Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1.
Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1.
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DOI：
10.1165/rcmb.2009-0257oc
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发表时间：
2010-12
影响因子：
6.4
通讯作者：
T. Nassar;S. Yarovoi;R. A. Fanne;S. Akkawi;Mahmud Jammal;T. Allen;S. Idell;D. Cines;A. Higazi
中科院分区：
文献类型：
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作者：
T. Nassar;S. Yarovoi;R. A. Fanne;S. Akkawi;Mahmud Jammal;T. Allen;S. Idell;D. Cines;A. Higazi
反应性气道疾病是由通过几种激动剂依赖性途径引发的平滑肌收缩介导的。纤溶酶原激活剂 (PA) 激活 1 型 N-甲基-D-天冬氨酸受体 (NMDA-R1) 与血管张力的控制有关，但据我们所知，此前尚未研究过它们对气道平滑肌收缩力的影响。我们观察到 NMDA-R1 由人气道平滑肌细胞表达，并持续抑制离体大鼠气管环响应乙酰胆碱 (Ach) 的收缩。组织型 PA (tPA) 和尿激酶型 PA (uPA) 均与 NMDA-R1 结合并逆转这种效应，从而增强 Ach 诱导的气管收缩力。与野生型小鼠相比，从 tPA(-/-) 和 uPA(-/-) 小鼠分离的环中，Ach 引发的气管收缩力降低。一氧化氮合酶抑制剂 l-NAME 模拟并增强了 uPA 或 tPA 的前收缩作用。 uPA 和 tPA 进一步增强了上皮剥脱环的收缩性，这种作用被 NMDA-R 拮抗剂 MK-801 抑制。 PA 与 NMDA-R1 的结合以及随后受体的激活受到 1 型 PA 抑制剂、1 型 PA 抑制剂衍生的识别 tPA 和 uPA 对接结构域的六肽以及 tPA 对接位点内的特定突变的抑制。这些研究确定了 PA 和 NMDA-R1 在气道收缩性中的参与，并确定了可能导致反应性气道疾病新干预措施开发的新位点。
Reactive airway disease is mediated by smooth muscle contraction initiated through several agonist-dependent pathways. Activation of type 1 N-methyl-D-aspartate receptors (NMDA-R1s) by plasminogen activators (PAs) has been linked to control of vascular tone, but their effect on airway smooth muscle contractility has not previously been studied to our knowledge. We observed that NMDA-R1s are expressed by human airway smooth muscle cells and constitutively inhibit the contraction of isolated rat tracheal rings in response to acetylcholine (Ach). Both tissue-type PA (tPA) and urokinase-type PA (uPA) bind to NMDA-R1 and reverse this effect, thereby enhancing Ach-induced tracheal contractility. Tracheal contractility initiated by Ach is reduced in rings isolated from tPA(-/-) and uPA(-/-) mice compared with their wild-type counterparts. The procontractile effect of uPA or tPA was mimicked and augmented by the nitric oxide synthase inhibitor, l-NAME. uPA and tPA further enhanced the contractility of rings denuded of epithelium, an effect that was inhibited by the NMDA-R antagonist, MK-801. Binding of PAs to NMDA-R1 and the subsequent activation of the receptor were inhibited by PA inhibitor type 1, by a PA inhibitor type 1-derived hexapeptide that recognizes the tPA and uPA docking domains, as well as by specific mutations within the docking site of tPA. These studies identify involvement of PAs and NMDA-R1 in airway contractility, and define new loci that could lead to the development of novel interventions for reactive airway disease.