Henry Peter J, D'Aprile Angela, Self Glenn, Hong Tracy, Mann Tracy S
School of Medicine and Pharmacology, University of Western Australia, Nedlands.
J Pharmacol Exp Ther. 2005 Sep;314(3):995-1001. doi: 10.1124/jpet.105.086124. Epub 2005 Jun 3.
Stimulants of protease-activated receptor-2 (PAR(2)), such as Ser-Leu-Ile-Gly-Arg-Leu-NH(2) (SLIGRL), cause airway smooth muscle relaxation via the release of the bronchodilatory prostanoid prostaglandin E(2) (PGE(2)). The principal aim of the current study was to determine whether compounds that inhibit PGE(2) reuptake by the prostaglandin transporter [bromocresol green and U46619 (9,11-dideoxy-9alpha,11alpha-methanoepoxy PGF2alpha) and PGE(2) metabolism by 15-hydroxyprostaglandin dehydrogenase (thiazolidenedione compounds rosiglitazone and ciglitazone) significantly enhanced the capacity of SLIGRL to elevate PGE(2) levels and produce relaxation in isolated segments of upper and lower mouse trachea. SLIGRL produced concentration-dependent increases in PGE(2) levels and smooth muscle relaxation, although both effects were significantly greater in lower tracheal segments than in upper tracheal segments. SLIGRL-induced increases in PGE(2) levels were significantly enhanced in the presence of ciglitazone and rosiglitazone, and these effects were not inhibited by GW9662 (2-chloro-5-nitrobenzanilide), a peroxisome proliferator-activated receptor-gamma antagonist. SLI-GRL-induced relaxation responses were also significantly enhanced by ciglitazone and rosiglitazone, whereas responses to isoprenaline, a PGE(2)-independent smooth muscle relaxant, were unaltered. Ciglitazone and rosiglitazone alone produced concentration-dependent increases in PGE(2) 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 PGE(2) 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 PGE(2) reuptake and metabolism significantly potentiate PAR(2)-mediated increases in PGE(2) levels and smooth muscle relaxation in murine-isolated airways.
蛋白酶激活受体-2（PAR(2)）的激动剂，如丝氨酸-亮氨酸-异亮氨酸-甘氨酸-精氨酸-亮氨酸-氨基（SLIGRL），通过释放支气管扩张性前列腺素前列腺素E2（PGE(2)）引起气道平滑肌舒张。本研究的主要目的是确定抑制前列腺素转运体对PGE(2)再摄取的化合物[溴甲酚绿和U46619（9,11-二脱氧-9α,11α-甲氧基环氧前列腺素F2α）]以及抑制15-羟基前列腺素脱氢酶对PGE(2)代谢的化合物（噻唑烷二酮类化合物罗格列酮和环格列酮）是否能显著增强SLIGRL升高PGE(2)水平并使小鼠上下段气管离体节段产生舒张的能力。SLIGRL使PGE(2)水平和平滑肌舒张呈浓度依赖性增加，尽管这两种效应在下段气管节段中均显著大于上段气管节段。在环格列酮和罗格列酮存在的情况下，SLIGRL诱导的PGE(２)水平升高显著增强，并且这些效应未被过氧化物酶体增殖物激活受体-γ拮抗剂GW9662（2-氯-5-硝基苯甲酰苯胺）抑制。环格列酮和罗格列酮也显著增强了SLI-GRL诱导的舒张反应，而对异丙肾上腺素（一种不依赖PGE(2)的平滑肌舒张剂）的反应未改变。单独使用环格列酮和罗格列酮可使PGE(2)水平和平滑肌舒张呈浓度依赖性增加，并且这些反应被环氧化酶抑制剂吲哚美辛抑制。前列腺素转运抑制剂溴甲酚绿显著增强了SLIGRL诱导的PGE(2)水平升高和舒张。气道平滑肌上15-羟基前列腺素脱氢酶的免疫组织化学染色相对较强，气道平滑肌和上皮细胞上前列腺素转运体的染色也是如此。总之，PGE(2)再摄取和代谢抑制剂显著增强了PAR(2)介导的小鼠离体气道中PGE(2)水平升高和平滑肌舒张。
