TY - JOUR T1 - Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 622 LP - 630 DO - 10.1124/jpet.107.132753 VL - 324 IS - 2 AU - Sham Mohd Saleh AU - Tracy S. Mann AU - Terence Peters AU - Richard J. Betts AU - Peter J. Henry Y1 - 2008/02/01 UR - http://jpet.aspetjournals.org/content/324/2/622.abstract N2 - Stimulants of protease-activated receptor (PAR)2 promote the generation of the bronchoprotective prostanoid prostaglandin (PG) E2 by airway epithelial cells. In contrast, glucocorticoids reduce the levels of PGE2 in airway epithelial cell cultures by concomitantly inhibiting pathways required for PGE2 synthesis and facilitating pathways involved in PGE2 inactivation. The aim of this study was to determine whether glucocorticoids inhibited PAR2-mediated, PGE2-dependent responses in epithelial cell cultures, in intact airway preparations, and in whole animals. In cultures of A549 cells, a PAR2-activating peptide SLI-GRL-NH2 produced concentration and time-dependent increases in PGE2 levels, which were significantly enhanced after exposure to lipopolysaccharide (LPS). However, SLIGRL-NH2-induced increases in PGE2 levels were abolished by pretreatment of cells with the glucocorticoid, dexamethasone. In mouse isolated tracheal preparations, SLIGRL-NH2 and PGE2 induced concentration-dependent relaxation responses that were unaffected by dexamethasone, irrespective of whether dexamethasone exposure occurred in vitro or in vivo. Intranasal administration of LPS produced a pronounced increase in the numbers of neutrophils recovered from the bronchoalveolar lavage fluid of BALB/c mice. Numbers of recovered neutrophils were 40 to 60% lower in mice that received f-LIGRL-NH2 (PAR2-activating peptide, 30 μg intranasally), PGE2 (10 μgintranasally), or dexamethasone (1 mg/kg i.p.). In the combined presence of dexamethasone and f-LIGRL-NH2 or dexamethasone and PGE2, the number of neutrophils was suppressed further (80–83% lower). Thus, although dexamethasone abolished PAR2-mediated generation of PGE2 in A549 cells, neither the smooth muscle relaxant nor the anti-inflammatory effects of PAR2-activating peptides (and PGE2) were diminished by in vitro or in vivo exposure to dexamethasone. The American Society for Pharmacology and Experimental Therapeutics ER -