Abstract
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.
Footnotes
-
This study was supported by the National Health and Medical Research Council of Australia.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.132753.
-
ABBREVIATIONS: PAR, protease-activated receptor; PG, prostaglandin; COX, cyclooxygenase; PGES, prostaglandin E synthase; EP, prostanoid; BAL, bronchoalveolar lavage; NF, nuclear factor; LPS, lipopolysaccharide.
- Received October 8, 2007.
- Accepted November 13, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|