Targeted inhibition of KCa3.1 channel attenuates airway inflammation and remodeling in allergic asthma.
Targeted inhibition of KCa3.1 channel attenuates airway inflammation and remodeling in allergic asthma.
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DOI：
10.1165/rcmb.2012-0236oc
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发表时间：
2013-06
影响因子：
6.4
通讯作者：
Zhi-Hua Yu;Jian‐rong Xu;Yan‐Xia Wang;Guang-Ni Xu;Zu-Peng Xu;Kai Yang;Da-zheng Wu;Yong-yao Cui
中科院分区：
文献类型：
--
作者：
Zhi-Hua Yu;Jian‐rong Xu;Yan‐Xia Wang;Guang-Ni Xu;Zu-Peng Xu;Kai Yang;Da-zheng Wu;Yong-yao Cui
KCa3.1被认为参与调节多种细胞类型中的细胞活化、增殖和迁移，包括气道炎症和结构细胞。然而，KCa 3.1在过敏性哮喘气道炎症和重塑以及随后的气道高反应性（AHR）中的作用仍有待研究。本研究的主要目的是阐明KCa3.1在慢性过敏性哮喘中的作用以及KCa3.1阻断剂的潜在治疗价值。使用实时PCR，蛋白质印迹，或免疫组化分析，我们探讨了KCa3.1在过敏性小鼠和哮喘人支气管平滑肌细胞（BSMCs）的支气管中的确切作用。我们发现，KCa3.1 mRNA和蛋白质的表达在过敏小鼠的支气管升高，双标记显示，上调主要发生在气道平滑肌细胞。三芳基甲烷（TRAM）-34是一种KCa3.1阻滞剂，可剂量依赖性地抑制卵清蛋白诱导的气道炎症的产生和维持，该炎症与Th 2型细胞因子增加和Th 1型细胞因子减少以及上皮下细胞外基质沉积、杯状细胞增生和哮喘小鼠模型中的AHR相关。此外，药物阻断和基因沉默的KCa 3.1，这是显着升高后，有丝分裂原刺激，抑制哮喘人BSMC的增殖和迁移，并阻止细胞周期在G 0/G1期。此外，KCa3.1激活剂1-乙基苯并咪唑啉酮诱导的哮喘人BSMCs的膜超极化和细胞内钙增加被TRAM-34减弱。我们首次证明了KCa3.1在过敏性哮喘气道炎症和重塑的发病机制中的重要作用，我们认为KCa3.1阻滞剂可能是一种有前途的哮喘治疗策略。
KCa3.1 has been suggested to be involved in regulating cell activation, proliferation, and migration in multiple cell types, including airway inflammatory and structural cells. However, the contributions of KCa3.1 to airway inflammation and remodeling and subsequent airway hyperresponsiveness (AHR) in allergic asthma remain to be explored. The main purpose of this study was to elucidate the roles of KCa3.1 and the potential therapeutic value of KCa3.1 blockers in chronic allergic asthma. Using real-time PCR, Western blotting, or immunohistochemical analyses, we explored the precise role of KCa3.1 in the bronchi of allergic mice and asthmatic human bronchial smooth muscle cells (BSMCs). We found that KCa3.1 mRNA and protein expression were elevated in the bronchi of allergic mice, and double labeling revealed that up-regulation occurred primarily in airway smooth muscle cells. Triarylmethane (TRAM)-34, a KCa3.1 blocker, dose-dependently inhibited the generation and maintenance of the ovalbumin-induced airway inflammation associated with increased Th2-type cytokines and decreased Th1-type cytokine, as well as subepithelial extracellular matrix deposition, goblet-cell hyperplasia, and AHR in a murine model of asthma. Moreover, the pharmacological blockade and gene silencing of KCa3.1, which was evidently elevated after mitogen stimulation, suppressed asthmatic human BSMC proliferation and migration, and arrested the cell cycle at the G0/G1 phase. In addition, the KCa3.1 activator 1-ethylbenzimidazolinone-induced membrane hyperpolarization and intracellular calcium increase in asthmatic human BSMCs were attenuated by TRAM-34. We demonstrate for the first time an important role for KCa3.1 in the pathogenesis of airway inflammation and remodeling in allergic asthma, and we suggest that KCa3.1 blockers may represent a promising therapeutic strategy for asthma.