Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype.
Defining cutaneous molecular pathobiology of arsenicals using phenylarsine oxide as a prototype.
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DOI：
10.1038/srep34865
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发表时间：
2016-10-11
影响因子：
4.6
通讯作者：
Athar M
中科院分区：
文献类型：
--
作者：
Srivastava RK;Li C;Weng Z;Agarwal A;Elmets CA;Afaq F;Athar M
砷剂是一种疼痛、发炎和起泡的物质，在第一次世界大战/第二次世界大战中作为化学武器被开发出来。然而，它们的大量库存仍然存在，对公众健康构成威胁。氧化苯胂（PAO）是一种强氧化剂，也是一种砷化物的原型，它被用来确定砷化物介导的组织损伤的分子机制。局部施用的PAO诱导皮肤红斑、水肿和微水泡。这些总体炎症反应伴随着促炎细胞因子、ROS和未折叠蛋白反应（UPR）信号传导激活的增强的产生。为了证明UPR在这些病变的病理生物学中的参与，我们采用了化学伴侣，4-苯基丁酸（4-PBA），其减弱UPR。4-PBA显著减少PAO诱导的炎症和起泡。与其在小鼠表皮中的作用相似，在PAO处理的人皮肤角质形成细胞NHEK和HaCaT中观察到ROS、细胞因子、UPR蛋白（GRP 78、p-PERK、p-eIF 2 α、ATF 4和CHOP）和细胞凋亡的剂量和时间依赖性上调。此外，4-PBA显著恢复了这些细胞中的这些分子改变。采用基于RNA干扰（RNAi）的方法，发现CHOP是这些反应的关键调节剂。这些作用与路易氏剂的作用相似，表明PAO可以作为砷剂的原型，用于确定化学损伤的分子发病机制。
Arsenicals are painful, inflammatory and blistering causing agents developed as chemical weapons in World War I/II. However, their large stockpiles still exist posing threat to public health. Phenylarsine oxide (PAO), a strong oxidant and a prototype arsenical is tested for its suitability to defining molecular mechanisms underlying arsenicals-mediated tissue injury. Topically applied PAO induces cutaneous erythema, edema and micro-blisters. These gross inflammatory responses were accompanied by the enhanced production of pro-inflammatory cytokines, ROS and unfolded protein response (UPR) signaling activation. To demonstrate the involvement of UPR in the pathobiology of these lesions, we employed chemical chaperone, 4-phenylbutyric acid (4-PBA) which attenuates UPR. 4-PBA significantly reduced PAO-induced inflammation and blistering. Similar to its effects in murine epidermis, a dose- and time-dependent upregulation of ROS, cytokines, UPR proteins (GRP78, p-PERK, p-eIF2α, ATF4 and CHOP) and apoptosis were observed in PAO-treated human skin keratinocytes NHEK and HaCaT. In addition, 4-PBA significantly restored these molecular alterations in these cells. Employing RNA interference (RNAi)-based approaches, CHOP was found to be a key regulator of these responses. These effects are similar to those manifested by lewisite suggesting that PAO could be used as a prototype of arsenicals to define the molecular pathogenesis of chemical injury.
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DOI：
10.1016/j.bbrc.2008.04.009
发表时间：
2008-06-27
影响因子：
3.1
作者：
Fanelus, Irvens;Desrosiers, Richard R.
通讯作者：
Desrosiers, Richard R.
影响因子：
3.8
作者：
Hughes, Michael F.;Beck, Barbara D.;Thomas, David J.
通讯作者：
Thomas, David J.
影响因子：
7.4
作者：
Inturi, Swetha;Tewari-Singh, Neera;Agarwal, Rajesh
通讯作者：
Agarwal, Rajesh
影响因子：
4.1
作者：
BARRON, ESG;MILLER, ZB;SINGER, TP
通讯作者：
SINGER, TP
影响因子：
15.9
作者：
EAGLE, H;MAGNUSON, HJ;FLEISCHMAN, R
通讯作者：
FLEISCHMAN, R