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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia

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.

Address correspondence to: Dr. Peter J. Henry, School of Medicine and Pharmacology, University of Western Australia, Stirling Highway, Nedlands, Australia 6009. E-mail: Peter.Henry{at}uwa.edu.au