Abstract
Background and PurposeAlthough the ‘cromones’ (di-sodium cromoglycate and sodium nedocromil) are used to treat allergy and asthma, their ‘mast cell stabilising’ mechanism of pharmacological action has never been convincingly explained. Here, we investigate the hypothesis that these drugs act by stimulating the release of the anti-inflammatory protein Annexin-A1 (Anx-A1) from mast cells.Experimental approachWe used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice.Key resultsCDMCs activated by IgE-FcRε1 crosslinking, released histamine and prostaglandin (PG) D2, which were inhibited (30–65%) by 5 min pre-treatment with cromoglycate (10 nM) or nedocromil (10 nM), as well as dexamethasone (2 nM) and human recombinant Anx-A1 (1–10 nM). In CDMCs cromones potentiated (2–5 fold) protein kinase C (PKC) phosphorylation and Anx-A1 phosphorylation and secretion (3–5 fold). Incubation of CDMCs with a neutralising anti-Anx-A1 monoclonal antibody reversed the cromone inhibitory effect.Nedocromil (10 nM) also inhibited (40–60%) the release of mediators from murine bone marrow derived-mast cells from wild type mice activated by compound 48/80 and IgE-FcRε1 cross-linking, but were inactive in such cells when these were prepared from Anx-A1 null mice or when the neutralising anti-Anx-A1 antibody was present.Conclusions and ImplicationsWe conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy. These findings also highlight a new pathway for reducing mediator release from these cells.
Highlights
Disodium cromoglycate was the first cromone anti-allergic agent to be discovered but since its introduction into clinical medicine some 50 years ago [1], other cromones or ‘cromoglycatelike’ drugs have been developed including nedocromil, lodoxamide, traxanol and amlexanox
We conclude that stimulation of phosphorylation and secretion of Anx-A1 is an important component of inhibitory cromone actions on mast cells, which could explain their acute pharmacological actions in allergy
Culture was continued until greater than 95% of evaluated cells were identified as cord-derived human mast cells (CDMCs) and the required cell numbers for experiments were reached
Summary
Disodium cromoglycate was the first cromone anti-allergic agent to be discovered but since its introduction into clinical medicine some 50 years ago [1], other cromones or ‘cromoglycatelike’ drugs have been developed including nedocromil, lodoxamide, traxanol and amlexanox. Some H1 antagonists (e.g. ketotifen, azelastine, pemirolast and olopatidine) appear to share a similar pharmacology (or exhibit cross-tachyphylaxis) with cromoglycate [2] Most of these drugs are used for the routine treatment of mild to moderate asthma and/or the topical treatment of ocular and other allergic symptoms. The cromoglycate-like drugs can inhibit both the early and the late phase of the asthmatic reaction in man [5,6] as well as allergic ‘asthma’ or pulmonary inflammation in animal models of the disease [7,8,9,10,11,12,13] Their anti-asthmatic activity is attributed to their anti-inflammatory properties by most authorities [14,15,16]. Experimental approach: We used biochemical and immuno-neutralisation techniques to investigate the mechanism by which cromones suppress histamine and eicosanoid release from cord-derived human mast cells (CDMCs) or murine bone marrow-derived mast cells (BMDMCs) from wild type and Anx-A1 null mice
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