Additive blockade of beta 2-integrin adhesion of eosinophils by salmeterol and fluticasone propionate.
Migration of human eosinophils is regulated by integrin expression, conformational change, and activation of cytosolic phospholipase A2 (cPLA2). Corticosteroids have been shown to inhibit cPLA2 hydrolysis in human eosinophils. The objective of this study was to determine the mechanisms of fluticasone propionate (FP) alone or in combination with salmeterol (SM) in blocking adhesion mediated by beta 2-integrin in human eosinophils. Human eosinophils were isolated by negative magnetic selection. beta 2-integrin-mediated eosinophil adhesion was measured by residual eosinophil peroxidase activity. Eosinophils were pretreated for 12 h to 24 h with FP and with or without SM for 30 min. Both SM alone and FP alone inhibited eosinophil adhesion in concentration- and time-dependent manner. SM alone modestly (approximately 30%) inhibited interleukin (IL)-5-induced eosinophil adhesion. Blockade of IL-5-induced eosinophil adhesion caused by 10(-7) M FP at 24 h was augmented by 10(-7) M SM from 41.5% to 72.5%. Similar blockade was also observed for eotaxin-induced eosinophil adhesion. Neither SM, FP, nor FP + SM blocked either: 1) upregulation of CD11b surface expression; or 2) phosphorylation of cPLA2. Blockade of beta 2-integrin-mediated eosinophil adhesion by fluticasone propionate is augmented by salmeterol. Decreased adhesion results from augmented blockade of nuclear translocation of cytosolic phospholipase A2 caused by addition of salmeterol to fluticasone.
Myo
S
S
Section of Pulmonary and Critical Care Medicine, Depts of Medicine, Neurobiology Pharmacology and Physiology, Pediatrics, Anesthesia and Critical Care, University of Chicago, IL 60637, USA.
Zhu
X
X
Myou
S
S
Meliton
A Y
AY
Liu
J
J
Boetticher
E
E
Lambertino
A T
AT
Xu
C
C
Muñoz
N M
NM
Leff
A R
AR
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000730:Androstadienes / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D018821:CD18 Antigens / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000494:pharmacology; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004804:Eosinophils / Q000187:drug effects*; D005260:Female; D000068298:Fluticasone; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D000068299:Salmeterol Xinafoate
D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; C515456:CCL11 protein, human; D018821:CD18 Antigens; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D015848:Interleukin-5; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D010741:Phospholipases A; D054467:Phospholipases A2; D000420:Albuterol