Combination of ebselen and hydrocortisone substantially reduces nitrogen mustard-induced cutaneous injury.
Combination of ebselen and hydrocortisone substantially reduces nitrogen mustard-induced cutaneous injury.
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DOI：
10.1016/j.crtox.2021.10.002
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发表时间：
2021
影响因子：
3.3
通讯作者：
Billack B
中科院分区：
文献类型：
--
作者：
Tumu HCR;Cuffari BJ;Billack B
HC + EB-1抵消HN 2对真皮：表皮连接的破坏。HC + EB-1减少HN 2介导的DNA损伤，如TUNEL测定所识别的。HC + EB-1降低HN 2介导的MMP-9和iNOS的组织表达。本研究的目的是探讨氢化可的松（HC）和依布硒啉（EB-1），作为单药治疗或联合治疗的发泡对策的影响。采用小鼠耳肿胀模型（MEVM），（0.016、0.023、0.031、0.047、0.063、0.125或0.250 mg/耳），EB-1在氮芥暴露后15 min、4 h和8 h局部施用0.125、0.187、0.250、0.375或0.500 mg/耳）或HC + EB-1的组合。在氮芥（HN 2）暴露后24小时获得耳穿孔活检。与对照耳相比，局部暴露于HN 2（0.500 µmol/耳）的耳组织表现为耳厚度、水疱、TUNEL荧光以及基质金属蛋白酶9（MMP-9）和诱导型一氧化氮合酶（iNOS）表达增加。相比之下，用EB-1局部处理的暴露于HN 2的耳朵与单独的HN 2相比显示出形态测量厚度和水疱的显著降低。暴露于HN 2然后用HC处理的耳组织也表现出形态厚度和囊泡的减少。发现HC + EB-1的组合治疗在减少HN 2诱导的耳水肿和水疱方面最有效。该组合还显著降低HN 2介导的皮肤iNOS和MMP-9的表达，并降低HN 2诱导的TUNEL染色。综上所述，我们的研究表明，HC + EB-1的组合是HN 2的有效对策。
HC + EB-1 counteracts dermal:epidermal junction disruption by HN2. HC + EB-1 reduces HN2-mediated DNA damage, as recognized by TUNEL assay. HC + EB-1 reduces HN2-mediated tissue expression of MMP-9 and iNOS. The purpose of the present study was to investigate the vesicant countermeasure effects of hydrocortisone (HC) and ebselen (EB-1), administered as monotherapy or as a combination treatment. The mouse ear vesicant model (MEVM) was utilized and test doses of HC (0.016, 0.023, 0.031, 0.047, 0.063, 0.125 or 0.250 mg/ear), EB-1 (0.125, 0.187, 0.250, 0.375 or 0.500 mg/ear) or the combination of HC + EB-1 were topically applied at 15 min, 4 h and 8 h after nitrogen mustard exposure. Ear punch biopsies were obtained 24 h after mechlorethamine (HN2) exposure. Compared to control ears, ear tissues exposed topically to HN2 (0.500 µmol/ear) presented with an increase in ear thickness, vesication, TUNEL fluorescence and expression of matrix metalloproteinase 9 (MMP-9) and inducible nitric oxide synthase (iNOS). In contrast, HN2 exposed ears treated topically with EB-1 showed a significant decrease in morphometric thickness and vesication vs. HN2 alone. Ear tissues exposed to HN2 and then treated with HC also demonstrated reductions in morphometric thickness and vesication. Combination treatment of HC + EB-1 was found to be the most effective at reducing HN2-induced ear edema and vesication. The combination also dramatically decreased HN2-mediated cutaneous expression of iNOS and MMP-9 and decreased HN2-induced TUNEL staining. Taken together, our study demonstrates that the combination of HC + EB-1 is an efficacious countermeasure to HN2.
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