Pharmacologic Inhibition of Transient Receptor Potential Ion Channel Ankyrin 1 Counteracts 2-Chlorobenzalmalononitrile Tear Gas Agent-Induced Cutaneous Injuries.
Pharmacologic Inhibition of Transient Receptor Potential Ion Channel Ankyrin 1 Counteracts 2-Chlorobenzalmalononitrile Tear Gas Agent-Induced Cutaneous Injuries.
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DOI：
10.1124/jpet.123.001666
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发表时间：
2024-01-17
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近年来，使用催泪瓦斯剂2-氯苯亚甲基丙二腈（CS）控制骚乱的情况显著增加。CS的影响被认为是短暂的和良性的。然而，CS引起剧烈疼痛、眼睑痉挛、流泪、气道阻塞和皮肤水疱。据报告，接触后经常受伤和住院。我们已经确定了感觉神经元离子通道，瞬时受体电位锚蛋白1（TRPA 1），作为一个关键的CS目标，导致急性刺激和疼痛，也作为神经源性炎症的介质。在这里，我们研究了药理学TRPA 1抑制CS诱导的皮肤损伤的影响。我们通过将10 μl CS试剂[200 mM二甲亚砜（DMSO）中]应用于8- 9周龄C57 BL/6雄性小鼠右耳的每一侧，而左耳仅应用溶剂（DMSO），对CS诱导的皮肤损伤进行建模。CS暴露后给予TRPA 1抑制剂HC-030031或A-967079。CS暴露会诱导小鼠耳部皮肤中强烈的组织肿胀、血浆渗出以及炎症细胞因子水平急剧增加。我们还发现，CS的影响不是短暂的，但会导致持续的皮肤损伤。这些损伤参数随着TRPA 1抑制剂治疗而降低。此外，我们测试了先进的TRPA 1拮抗剂在体外的药理活性。我们的研究结果表明，TRPA 1是CS诱导的伤害性感受和组织损伤的重要介质，TRPA 1抑制剂是有效的对策，减少暴露后给药时的关键损伤参数。需要对先进的TRPA 1拮抗剂和去污策略进行额外的治疗效果研究。2-近年来，氯苯亚甲基丙二腈（CS）催泪瓦斯剂已被用作人群分散化学剂。暴露于CS催泪瓦斯剂被认为会引起短暂的急性毒性作用，最多是最小的。在这里，我们发现CS催泪瓦斯暴露会导致急性和持续性皮肤损伤，而瞬时受体电位离子通道锚蛋白1（TRPA 1）拮抗剂治疗可改善皮肤损伤。
Deployment of the tear gas agent 2-chlorobenzalmalononitrile (CS) for riot control has significantly increased in recent years. The effects of CS have been believed to be transient and benign. However, CS induces severe pain, blepharospasm, lachrymation, airway obstruction, and skin blisters. Frequent injuries and hospitalizations have been reported after exposure. We have identified the sensory neuronal ion channel, transient receptor potential ankyrin 1 (TRPA1), as a key CS target resulting in acute irritation and pain and also as a mediator of neurogenic inflammation. Here, we examined the effects of pharmacologic TRPA1 inhibition on CS-induced cutaneous injury. We modeled CS-induced cutaneous injury by applying 10 μl CS agent [200 mM in dimethyl sulfoxide (DMSO)] to each side of the right ears of 8- to 9-week-old C57BL/6 male mice, whereas left ears were applied with solvent only (DMSO). The TRPA1 inhibitor HC-030031 or A-967079 was administered after CS exposure. CS exposure induced strong tissue swelling, plasma extravasation, and a dramatic increase in inflammatory cytokine levels in the mouse ear skin. We also showed that the effects of CS were not transient but caused persistent skin injuries. These injury parameters were reduced with TRPA1 inhibitor treatment. Further, we tested the pharmacologic activity of advanced TRPA1 antagonists in vitro. Our findings showed that TRPA1 is a crucial mediator of CS-induced nociception and tissue injury and that TRPA1 inhibitors are effective countermeasures that reduce key injury parameters when administered after exposure. Additional therapeutic efficacy studies with advanced TRPA1 antagonists and decontamination strategies are warranted. 2-Chlorobenzalmalononitrile (CS) tear gas agent has been deployed as a crowd dispersion chemical agent in recent times. Exposure to CS tear gas agents has been believed to cause transient acute toxic effects that are minimal at most. Here we found that CS tear gas exposure causes both acute and persistent skin injuries and that treatment with transient receptor potential ion channel ankyrin 1 (TRPA1) antagonists ameliorated skin injuries.
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