Received for publication March 11, 2005.
Revised May 11, 2005.
Accepted for publication June 2, 2005.

Inhibitors of prostaglandin transport and metabolism augment PAR₂-mediated increases in PGE₂ levels and smooth muscle relaxation in mouse isolated trachea

Abstract

Stimulants of protease-activated receptor-2 (PAR₂), such as SLIGRL, cause airway smooth muscle relaxation via the release of the bronchodilatory prostanoid PGE₂ (Lan et al., 2001). The principal aim of the current study was to determine whether compounds that inhibit PGE₂ re-uptake by the prostaglandin transporter (bromocresol green, U46619) and PGE₂ metabolism by 15-hydroxyprostaglandin dehydrogenase (thiazolidenedione compounds - rosiglitazone and ciglitazone) significantly enhanced the capacity of SLIGRL to elevate PGE₂ levels and produce relaxation in isolated segments of upper and lower mouse trachea. SLIGRL produced concentration-dependent increases in PGE₂ levels and smooth muscle relaxation, although both effects were significantly greater in lower tracheal segments than in upper tracheal segments. SLIGRL-induced increases in PGE₂ levels were significantly enhanced in the presence of ciglitazone and rosiglitazone - and these effects were not inhibited by GW9662, a peroxisome proliferator-activated receptor antagonist. SLIGRL-induced relaxation responses were also significantly enhanced by ciglitazone and rosiglitazone, whereas responses to isoprenaline, a PGE₂-independent smooth muscle relaxant, were unaltered. Ciglitazone and rosiglitazone alone produced concentration-dependent increases in PGE₂ levels and smooth muscle relaxation, and these responses were inhibited by indomethacin, a cyclooxygenase inhibitor. Bromocresol green, an inhibitor of prostaglandin transport, significantly enhanced SLIGRL-induced increases in PGE₂ levels and relaxation. Immunohistochemical staining for 15-hydroxyprostaglandin dehydrogenase was relatively intense over airway smooth muscle, as was staining for the prostaglandin transporter over both airway smooth muscle and epithelium. In summary, inhibitors of PGE₂ re-uptake and metabolism significantly potentiate PAR₂-mediated increases in PGE₂ levels and smooth muscle relaxation in murine isolated airways.

Key words: airway smooth muscle, ciglitazone, prostaglandin E2, prostaglandin dehydrogenase, prostaglandin transporter, protease-activated receptors

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