抗炎药、抗生素和多效因子在逆转体外培养兔角膜氮芥损伤中的疗效。
Efficacy of anti-inflammatory, antibiotic and pleiotropic agents in reversing nitrogen mustard-induced injury in ex vivo cultured rabbit cornea.
机构信息
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
出版信息
Toxicol Lett. 2018 Sep 1;293:127-132. doi: 10.1016/j.toxlet.2017.11.026. Epub 2017 Nov 23.
Vesicating agent, Sulfur mustard (SM), causes devastating eye injury; however, there are no effective antidotes available. Using nitrogen mustard (NM), a bi-functional analog of SM, we have earlier reported that NM-induced corneal injury in ex vivo rabbit cornea organ culture model parallels corneal injury reported with SM. Using this model, we have demonstrated the therapeutic efficacy of dexamethasone (DEX), doxycycline (DOX) and silibinin (SB) in reversing NM (2h exposure)-induced corneal injuries when added immediately after washing NM. In the present study, we further examined the efficacy of similar/higher doses of these agents when added immediately, 2, or 4h after washing NM following its 2h exposure. All three treatment agents caused a reversal in established NM-induced injury biomarkers when added immediately or 2h after washing NM following its 2h exposure; however, when treatments were carried out 4h after washing NM, there was no significant effect. Together, our results further show the beneficial effect of these agents in reversing NM-induced corneal injury and indicate the time window for effective treatment. This could be useful towards future development of targeted therapeutics against vesicant-induced ocular injury.
发泡剂，芥子气（SM），会造成毁灭性的眼部损伤；但是，目前还没有有效的解毒剂。我们曾使用氮芥（NM），SM 的双功能类似物，报告称 NM 诱导的离体兔角膜器官培养模型中的角膜损伤与 SM 引起的角膜损伤相似。使用该模型，我们证明了地塞米松（DEX）、强力霉素（DOX）和水飞蓟素（SB）在 NM（2 小时暴露）引起的角膜损伤后立即冲洗 NM 时，具有逆转角膜损伤的疗效。在本研究中，我们进一步研究了在 NM 暴露 2 小时后立即、2 小时或 4 小时冲洗 NM 时，这些药物的类似/更高剂量的疗效。当在 NM 暴露 2 小时后立即或 2 小时后冲洗 NM 时，这三种治疗药物都能逆转 NM 诱导的损伤生物标志物，但在 NM 暴露 4 小时后冲洗 NM 时，没有明显效果。总之，我们的结果进一步表明这些药物在逆转 NM 诱导的角膜损伤方面具有有益作用，并指出了有效治疗的时间窗口。这对于未来针对发泡剂诱导的眼部损伤的靶向治疗药物的开发可能是有用的。
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