碘刺激性作用的离子通道靶点的发现和机制研究

Elemental iodine is an effective broad spectrum antimicrobial that has been used clinically for about two centuries, and it has aslo had an important role in the treatment and prevention of infection. However, a major limitation of its clinical application is that iodine causes noxious stimuli including acute irritation and pain. Recent years,novel preparations of iodine have been developed to control the slow release of a low concentration of free iodine, which helps to minimise the negative side effects. Despite the utility and widespread use of iodine,the molecular mechanism through which iodine mediates its noxious effects remains unknown.For the first time, our preliminary data show that iodine activates a damage-sensing ion channel,TRPA1,which is involved in pain and inflammation.In this study, we will investigate the mechanisms of iondine-induced TRPA1 activation and the involvement of TRPA1 in the noxioux effects of iodine. This study not only provides a scientific basis and theoretical foundations for developing new iodine preparations, and also promotes and deepens the the pharmocology research of TRPA1.

单质碘作为一种高效广谱的消毒杀菌剂应用于临床已将近两个世纪,在预防和治疗感染方面发挥了巨大作用。限制碘临床应用的一个主要问题是它的伤害性刺激作用，如引起粘膜、伤口的剧烈疼痛。目前发展的各种新型碘杀菌剂主要通过控释技术降低游离碘在作用部位的浓度从而降低其刺激性。但碘伤害性刺激作用在体内的分子靶点从未被发现，其细胞、分子机制也从未得以阐明。本课题初步的试验结果首次发现碘特异性激活分布在外周神经元上的受体型离子通道TRPA1。TRPA1是一种伤害性化学信号分子感受器，它的激活导致疼痛和炎症相关反应。为了进一步了解TRPA1在碘毒性机制中的作用，本课题将首次从分子、细胞、组织和动物水平探讨碘激活TRPA1机制以及TRPA1与碘伤害性刺激作用的关系，从而为含碘药物的进一步发展提供科学依据和理论基础，同时也将促进TRPA1受体药理学以及病理生理作用研究。

碘杀菌剂具有很好的杀菌活性并且不会引起微生物耐药性。但是在临床感染治疗中，相较于抗生素，碘杀菌剂由于会引起疼痛及过敏等副作用，从而导致其使用率较低。碘引起这些副作用的原因不清楚，参与的特异性靶点及作用机制尚未揭示。在本研究中，我们发现碘杀菌剂能够引起小鼠产生疼痛反应，并且促进过敏性皮炎反应， 并且碘能够激活一类表达TRPA1及TRPV1离子通道的外周感受神经元。通过活体动物的药理学抑制或基因敲除实验，表明TRPA1是碘引起副作用的主要作用靶点，TRPV1部分参与此过程。进一步的实验表明碘通过氧化还原机制激活TRPA1，但对TRPV1没有直接作用。我们的研究首次揭示了碘杀菌剂副作用产生的机制，提示可以通过局部抑制TRPA1和TRPV1离子通道来降低碘杀菌剂的副作用，为新型碘杀菌剂的开发提供思路。