Antiallergic cromones inhibit neutrophil recruitment onto vascular endothelium via Annexin-A1 mobilization

Yazid, Samia, Leoni , Giovanna, Getting, Stephen J., Cooper, Dianne, Solito, Egle, Perretti, Mauro and Flower, Roderick J. (2010) Antiallergic cromones inhibit neutrophil recruitment onto vascular endothelium via Annexin-A1 mobilization. Arteriosclerosis, Thrombosis, and Vascular Biology, 30 (9). pp. 1718-1724. ISSN 1079-5642

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Objective—To determine whether a mechanism exists that could operate on application of cromones, antiallertic "mast cell–stabilizing" drugs that release the anti-inflammatory protein annexin-A1 (Anx-A1) from U937 cells and inhibit polymorphonuclear leukocyte (PMN) trafficking, because PMNs can synthesize and release large amounts of Anx-A1. Methods and Results—Intravital microscopy was used to monitor the actions of cromones in the inflamed microcirculation. Reperfusion injury provoked a dramatic increase in adherent and emigrated leukocytes in the mesenteric vascular bed, associated with augmented tissue levels of myeloperoxidase. Nedocromil, 2 to 20 mg/kg, significantly (P<0.05) inhibited cell adhesion and emigration, as well as myeloperoxidase release, in wild-type but not Anx-A1-/- mice. Short pretreatment of human PMNs with nedocromil, 10 nmol/L, inhibited cell adhesion (P<0.05) in the flow chamber assay, and this effect was reversed by specific anti-AnxA1 or a combination of anti–formyl peptide receptors 1 and 2, but not irrelevant control, antibodies. Western blotting experiments revealed that cromones stimulate protein kinase C–dependent phosphorylation and release Anx-A1 in human PMNs. Conclusion—We propose a novel mechanism to explain the anti-inflammatory actions of cromones on PMN trafficking, an effect that has long puzzled investigators.

Item Type: Article
Subjects: University of Westminster > Science and Technology > Life Sciences, School of (No longer in use)
Depositing User: Miss Nina Watts
Date Deposited: 28 Jun 2010 13:15
Last Modified: 21 Sep 2010 10:59

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