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Role of Rho in the pathophysiology of bronchial asthma

Rho 在支气管哮喘病理生理学中的作用

基本信息

批准号：
15590805
负责人：
KUME Hiroaki
金额：
$ 2.3万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

This study was designed to determine involvement of Rho in the pathophysiology of bronchial asthma such as bronchial hyperreactivity, β-adrenergic desensitization, and airway remodeling. After exposure of the fura-2 loaded strip of tracheal smooth muscle to sphingosine 1-phosphate (S1IP,10 μM) for more than 15 min, contraction by methacholine(MCh), a muscarinic receptor agonist, was markedly augmented in a time-dependent fashion. However, concentration of intracellular Ca^<2+>([Ca^<2+>]i) by MCh was not affected. The increased response to MCh (bronchial hyperreactivity) by S1P was antagonized in the presence of 0.01-1 μM Y-27632, a selective inhibitor of Rho-kinase, in a concentration-dependent fashion. Pre exposure to pertussis toxin over 6 hours also prohibited the increased response to MCh by S1P. Next, after exposure of the tissues to S1P (<1 μM) for an equivalent time, the inhibitory effect of isoproterenol (ISO), a β-adrenergic receptor agonist, against MCh-induced contraction wa … More s markedly attenuated without no change in [Ca^<2+>]i. The reduced responsiveness to ISO (desensitization of β-adrenergic receptors) by S1P was inhibited by Y-27632 in a concentration-dependent fashion. Pre exposure to pertussis toxin over an equivalent time also prohibited the reduced response to ISO by S1P. On the other hand, after repeated exposure to ISO every 30 min, response to ISO was gradually attenuated with an increase in [Ca^<2+>]i. This reduced responsiveness to ISO was inhibited in the presence of verapamil, a selective antagonist of voltage-dependent Ca^<2+> channels. In cultured bronchial smooth muscle cells, S1P phosphorylated myosin phosphatase targeting protein (MYPT1) that is a specific protein in myosin phosphatase affected by Rho-kinase. Proliferation of the bronchial smooth muscle cells (airway remodeling) was reduced by Y-27632 in a concentration-dependent fashion. In conclusion, Rho/Rho-kinase processes play an important role in the pathophysiology of bronchial asthma. Less

本研究旨在确定Rho在支气管哮喘病理生理学中的作用，如支气管高反应性、β-肾上腺素能脱敏和气道重塑。将Fura-2负载的气管平滑肌条暴露于1-磷酸鞘氨醇（S1 IP，10 μM）超过15分钟后，乙酰甲胆碱（MCh）（一种毒蕈碱受体激动剂）以时间依赖的方式显著增强收缩。但MCh对细胞内Ca^2+浓度（[Ca^2+]i）无影响。Rho激酶选择性抑制剂Y-27632（0.01-1 μM）可浓度依赖性地拮抗S1 P引起的对MCh（支气管高反应性）的增强反应。预先暴露于百日咳毒素超过6小时也抑制了S1 P对MCh的反应增加。接着，将组织暴露于S1 P（<1 μM）相同时间后，β-肾上腺素能受体激动剂异丙肾上腺素（ISO）对MCH诱导的收缩的抑制作用被证实。 ...更多信息 s明显减弱，[Ca^<2+>]i无变化。Y-27632以浓度依赖性方式抑制S1 P对ISO（β-肾上腺素能受体脱敏）的反应性降低。预先暴露于百日咳毒素超过相同的时间也禁止减少ISO的S1 P的反应。另一方面，在每30分钟重复暴露于ISO后，随着[Ca^<2+>]i的增加，对ISO的反应逐渐减弱。这种对ISO反应性的降低在维拉帕米（一种电压依赖性Ca^2+通道的选择性拮抗剂）存在时被抑制。在培养的支气管平滑肌细胞中，S1 P磷酸化的肌球蛋白磷酸酶靶向蛋白（MYPT 1）是肌球蛋白磷酸酶中受Rho激酶影响的特异性蛋白。Y-27632以浓度依赖性方式降低支气管平滑肌细胞的增殖（气道重塑）。总之，Rho/Rho激酶过程在支气管哮喘的病理生理学中起重要作用。少