mRNA expression of MUC5AC, TNF-α, and IL-1β in human bronchial epithelial cell (NCI-H292) by inhibiting the Erk signaling pathway. These results demonstrate the beneficial effects of ambroxol in inhalation therapy for the airway inflammatory diseases.
authors.affiliation: Department of Pharmacy, Zhejiang Chinese Medical University, # 548 Binwen Rd., Hangzhou 310053, China.
authors.forename: Shui-juan
authors.initials: SJ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Juan-xia
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Department of Pharmacy, Zhejiang Chinese Medical University, # 548 Binwen Rd., Hangzhou 310053, China.
authors.forename: Qian-qian
authors.initials: QQ
authors.lastname: Ren
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Yong-liang
authors.initials: YL
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Hui-juan
authors.initials: HJ
authors.lastname: Shen
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Xi-xi
authors.initials: XX
authors.lastname: Lin
authors.affiliation: Department of Pharmacy, Zhejiang Chinese Medical University, # 548 Binwen Rd., Hangzhou 310053, China. Electronic address: luhong03@hotmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhejiang University School of Medicine, # 866 Yuhangtang Rd., 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* / Q000276:immunology / Q000378:metabolism; D000280:Administration, Inhalation; D000551:Ambroxol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D005100:Expectorants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008813:Mice, Inbred ICR; D055271:Mucin 5AC / Q000235:genetics; D009079:Mucociliary Clearance / Q000187:drug effects; D009093:Mucus / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005100:Expectorants; D006025:Glycosaminoglycans; D008070:Lipopolysaccharides; C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D012333:RNA, Messenger; D000551:Ambroxol
keywords: Airway inflammatory diseases; Ambroxol; Anti-inflammation; Drug delivery; Lipopolysaccharide; Mucokinetic activity