Chang Yoke-Chen, Soriano Melannie, Hahn Rita A, Casillas Robert P, Gordon Marion K, Laskin Jeffrey D, Gerecke Donald R
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA.
Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA.
Toxicol Appl Pharmacol. 2018 Sep 15;355:52-59. doi: 10.1016/j.taap.2018.06.008. Epub 2018 Jun 20.
Sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) is a chemical warfare agent that generates an inflammatory response in the skin and causes severe tissue damage and blistering. In earlier studies, we identified cutaneous damage induced by SM in mouse ear skin including edema, erythema, epidermal hyperplasia and microblistering. The present work was focused on determining if SM-induced injury was associated with alterations in mRNA and protein expression of specific cytokines and chemokines in the ear skin. We found that SM caused an accumulation of macrophages and neutrophils in the tissue within one day which persisted for at least 7 days. This was associated with a 2-15 fold increase in expression of the proinflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α at time points up to 7 days post-SM exposure. Marked increases (20-1000 fold) in expression of chemokines associated with recruitment and activation of macrophages were also noted in the tissue including growth-regulated oncogene α (GROα/CXCL1), monocyte chemoattractant protein 1 (MCP-1/CCL2), granulocyte-colony stimulating factor (GCSF/CSF3), macrophage inflammatory protein 1α (MIP1α/CCL3), and IFN-γ-inducible protein 10 (IP10/CXCL10). The pattern of cytokines/chemokine expression was coordinate with expression of macrophage elastase/MMP12 and neutrophil collagenase/MMP8 suggesting that macrophages and neutrophils were, at least in part, a source of cytokines and chemokines. These data support the idea that inflammatory cell-derived mediators contribute to the pathogenesis of SM induced skin damage. Modulating the infiltration of inflammatory cells and reducing the expression of inflammatory mediators in the skin may be an important strategy for mitigating SM-induced cutaneous injury.
硫芥（2,2'-二氯二乙硫醚，SM）是一种化学战剂，可在皮肤中引发炎症反应，导致严重的组织损伤和水疱形成。在早期研究中，我们确定了SM在小鼠耳部皮肤中引起的皮肤损伤，包括水肿、红斑、表皮增生和微水疱形成。目前的工作重点是确定SM诱导的损伤是否与耳部皮肤中特定细胞因子和趋化因子的mRNA和蛋白质表达变化有关。我们发现，SM在一天内导致组织中巨噬细胞和中性粒细胞积聚，这种积聚至少持续7天。这与促炎细胞因子白细胞介素-1β、白细胞介素-6和肿瘤坏死因子α在SM暴露后7天内的表达增加2至15倍有关。在组织中还观察到与巨噬细胞募集和激活相关的趋化因子表达显著增加（20至1000倍），包括生长调节致癌基因α（GROα/CXCL1）、单核细胞趋化蛋白1（MCP-1/CCL2）、粒细胞集落刺激因子（GCSF/CSF3）、巨噬细胞炎性蛋白1α（MIP1α/CCL3）和干扰素-γ诱导蛋白10（IP10/CXCL10）。细胞因子/趋化因子的表达模式与巨噬细胞弹性蛋白酶/MMP12和中性粒细胞胶原酶/MMP8的表达一致，表明巨噬细胞和中性粒细胞至少部分是细胞因子和趋化因子的来源。这些数据支持炎症细胞衍生介质促成SM诱导的皮肤损伤发病机制的观点。调节炎症细胞的浸润并减少皮肤中炎症介质的表达可能是减轻SM诱导的皮肤损伤的重要策略。
