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Immunomodulatory Effects of Ambroxol on Airway Hyperresponsiveness and Inflammation

  • Katsuyuki Takeda (Division of Cell Biology, Department of Pediatrics, National Jewish Health) ;
  • Nobuaki Miyahara (Division of Cell Biology, Department of Pediatrics, National Jewish Health) ;
  • Shigeki Matsubara (Division of Cell Biology, Department of Pediatrics, National Jewish Health) ;
  • Christian Taube (Division of Cell Biology, Department of Pediatrics, National Jewish Health) ;
  • Kenichi Kitamura (Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) ;
  • Astushi Hirano (Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) ;
  • Mitsune Tanimoto (Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences) ;
  • Erwin W. Gelfand (Division of Cell Biology, Department of Pediatrics, National Jewish Health)
  • Received : 2016.02.12
  • Accepted : 2016.05.27
  • Published : 2016.06.30
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Abstract

Ambroxol is used in COPD and asthma to increase mucociliary clearance and regulate surfactant levels, perhaps through anti-oxidant and anti-inflammatory activities. To determine the role and effect of ambroxol in an experimental model of asthma, BALB/c mice were sensitized to ovalbumin (OVA) followed by 3 days of challenge. Airway hyperresponsiveness (AHR), lung cell composition and histology, and cytokine and protein carbonyl levels in bronchoalveolar lavage (BAL) fluid were determined. Ambroxol was administered either before the first OVA challenge or was begun after the last allergen challenge. Cytokine production levels from lung mononuclear cells (Lung MNCs) or alveolar macrophages (AM) were also determined. Administration of ambroxol prior to challenge suppressed AHR, airway eosinophilia, goblet cell metaplasia, and reduced inflammation in subepithelial regions. When given after challenge, AHR was suppressed but without effects on eosinophil numbers. Levels of IL-5 and IL-13 in BAL fluid were decreased when the drug was given prior to challenge; when given after challenge, increased levels of IL-10 and IL-12 were detected. Decreased levels of protein carbonyls were detected in BAL fluid following ambroxol treatment after challenge. In vitro, ambroxol increased levels of IL-10, IFN-γ, and IL-12 from Lung MNCs and AM, whereas IL-4, IL-5, and IL-13 production was not altered. Taken together, ambroxol was effective in preventing AHR and airway inflammation through upregulation of Th1 cytokines and protection from oxidative stress in the airways.

Keywords

Acknowledgement

This study was supported by National Institute of Health grant HL-36577 (to E.W.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. The authors thank Diana Nabighian for assistance in preparing the manuscript.

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