背景:吸入前列腺素(PG)E2可能会抑制哮喘反应,但所涉及的机制仍未定义。
目的:我们试图表征PGE2对人类小气道的直接和间接影响,特别涉及介导反应的受体。
方法:在内径为1mm或更小的分离的人支气管中研究了收缩和松弛。
结果:低浓度的PGE2(0.01-1μmol/L)使组胺预收缩的支气管松弛。支气管扩张剂反应被E类前列腺素(EP)亚型4受体拮抗剂ONO-AE3-208抑制,但不受EP2受体拮抗剂PF-04418948的影响。较高浓度的PGE2(10-100μmol/L)使小气道收缩。然而,TP受体激动剂U-46,619,PGF2α,PGD2比PGE2更有效。此外,支气管收缩对PGE2和所有其他测试的前列腺素的反应,包括EP1/EP3受体激动剂17-苯基trinorPGE2和部分FP受体激动剂AL-8810,均被TP受体拮抗剂SQ-29,548消除。在TP和EP4拮抗剂的存在下,PGE2抑制由抗IgE攻击引起的肥大细胞介导的支气管收缩。测量组胺和半胱氨酰白三烯的释放证明PGE2的这种支气管保护作用是由EP2受体介导的。与支气管扩张无关,并随着暴露时间的增加而增加。
结论:PGE2在人小气道中的药理学不同于其在动物模型中的谱。这种强有力的EP2受体介导的抑制人气道中IgE依赖性收缩的首次证明为哮喘的治疗引入了新的选择性靶标。在阿司匹林加重的呼吸道疾病患者中,这种EP2对肥大细胞介导的支气管收缩的控制可能被夸大了。
BACKGROUND: Inhaled prostaglandin (PG) E2 might inhibit asthmatic responses, but the mechanisms involved remain undefined.
OBJECTIVE: We sought to characterize the direct and indirect effects of PGE2 on human small airways with particular reference to the receptors mediating the responses.
METHODS: Contraction and relaxation were studied in isolated human bronchi with an inner diameter of 1 mm or less.
RESULTS: Low concentrations of PGE2 (0.01-1 μmol/L) relaxed the bronchi precontracted by histamine. The bronchodilator response was inhibited by the E prostanoid (EP) subtype 4 receptor antagonist ONO-AE3-208 but unaffected by the EP2 receptor antagonist PF-04418948. Higher concentrations of PGE2 (10-100 μmol/L) contracted the small airways. However, the TP receptor agonists U-46,619, PGF2α, and PGD2 were more potent than PGE2. Moreover, the bronchoconstrictor responses to PGE2 and all other tested prostanoids, including the EP1/EP3 receptor agonist 17-phenyl trinor PGE2 and the partial FP receptor agonist AL-8810, were uniformly abolished by the TP receptor antagonist SQ-29,548. In the presence of TP and EP4 antagonists, PGE2 inhibited the mast cell-mediated bronchoconstriction resulting from anti-IgE challenge. Measurement of the release of histamine and cysteinyl leukotrienes documented that this bronchoprotective action of PGE2 was mediated by the EP2 receptor, unrelated to bronchodilation, and increased with time of exposure.
CONCLUSIONS: The pharmacology of PGE2 in isolated human small airways was different from its profile in animal models. This first demonstration of powerful EP2 receptor-mediated inhibition of IgE-dependent contractions in human airways introduces a new selective target for the treatment of asthma. This EP2 control of mast cell-mediated bronchoconstriction is presumably exaggerated in patients with aspirin-exacerbated respiratory disease.