Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America.
Biomolecular Resource Facility, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS One. 2014 Jun 3;9(6):e98660. doi: 10.1371/journal.pone.0098660. eCollection 2014.
Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs) including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC) supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water). TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.
三氯乙烯（TCE）是一种普遍存在的环境污染物，它与多种自身免疫性疾病（AD）有关，包括系统性红斑狼疮、硬皮病和肝炎。AD 发病机制涉及的机制在很大程度上尚不清楚。我们实验室之前在 MRL+/+小鼠中的研究表明，氧化/硝化应激在 TCE 诱导的自身免疫中起作用，N-乙酰半胱氨酸（NAC）补充通过减轻氧化应激提供保护。本研究旨在进一步评估硝化应激在 TCE 介导的自身免疫中的作用，并确定易受硝化应激影响的蛋白质。将雌性 MRL +/+小鼠分为 TCE、NAC 或 TCE+NAC 组，分别给予 TCE（10mmol/kg，腹腔注射，每 4 天 1 次）、NAC（通过饮用水约 250mg/kg/天）6 周。TCE 暴露导致血清抗核和抗组蛋白抗体显著增加，同时诱导 iNOS 显著增加，血清和肝脏中硝基酪氨酸（NT）形成增加。蛋白质组学分析鉴定出 TCE 处理小鼠肝脏中另外 14 种硝化蛋白。此外，TCE 暴露导致 GSH 水平降低和 NF-κB 激活增加。值得注意的是，NAC 补充不仅减轻了 TCE 诱导的硝化应激，表现为 iNOS、NT、硝化蛋白、NF-κB p65 激活和 GSH 水平增加减少，而且还减轻了自身免疫标志物，表现为血清中自身抗体水平降低。这些发现为硝化应激在 TCE 介导的自身免疫反应中的作用提供了支持，并确定了具有自身免疫潜力的特定硝化蛋白。NAC 减轻小鼠 TCE 诱导的自身免疫反应为设计治疗策略提供了一种方法。
