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首页> 外文期刊>American Journal of Physiology >Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca2+ handling and Rho/ROCK signaling.
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Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca2+ handling and Rho/ROCK signaling.

机译：异前列腺素诱导的气道高反应性取决于内部Ca2 +处理和Rho / ROCK信号传导。

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摘要

We previously reported the ability of isoprostanes to induce airway hyperresponsiveness (AHR). In this study, we examined the signaling mechanisms underlying that phenomenon with the standard muscle bath technique. Responses to a threshold concentration of carbachol (CCh, 3 x 10(-9) M) were significantly augmented by pretreatment for 20 min with 8-isoprostaglandin E(2) (15-E(2t)-IsoP, 10(-6) M): this AHR was obliterated in tissues pretreated with the selective Rho kinase (ROCK) inhibitor Y-27632 added 20 min before isoprostane, but not by cyclopiazonic acid (CPA). Increasing the CCh concentration to 3 x 10(-8) M (still considerably less than the half-maximally effective concentration of CCh) evoked larger contractions that were also augmented significantly by 15-E(2t)-IsoP: this AHR was completely abolished in tissues pretreated with CPA as well as those pretreated with Y-27632. We noted, however, that Y-27632 and CPA profoundly effect baseline tone and the cholinergic response per se, which confounds the interpretation of the data summarized above. We therefore modified the protocol by using combinations of CCh and blocker (CPA, Y-27632, or nifedipine) that were equieffective. In this way, we found that AHR could not be demonstrated under conditions in which Rho/ROCK signaling or Ca(2+) release was abolished (by Y-27632 and CPA, respectively). Likewise, other autacoids that act through G protein-coupled receptors via Rho/ROCK and Ca(2+) release (serotonin, histamine) mimicked this effect of isoprostane, whereas bradykinin did not. We conclude that isoprostane-induced AHR is mediated in part through an action on Rho/ROCK signaling. This novel finding may contribute to a better understanding of the mechanisms underlying AHR and asthma.
机译：我们先前曾报道异前列腺素诱导气道高反应性（AHR）的能力。在这项研究中，我们使用标准的肌肉浴技术检查了该现象背后的信号传导机制。通过使用8-isoprostaglandin E（2）（15-E（2t）-IsoP，10（-6）预处理20分钟可显着提高对阈浓度的卡巴胆碱（CCh，3 x 10（-9）M）的响应M）：在异前列腺素前20分钟加入选择性Rho激酶（ROCK）抑制剂Y-27632预处理的组织中消除了该AHR，但未被环吡嗪酸（CPA）消除。将CCh浓度增加到3 x 10（-8）M（仍远低于CCh的最大有效浓度的一半）会引起更大的收缩，而收缩率也会明显增加15-E（2t）-IsoP：此AHR被完全废除在用CPA预处理过的组织以及用Y-27632预处理过的组织中但是，我们注意到，Y-27632和CPA会对基线基调和胆碱能反应本身产生深远影响，这混淆了上面总结的数据的解释。因此，我们通过使用等效的CCh和阻断剂（CPA，Y-27632或硝苯地平）的组合来修改协议。通过这种方式，我们发现在Rho / ROCK信号或Ca（2+）释放被取消的条件下（分别由Y-27632和CPA取消）无法证明AHR。同样，其他通过Rho / ROCK和Ca（2+）通过G蛋白偶联受体起作用的自噬类物质（5-羟色胺，组胺）也能模拟异前列腺素的这种作用，而缓激肽则没有。我们得出结论，异前列腺素诱导的AHR部分通过对Rho / ROCK信号传导的作用介导。这一新发现可能有助于更好地了解AHR和哮喘的潜在机制。

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