Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin.
Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin.
复制标题
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。
DOI：
10.1016/j.tox.2013.06.013
复制
发表时间：
2013-09-15
期刊：
影响因子：
4.5
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
--
作者：
Inturi, Swetha;Tewari-Singh, Neera;Jain, Anil K.;Roy, Srirupa;White, Carl W.;Agarwal, Rajesh
双功能烷化剂硫芥（SM）及其类似物氮芥（NM）会导致DNA损伤，导致细胞死亡，并可能激活炎症。转录因子p53通过调节细胞周期进程和凋亡在DNA损伤中起关键作用。我们实验室的早期研究表明，在体外和体内暴露于NM后，表皮细胞中p53在Ser 15处磷酸化，总p53增加。为了阐明p53在NM诱导的皮肤毒性中的作用，我们使用携带野生型（WT）或杂合型p53（p53+/−）的SKH-1无毛小鼠。与p53+/−小鼠相比，暴露于NM（3.2 mg）24 h时WT中表皮厚度和凋亡细胞死亡的增加更为显著。然而，到暴露后72小时，WT和p53+/−小鼠中NM诱导的表皮细胞死亡增加相当。髓过氧化物酶活性数据表明，中性粒细胞浸润强烈增强NM暴露WT小鼠在24小时持续通过72小时的曝光。相反，在p53+/−小鼠中，仅在暴露后72 h观察到强烈的NM诱导的中性粒细胞浸润（与WT小鼠相当）。类似地，NM暴露强烈诱导WT中的巨噬细胞和肥大细胞浸润，但不是p53+/−小鼠。总之，这些数据表明，小鼠皮肤中NM诱导的早期细胞凋亡和炎症是p53依赖性的。因此，针对这一途径可能是一种新的策略，用于开发对抗水疱剂诱导的皮肤损伤的对策。
Bifunctional alkylating agent sulfur mustard (SM) and its analog nitrogen mustard (NM) cause DNA damage leading to cell death, and potentially activating inflammation. Transcription factor p53 plays a critical role in DNA damage by regulating cell cycle progression and apoptosis. Earlier studies by our laboratory demonstrated phosphorylation of p53 at Ser15 and an increase in total p53 in epidermal cells both in vitro and in vivo following NM exposure. To elucidate the role of p53 in NM-induced skin toxicity, we employed SKH-1 hairless mice harboring wild type (WT) or heterozygous p53 (p53+/−). Exposure to NM (3.2 mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/− mice at 24 h. However, by 72 h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/− mice. Myeloperoxidase activity data showed that neutrophil infiltration was strongly enhanced in NM-exposed WT mice at 24 h persisting through 72 h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72 h after exposure in p53+/− mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/− mice. Together, these data indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway could be a novel strategy for developing countermeasures against vesicants-induced skin injury.
登录
查看更多内容
影响因子：
4
作者：
Lefkowitz, DL;Lefkowitz, SS
通讯作者：
Lefkowitz, SS
影响因子：
3.6
作者：
Joseph, Laurie B.;Gerecke, Donald R.;Laskin, Jeffrey D.
通讯作者：
Laskin, Jeffrey D.
影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.
影响因子：
12.4
作者：
Matas, D;Milyavsky, M;Rotter, V
通讯作者：
Rotter, V
影响因子：
7.4
作者：
Inturi, Swetha;Tewari-Singh, Neera;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh