INSERM U1148, Hôpital Bichat, Paris, France.
Faculty of Pharmacy, Department of Pharmacology, Istanbul University, Istanbul, Turkey.
Br J Pharmacol. 2020 Jan;177(1):161-174. doi: 10.1111/bph.14854. Epub 2019 Oct 31.
In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE and PGI induce potent relaxation of human bronchi from non-PH (control) patients via EP and IP receptors, respectively. However, the effects of PGE /PGI and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI -mimetics approved for treating PH Group I with several PGE -mimetics, in bronchial preparations derived from PH Group III and control patients.
Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE , PGI , and cAMP levels were determined by ELISA.
Maximal relaxations induced by different EP receptor agonists (PGE , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI -mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI but not with PGE levels.
The PGI -mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP receptor agonists was decreased. Restoration of EP receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit.
在与肺部疾病和/或缺氧相关的肺动脉高压（PH）患者（III 组）中，降低肺血管张力和组织缺氧具有治疗益处。PGE 和 PGI 通过 EP 和 IP 受体分别诱导非 PH（对照）患者的人支气管产生强大的舒张作用。然而，PGE/PGI 及其类似物对 PH 患者的人支气管的作用尚不清楚。在这里，我们比较了几种已批准用于治疗 I 组 PH 的 PGI 类似物以及几种 PGE 类似物对来自 III 组 PH 和对照患者的支气管制剂的舒张作用。
评估了从对照和 PH 组 III 患者分离的支气管标本的支气管平滑肌松弛作用。通过 Western blot 和实时 PCR 分析前列腺素受体的表达，并通过 ELISA 测定内源性 PGE、PGI 和 cAMP 水平。
与对照组相比，来自 PH 患者的人支气管中不同 EP 受体激动剂（PGE、L-902688 和 ONO-AE1-329）诱导的最大松弛作用降低。然而，PGI 类似物（伊洛前列素、曲前列尼尔和贝前列素）产生的最大松弛作用在两组患者中相似。PH 患者的人支气管中 EP 和 IP 受体蛋白和 mRNA 的表达均显著降低。cAMP 水平与 PGI 显著相关，但与 PGE 水平无关。
PGI 类似物在 PH 组 III 患者中保留了最大的支气管扩张作用，而 EP 受体激动剂诱导的支气管扩张作用降低。呼吸疾病 PH 组 III 患者气道中 EP 受体表达的恢复可能会带来额外的治疗益处。
