Downregulation of sphingosine-1-phosphate receptors in bronchial smooth muscle of mouse experimental asthma
Downregulation of sphingosine-1-phosphate receptors in bronchial smooth muscle of mouse experimental asthma
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DOI：
10.1016/j.phrs.2010.05.005
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发表时间：
2010-10-01
影响因子：
9.3
通讯作者：
Misawa, Miwa
中科院分区：
文献类型：
--
作者：
Chiba, Yoshihiko;Suzuki, Kanako;Misawa, Miwa
为了确定鞘氨醇-1-磷酸（SIP）是否参与增强支气管平滑肌（BSM）收缩性，哮喘患者气道高反应性的原因之一，Sip对BSM张力的影响进行了研究，在对照组和反复抗原激发的小鼠。在对照和抗原激发的动物中。S1 P对离体BSM组织的基础张力无影响。然而，在BSMs预去极化60 mM K+，S1 P引起了显着的增加，在对照组小鼠的张力。选择性S1 P受体2（S1 PR 2）拮抗剂JTE-013可阻断S1 P介导的收缩，而选择性S1 PR 1拮抗剂W123和选择性S1 PR 3拮抗剂BML-241则不能阻断S1 P介导的收缩。在对照小鼠的BSM中观察到的SIP介导的收缩也被Rho激酶抑制剂Y-27632抑制，表明收缩是通过激活S1 PR 2和可能是其下游Rho激酶介导的。另一方面，有趣的是，在反复抗原攻击的小鼠的BSM中根本没有观察到SIP介导的收缩。在患病动物的BSM组织中也观察到S1 PR 2的mRNA的显著和显著下调。总之，SIP可以通过激活其JTE-013敏感受体（可能是S1 PR 2）和RhoA/Rho激酶信号来增强正常小鼠BSM收缩。在反复抗原攻击小鼠的BSM中，S1 PR 2的表达水平显著降低，导致S1 P介导的收缩丧失。(C)2010爱思唯尔有限公司保留所有权利。
To determine whether or not sphingosine-1-phosphate (SIP) is involved in the augmented bronchial smooth muscle (BSM) contractility, one of the causes of airway hyperresponsiveness in asthmatics, the effects of Sip on BSM tone were investigated in control and repeatedly antigen-challenged mice. Both in the control and antigen-challenged animals. S1P had no effect on basal tone of the isolated BSM tissues. However, in the BSMs pre-depolarized by 60 mM K+, S1P caused a significant increase in tension in the control mice. The S1P-mediated contraction was abolished by JTE-013, a selective S1P receptor 2 (S1PR2) antagonist, but not by W123, a selective S1PR1 antagonist, and BML-241, a selective S1PR3 antagonist. The SIP-mediated contraction observed in BSMs of the control mice was also inhibited by Y-27632, a Rho-kinase inhibitor, suggesting that the contraction is mediated via activations of S1PR2 and probably its downstream Rho-kinase. On the other hand, interestingly, the SIP-mediated contraction was not observed at all in BSMs of the repeatedly antigen-challenged mice. A marked and significant downregulation of mRNA for S1PR2 was also observed in BSM tissues of the diseased animals. In conclusion, SIP could augment the BSM contraction via activations of its JTE-013-sensitive receptor, probably S1PR2, and the RhoA/Rho-kinase signaling in normal mice. In BSMs of the repeatedly antigen-challenged mice, the expression level of S1PR2 was much decreased, resulting in a loss of the S1P-mediated contraction. (C) 2010 Elsevier Ltd. All rights reserved.