Class III antiarrhythmic methanesulfonanilides inhibit leukocyte recruitment in zebrafish
Class III antiarrhythmic methanesulfonanilides inhibit leukocyte recruitment in zebrafish
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DOI：
10.1189/jlb.0107030
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发表时间：
2007-07-01
影响因子：
5.5
通讯作者：
Mullins, John J.
中科院分区：
文献类型：
--
作者：
Brown, Simon B.;Tucker, Carl S.;Mullins, John J.
了解支配白细胞向组织损伤和感染部位的迁移和间质性迁移的基本分子机制对于确定用于管理慢性炎症性疾病的新治疗靶点具有潜在意义。CD 31是一种哺乳动物细胞粘附分子，调节白细胞从循环中的募集。我们最近未发表的工作表明，CD 31的同嗜性连接可以负调节白细胞内的ether-a-go-go-related基因（ERG）电流，以调节细胞-细胞粘附。为了验证和探测ERG在白细胞中的功能意义，我们在斑马鱼中开发了一种感染的炎症伤口模型，并评估了两种ERG特异性抑制剂多非利特和E4031以及ERG特异性反义RNA吗啉代对中性粒细胞募集的功效。我们的数据证实了迄今为止未描述的作用，ERG在漏细胞，抑制或翻译敲低ERG导致显着衰减的炎症反应的感染刺激。通过心室心率降低独立验证了ERG的抑制，其中ERG还在心脏动作电位的复极中起作用。我们的研究结果表明，ERG特异性III类抗肿瘤药物可以调节感染的炎症反应。
Understanding fundamental molecular mechanisms that govern the transmigration and interstitial migration of leukocytes to sites of tissue damage and infection is of potential significance in identifying novel therapeutic targets for the management of chronic inflammatory disorders. CD31 is a mammalian cell adhesion molecule that regulates the recruitment of leukocytes from the circulation. Our recent unpublished work has suggested that homophilic ligation of CD31 can negatively regulate the ether-a-go-go-related gene (ERG) current within leukocytes to regulate cell-cell adhesion. To validate and probe the functional significance of ERG in leukocytes, we developed an infected wound model of inflammation in zebrafish and assessed the efficacy of two ERG-specific inhibitors, dofetilide and E4031, as well as an ERG-specific antisense RNA morpholino on neutrophil recruitment. Our data confirm a hitherto undescribed role for ERG in leakocytes, where inhibition or translational knockdown of ERG resulted in significant attenuation of the inflammatory response to an infections stimulus. Inhibition of ERG was verified independently by a decrease in the ventricular heart rate, where ERG also functions in the repolarization of the cardiac action potential. Our results suggest that ERG-specific Class III antiarrhythmic drugs can modulate inflammatory responses to infection.