Experimental Asthma and Allergy Research, The Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden.
Eur J Pharmacol. 2011 Nov 1;669(1-3):136-42. doi: 10.1016/j.ejphar.2011.07.046. Epub 2011 Aug 19.
Prostaglandin D(2) (PGD(2)), released through mast cell activation, is used as a non-invasive biomarker in patients with asthma. Since PGD(2) can elicit opposing effects on airway tone via activation of the PGD(2) receptors DP(1) and DP(2) as well as the thromboxane receptor TP, the aim of this study was to characterize the receptors that are activated by PGD(2) in the guinea pig lung parenchyma. PGD(2) and the thromboxane analog U46619 induced concentration-dependent contractions. U46619 was more potent and caused stronger effect than PGD(2). The specific TP receptor antagonist SQ-29548 and the combined TP and DP(2) receptor antagonist BAYu3405 concentration-dependently shifted the curves for both agonists to the right. The DP(1) receptor agonist BW245 induced a weak relaxation at high concentrations, whereas the DP(1) receptor antagonist BWA868C did not affect the PGD(2) induced contractions. The specific DP(2) receptor agonist 13,14-dihydro-15-keto-PGD(2) showed neither contractile nor relaxant effect in the parenchyma. Furthermore, studies in precision-cut lung slices specified that airways as well as pulmonary arteries and veins contracted to both PGD(2) and U46619. When the lung parenchyma from ovalbumin sensitized guinea pigs were exposed to ovalbumin, both thromboxane B(2) and PGD(2) were released. Ovalbumin also induced maximal contractions at similar level as PGD(2) in the parenchyma, which was partly reduced by SQ-29548. These data show that PGD(2) should be recognized as a TP receptor agonist in the peripheral lung inducing contraction on airways, arteries and veins. Therefore, a TP receptor antagonist can be useful in combination treatment of allergic responses in asthma.
前列腺素 D(2)(PGD(2))通过肥大细胞激活释放，可用作哮喘患者的非侵入性生物标志物。由于 PGD(2) 通过激活 PGD(2) 受体 DP(1)和 DP(2)以及血栓素受体 TP，对气道张力产生相反的影响，因此本研究旨在表征 PGD(2) 在豚鼠肺实质中激活的受体。PGD(2)和血栓素类似物 U46619 诱导浓度依赖性收缩。U46619 比 PGD(2)更有效且作用更强。特异性 TP 受体拮抗剂 SQ-29548 和联合 TP 和 DP(2)受体拮抗剂 BAYu3405 浓度依赖性地将两种激动剂的曲线向右移位。DP(1)受体激动剂 BW245 在高浓度下引起弱松弛，而 DP(1)受体拮抗剂 BWA868C 不影响 PGD(2)引起的收缩。特异性 DP(2)受体激动剂 13,14-二氢-15-酮-PGD(2)在实质中既没有收缩作用也没有松弛作用。此外，在精密切割的肺切片研究中，气道以及肺动静脉都对 PGD(2)和 U46619 收缩。当卵清蛋白致敏豚鼠的肺实质暴露于卵清蛋白时，都释放血栓素 B(2)和 PGD(2)。卵清蛋白也在肺实质中引起与 PGD(2)相似水平的最大收缩，这部分被 SQ-29548 减少。这些数据表明 PGD(2)应被视为外周肺中的 TP 受体激动剂，诱导气道、动脉和静脉收缩。因此，TP 受体拮抗剂在哮喘过敏反应的联合治疗中可能有用。
