Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells

Abstract.

Objectives and Design: The effects of the mucolytic agents ambroxol and N-acetylcystein (NAC) were studied on the release of histamine, leukotrienes, cytokines and superoxide anions from a variety of cells involved in the pathogenesis of allergic inflammation.¶Subjects: Mast cells were isolated from human adenoids and skin (n = 5–6). Basophils, monocytes and granulocytes were obtained from Buffy-coat blood obtained from healthy blood donors (n = 4–7) and enriched by density centrifugation.¶Treatment and Methods: Ambroxol or NAC were added to the cells for different periods before stimulation with various immunological and non-immunological secretagogues. Histamine release from mast cells, basophils and monocytes was assayed either by radioimmunoassay or spectrofluorometrically. LTC₄ (basophils), LTB₄ (neutrophil/eosinophil granulocytes or monocytes), IL-4 and IL-13 (basophils) were measured by ELISA.¶Results: Ambroxol inhibited histamine release by more than 50% from human adenoidal mast cells (1000 μM ambroxol) and skin mast cells (100 μM ambroxol) stimulated by Con A and compound 48/80, respectively. Ambroxol (100 μM) strikingly inhibited anti-IgE induced release of both histamine, LTC₄, IL-4 and IL-13 from basophils and reduced both histamine and LTB₄ release induced by C5a or Zymosan in monocytes. The drug also reduced LTB₄ and superoxide anion production in granulocytes stimulated by zymosan or fMLP. In all cell types studied, ambroxol was more efficacious following a short preincubation (5–15 min) of the drug with the cells before stimulation. In contrast, NAC produced no clear effects on any of the different cell types studied, regardless of the preincubation period, the concentration or the stimulus employed.¶Conclusions: Unlike NAC, ambroxol is able to not only inhibit acute mediator release from mast cells and leukocytes but also reduce immunomodulatory cytokine generation from basophils and may have beneficial effects in the treatment of allergic respiratory diseases.