Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage
Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage
复制标题
DOI：
10.1016/j.yexmp.2011.05.010
复制
发表时间：
2011-10-01
影响因子：
3.6
通讯作者：
Laskin, Jeffrey D.
中科院分区：
文献类型：
--
作者：
Joseph, Laurie B.;Gerecke, Donald R.;Laskin, Jeffrey D.
硫芥（SM，双（2-氯乙基）硫化物）是一种双功能烷化剂，可引起皮肤炎症、水肿和起泡。为了研究SM诱导的损伤的发病机制，我们使用了蒸汽杯模型，该模型提供了SM与皮肤持续接触的闭塞环境。将SKH-1无毛小鼠背部皮肤暴露于饱和SM蒸气或空气对照。术后1-14 d观察组织学变化、炎症标志物及DNA损伤情况。1天后，SM引起表皮变薄、角质层脱落、基底细胞核溶解、出血以及真皮中巨噬细胞和中性粒细胞积聚。切割的半胱天冬酶-3和磷酸化的组蛋白2A.X（磷酸-H2 A.X）。细胞凋亡和DNA损伤的标志物，分别增加，而增殖细胞核抗原（PCNA）下调后SM曝光。到第3天，观察到上皮细胞肥大、水肿、角化不全和表皮结构丧失。产生促炎介质的酶包括髓过氧化物酶和环氧合酶-2上调。7天后，角蛋白-10，分化标志物，在角质层中是明显的。这与潜在焦痂相关，因为新表皮开始在伤口边缘迁移。三色染色显示真皮中胶原蛋白沉积增加。PCNA在表皮中的表达与增生、角化过度和角化不全相关。到第14天，表皮再生，伴有广泛增生，并且切割的半胱天冬酶-3、环氧合酶-2和磷酸-H2 A的表达减少。这些发现与SM诱导的人类皮肤损伤的病理生理学一致，表明无毛小鼠可用于研究水疱剂的皮肤毒性和对抗措施的潜在功效。(C)2011 Elsevier Inc. All rights reserved.
Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1-14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X). markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures. (C) 2011 Elsevier Inc. All rights reserved.