In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism

Authors

  • Luciano Ottonello,

    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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  • Nicoletta Arduino,

    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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  • Maria Bertolotto,

    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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  • Patrizia Dapino,

    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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  • Marina Mancini,

    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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  • Franco Dallegri

    Corresponding author
    1. Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy
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    • 2

      Current address: Dipartimento di Medicina Interna e Specialita Mediche, Universita degli Studi di Genoa, Viale Benedetto XV, n.6, I-16132 Genova, Italy


Department of Internal Medicine and Medical Specialties, University of Genova Medical School, Genova, Italy. E-mail: otto@unige.it

Abstract

  • Neutrophils are major culprits for the protease/antiprotease imbalance during various lung diseases, that is, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis and adult respiratory distress syndrome. Thus, these cells are presently considered an ideal target for the pharmacologic control of tissue injury during these diseases.

  • This study was planned in order to investigate if ambroxol and its precursor bromhexine are actually capable of preventing alpha-1-antitrypsin (A1AT) inactivation by stimulated neutrophils and possibly to look into the mechanisms underlying this event.

  • Ambroxol inhibited the production of superoxide anion by activated neutrophils, whereas bromhexine had no inhibitory effect.

  • Ambroxol decreased the production of hypochlorous acid (HOCl) from activated neutrophils with high efficiency, whereas bromhexine had a modest activity.

  • Ambroxol and bromhexine were capable of limiting the chlorination of monochlorodimedon by HOCl, displaying the capacity of directly scavenging the oxidant.

  • Ambroxol decreased the release of elastase and myeloperoxidase from activated neutrophils, whereas bromhexine was ineffective.

  • Ambroxol prevented the A1AT inactivation by neutrophils, whereas bromhexine was completely ineffective.

  • Among drugs currently available for in vivo use in humans, ambroxol is unique by virtue of its ability to prevent neutrophil-mediated A1AT inactivation via inhibition of HOCl production as well as HOCl scavenging. Also taking into account its capacity for curbing elastase release, the drug displays the potential to lessen the burden of oxidants/proteases and to increase the antiprotease shield at the site of inflammation. Thus, ambroxol appears to be a good candidate for raising attempts to develop new therapeutic histoprotective approaches to inflammatory bronchopulmonary diseases.

British Journal of Pharmacology (2003) 140, 736–742. doi:10.1038/sj.bjp.0705497

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