Differential modulation of IgE-dependent activation of human basophils by ambroxol and related secretolytic analogues.
Ambroxol is a widely used secretolytic agent originally developed from vasicine, a natural alkaloid found in Adhatoda vasica, extracts of which have been used to treat bronchitis, asthma, and rheumatism. We previously reported that ambroxol inhibits IgE-dependent mediator secretion from human mast cells and basophils, key effector cells of allergic inflammation. Here, the mechanisms involved in the inhibitory properties of ambroxol were assessed in comparison to other secretolytic analogues (e.g. vasicine, bromhexine, sputolysin). The results show that, in comparison to ambroxol, which reduced IgE-dependent histamine release from basophils at 10 microM-1 mM, the release of the amine was only moderately reduced by sputolysin and vasicine at 1 mM. In contrast, above 10 microM, bromhexine was found to be toxic to basophils in vitro as evidenced by induction of histamine release and reduced cell viability. In contrast, the inhibitory actions of ambroxol at concentrations below 1 mM were not toxic and entirely reversible. Ambroxol was also more potent than either sputolysin or vasicine in attenuating basophil IL-4 and IL-13 secretions, whereas bromhexine-induced suppression of de novo cytokine synthesis was due to toxic effects. Additionally, ambroxol reduced IgE-dependent p38 MAPK phosphorylation in basophils, unlike bromhexine, sputolysin and vasicine. These results clearly show that ambroxol is both more potent and effective at inhibiting IgE-dependent basophil mediator release and p38 MAPK activity than the other secretolytic analogues employed. The therapeutic potential of ambroxol as an anti-allergic agent is further underlined by these data.
Gibbs
B F
BF
Department of Dermatology, University of Lübeck, Germany. B.F.Gibbs@kent.ac.uk
D000470:Alkaloids / Q000494:pharmacology; D000551:Ambroxol / Q000494:pharmacology* / Q000633:toxicity; D018926:Anti-Allergic Agents / Q000494:pharmacology* / Q000633:toxicity; D001491:Basophils / Q000187:drug effects* / Q000276:immunology; D001964:Bromhexine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005100:Expectorants / Q000494:pharmacology* / Q000633:toxicity; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000470:Alkaloids; D018926:Anti-Allergic Agents; D005100:Expectorants; C508598:IL4 protein, human; D018793:Interleukin-13; D011799:Quinazolines; D000551:Ambroxol; D015847:Interleukin-4; D007073:Immunoglobulin E; C019592:vasicine; D048051:p38 Mitogen-Activated Protein Kinases; D001964:Bromhexine; D004229:Dithiothreitol