Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, México DF, México.
Clin Exp Allergy. 2010 Feb;40(2):327-38. doi: 10.1111/j.1365-2222.2009.03412.x. Epub 2009 Dec 3.
A possible role of 5-hydroxytryptamine (5-HT) in the origin of antigen-induced airway hyperresponsiveness (AI-AHR) has been scarcely investigated.
To explore the participation of different 5-HT receptors in the development of AI-AHR in guinea-pigs.
Lung resistance was measured in anaesthetized guinea-pigs sensitized to ovalbumin (OVA). Dose-response curves to intravenous (i.v.) acetylcholine (ACh) were performed before and 1 h after antigenic challenge and expressed as the 200% provocative dose (PD(200)). Organ bath experiments, confocal microscopy and RT-PCR were additionally used. The 5-HT content in lung homogenates was measured by HPLC.
Antigenic challenge significantly decreased PD(200), indicating the development of AI-AHR. This hyperresponsiveness was abolished by a combination of methiothepin (5-HT(1)/5-HT(2)/5-HT(5)/5-HT(6)/5-HT(7) receptors antagonist) and tropisetron (5-HT(3)/5-HT(4) antagonist). Other 5-HT receptor antagonists showed three different patterns of response. Firstly, WAY100135 (5-HT(1A) antagonist) and ondansetron (5-HT(3) antagonist) did not modify the AI-AHR. Secondly, SB269970 (5-HT(7) antagonist), GR113808 (5-HT(4) antagonist), tropisetron or methiothepin abolished the AI-AHR. Thirdly, ketanserin (5-HT(2A) antagonist) produced airway hyporresponsiveness. Animals with bilateral vagotomy did not develop AI-AHR. Experiments in tracheal rings showed that pre-incubation with LP44 or cisapride (agonists of 5-HT(7) and 5-HT(4) receptors, respectively) induced a significant increase of the cholinergic contractile response to the electrical field stimulation. In sensitized lung parenchyma strips, ketanserin diminished the contractile responses to ACh. Sensitization was associated with a ninefold increase in the 5-HT content of lung homogenates. Confocal microscopy showed that sensitization enhanced the immunolabelling and co-localization of nicotinic receptor and 5-HT in airway epithelium, probably located in pulmonary neuroendocrine cells (PNECs). RT-PCR demonstrated that neither sensitization nor antigen challenge modified the 5-HT(2A) receptor mRNA levels.
Our results suggested that 5-HT was involved in the development of AI-AHR to ACh in guinea-pigs. Specifically, 5-HT(2A), 5-HT(4) and 5-HT(7) receptors seem to be particularly involved in this phenomenon. Participation of 5-HT might probably be favoured by the enhancement of the PNECs 5-HT content observed after sensitization.
5-羟色胺（5-HT）在抗原诱导的气道高反应性（AI-AHR）的起源中可能发挥作用，但这一作用尚未得到充分研究。
探讨不同 5-HT 受体在豚鼠 AI-AHR 发展中的作用。
在卵清蛋白（OVA）致敏的麻醉豚鼠中测量肺阻力。在抗原挑战前和 1 小时后进行静脉（i.v.）乙酰胆碱（ACh）剂量反应曲线测定，并表示为 200%激发剂量（PD（200））。还进行了器官浴实验、共聚焦显微镜和 RT-PCR。通过 HPLC 测量肺匀浆中的 5-HT 含量。
抗原挑战显著降低了 PD（200），表明 AI-AHR 的发展。这种高反应性被 methiothepin（5-HT（1）/5-HT（2）/5-HT（5）/5-HT（6）/5-HT（7）受体拮抗剂）和 tropisetron（5-HT（3）/5-HT（4）拮抗剂）的联合使用所消除。其他 5-HT 受体拮抗剂表现出三种不同的反应模式。首先，WAY100135（5-HT（1A）拮抗剂）和 ondansetron（5-HT（3）拮抗剂）并未改变 AI-AHR。其次，SB269970（5-HT（7）拮抗剂）、GR113808（5-HT（4）拮抗剂）、tropisetron 或 methiothepin 消除了 AI-AHR。第三，ketanserin（5-HT（2A）拮抗剂）引起气道低反应性。双侧迷走神经切断术的动物不会发生 AI-AHR。气管环实验表明，预孵育 LP44 或 cisapride（5-HT（7）和 5-HT（4）受体激动剂）可显著增加对电刺激的胆碱能收缩反应。在致敏的肺组织条中，ketanserin 减少了对 ACh 的收缩反应。致敏导致肺匀浆中 5-HT 含量增加了九倍。共聚焦显微镜显示，致敏增强了气道上皮中烟碱受体和 5-HT 的免疫标记和共定位，可能位于肺神经内分泌细胞（PNECs）中。RT-PCR 表明，致敏或抗原挑战均未改变 5-HT（2A）受体 mRNA 水平。
我们的结果表明，5-HT 参与了豚鼠对 ACh 的 AI-AHR 的发展。具体而言，5-HT（2A）、5-HT（4）和 5-HT（7）受体似乎特别参与了这一现象。5-HT 的参与可能得益于致敏后观察到的 PNECs 5-HT 含量的增加。
