Antiallergic cromones inhibit neutrophil recruitment onto vascular endothelium via annexin-A1 mobilization.
OBJECTIVE
To determine whether the inhibitory action of the antiallergic cromone "mast cell stabilizing" drugs on polymorphonuclear leukocyte (PMN) trafficking is mediated through an annexin-A1 (Anx-A1) dependent mechanism.


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 antiformyl 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.


CONCLUSIONS
We propose a novel mechanism to explain the antiinflammatory actions of cromones on PMN trafficking, an effect that has long puzzled investigators.
Yazid
Samia
S
William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom. s.yazid@qmul.ac.uk
Leoni
Giovanna
G
Getting
Stephen J
SJ
Cooper
Dianne
D
Solito
Egle
E
Perretti
Mauro
M
Flower
Roderick J
RJ
D000818:Animals; D017305:Annexin A1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D004205:Cromolyn Sodium / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036904:Leukocyte Rolling / Q000187:drug effects; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000187:drug effects; D018715:Microscopy, Video; D017835:Nedocromil / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D044042:Receptors, Formyl Peptide / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D017305:Annexin A1; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D044042:Receptors, Formyl Peptide; D017835:Nedocromil; D009195:Peroxidase; D011493:Protein Kinase C; D004205:Cromolyn Sodium