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Journal of Clinical and Experimental Toxicology | Volume: 3
February 21-22, 2019 | Paris, France
International Conference on
Environmental Toxicology and Pharmacology
Notes:
J Clin Exp Tox, Volume 3
DOI: 10.4066/2630-4570-C1-006
Anti-allergic cromones exert its mechanism of pharmacological actions by inducing the release of
Annexin A1
Sinniah A
University of Malaya, Malaysia
Anti-allergic cromones are well recognised as ‘mast cell
stabilizers’ which prevent mast cell degranulation upon
stimulation. Many studies have also reported that disodium
cromoglycate andnedocromil, which are exemplars of cromones,
can influence the other facets of inflammatory cascade including
inactivation of polymorphonuclear leukocytes, inhibition of
cytokine and eicosanoid release and chloride channel blockade.
However, the exact mechanism underlying these effects
remained a conundrum until recently. Our work now points
to a mechanism involving the endogenous anti-inflammatory
protein, Annexin (Anx) A1. The synthesis and secretion of this
protein is regulated by glucocorticoids and mediates their action
in many models of acute and chronic inflammation. We have
therefore investigated the possibility that cromones control mast
cell homeostasis and degranulation by promoting the release of
Anx-A1 (abundant in mast cells). Cultured cord blood derived
mast cells (CDMCs) and bone marrow-derived murine mast cells
(BMDMCs) from wild type or Anx-A1-/- mice were pre-treated
with nedocromil (0.5-10nM) for 5min prior to 10min stimulation
with compound 48/80 (10μg/ml) to trigger degranulation. PKC
activation is crucial for Anx-A1 externalization in CDMCs and
nedocromil-induced Anx-A1 phosphorylation/externalisation
was blocked by the PKC inhibitor Gö-6983 (10μM). Pre-treatment
with nedocromil significantly (p<0.05) inhibited the release of
histamine, PGD2, tryptase and β-hexosaminidase, however the
drug was inactive in the presence of anti-Anx-A1 neutralising
antibodys. The prospect that FPR2, the receptor for Anx-A1,
might be involved in the acute actions of nedocromil was tested
using the FPR2 antagonist (10μM) or in BMDMCs from fpr2/3-
/- mice. Nedocromil was then unable to prevent PGD2 release
in either model. However its action on histamine release does
not seem to exclusively depend on FPR2, hence might involve
another member of the FPR family. These findings indicate a
novel paradigm by which Anx-A1 mediates the pharmacological
actions of cromones as inhibitors of mast cell degranulation.
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