Nitrogen mustard exposure of murine skin induces DNA damage, oxidative stress and activation of MAPK/Akt-AP1 pathway leading to induction of inflammatory and proteolytic mediators.
Nitrogen mustard exposure of murine skin induces DNA damage, oxidative stress and activation of MAPK/Akt-AP1 pathway leading to induction of inflammatory and proteolytic mediators.
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氮皮肤的氮芥末酱会诱导DNA损伤，氧化应激以及MAPK/AKT-AP1途径的激活，从而导致炎症和蛋白水解介质的诱导。
DOI：
10.1016/j.toxlet.2015.04.006
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发表时间：
2015-06-15
影响因子：
3.5
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Kumar, Dileep;Tewari-Singh, Neera;Agarwal, Chapla;Jain, Anil K.;Inturi, Swetha;Kant, Rama;White, Carl W.;Agarwal, Rajesh
关键词：
我们最近在SKH-1无毛小鼠中的研究表明，局部暴露于氮芥（NM），硫芥（SM）的类似物，触发炎症反应，微泡形成和凋亡细胞死亡。在这里，我们试图确定参与这些NM诱导的损伤反应的机制。获得的结果显示，SKH-1无毛小鼠皮肤的NM暴露引起H2 A. X和p53磷酸化，并增加p53积累，表明DNA损伤。此外，NM还诱导MAPK/ERK 1/2、JNK 1/2和p38的激活以及Akt的激活，同时还诱导转录因子AP 1的激活。此外，NM暴露诱导了促炎介质即环氧合酶2和诱导型一氧化氮合酶和细胞因子肿瘤坏死因子α的稳健表达，并增加了蛋白水解介质基质金属蛋白酶9的水平。皮肤的NM暴露也增加脂质过氧化、5，5-二甲基-2-（8-辛酸）-1-吡咯啉N-氧化物蛋白加合物形成、蛋白质和DNA氧化，表明氧化应激升高。我们还发现NM诱导的同源重组修复途径增加，表明其参与NM诱导的DNA损伤的修复。总的来说，这些结果表明，NM诱导氧化应激，主要是DNA损伤和MAPK和Akt通路激活的双相反应，其激活转录因子AP 1并诱导炎症和蛋白水解介质的表达，从而促进NM引起的皮肤损伤反应。总之，本研究首次将NM诱导的机制变化与我们早期报道的NM引起的小鼠皮肤损伤病变联系起来，这对于确定潜在的治疗靶点和救援药物可能是有价值的。
Our recent studies in SKH-1 hairless mice have demonstrated that topical exposure to nitrogen mustard (NM), an analog of sulfur mustard (SM), triggers the inflammatory response, microvesication and apoptotic cell death. Here, we sought to identify the mechanism/s involved in these NM-induced injury responses. Results obtained show that NM exposure of SKH-1 hairless mouse skin caused H2A.X and p53 phosphorylation and increased p53 accumulation, indicating DNA damage. In addition, NM also induced the activation of MAPKs/ERK1/2, JNK1/2 and p38 as well as that of Akt together with the activation of transcription factor AP1. Also, NM exposure induced robust expression of pro-inflammatory mediators namely cyclooxygenase 2 and inducible nitric oxide synthase and cytokine tumor necrosis factor alpha, and increased the levels of proteolytic mediator matrix metalloproteinase 9. NM exposure of skin also increased lipid peroxidation, 5,5-dimethyl-2-(8-octanoic acid)-1-pyrroline N-oxide protein adduct formation, protein and DNA oxidation indicating an elevated oxidative stress. We also found NM-induced increase in the homologous recombinant repair pathway, suggesting its involvement in the repair of NM-induced DNA damage. Collectively, these results indicate that NM induces oxidative stress, mainly a bi-phasic response in DNA damage and activation of MAPK and Akt pathways, which activate transcription factor AP1 and induce the expression of inflammatory and proteolytic mediators, contributing to the skin injury response by NM. In conclusion, this study for the first time links NM-induced mechanistic changes with our earlier reported murine skin injury lesions with NM, which could be valuable to identify potential therapeutic targets and rescue agents.
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缺乏p53等位基因会延迟氮芥末引起的早期凋亡和鼠皮肤的炎症。
影响因子：
4.5
作者：
Inturi, Swetha;Tewari-Singh, Neera;Jain, Anil K.;Roy, Srirupa;White, Carl W.;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh
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作者：
Arroyo, CM;Schafer, RJ;Carmichael, AJ
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影响因子：
11.2
作者：
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通讯作者：
Valerie, Kristoffer
影响因子：
7.4
作者：
Inturi, Swetha;Tewari-Singh, Neera;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh