Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways

Abstract

Stimulants of protease-activated receptor (PAR)(2) promote the generation of the bronchoprotective prostanoid prostaglandin (PG) E(2) by airway epithelial cells. In contrast, glucocorticoids reduce the levels of PGE(2) in airway epithelial cell cultures by concomitantly inhibiting pathways required for PGE(2) synthesis and facilitating pathways involved in PGE(2) inactivation. The aim of this study was to determine whether glucocorticoids inhibited PAR(2)-mediated, PGE(2)-dependent responses in epithelial cell cultures, in intact airway preparations, and in whole animals. In cultures of A549 cells, a PAR(2)-activating peptide SLI-GRL-NH(2) produced concentration and time-dependent increases in PGE(2) levels, which were significantly enhanced after exposure to lipopolysaccharide (LPS). However, SLIGRL-NH(2)-induced increases in PGE(2) levels were abolished by pretreatment of cells with the glucocorticoid, dexamethasone. In mouse isolated tracheal preparations, SLIGRL-NH(2) and PGE(2) 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-NH(2) (PAR(2)-activating peptide, 30 microg intranasally), PGE(2) (10 mugintranasally), or dexamethasone (1 mg/kg i.p.). In the combined presence of dexamethasone and f-LIGRL-NH(2) or dexamethasone and PGE(2), the number of neutrophils was suppressed further (80-83% lower). Thus, although dexamethasone abolished PAR(2)-mediated generation of PGE(2) in A549 cells, neither the smooth muscle relaxant nor the anti-inflammatory effects of PAR(2)-activating peptides (and PGE(2)) were diminished by in vitro or in vivo exposure to dexamethasone.