Dietary Lipids and Silica-Accelerated Autoimmunity

自身免疫性疾病是由免疫系统攻击人体自身组织引起的一系列慢性致残性疾病，据估计，在美国有多达2500万人受到不利影响。自身免疫性疾病的患病率明显受到环境因素（如毒物暴露）和生活方式选择（如饮食）的影响。值得注意的是，系统性红斑狼疮（狼疮）是一种影响30万美国人的典型自身免疫性疾病，通常与肾小球肾炎和肾衰竭有关，其风险因职业暴露（如采矿、建筑、保管和制造业）而增加。研究表明，食用鱼油中的n-3多不饱和脂肪酸（PUFAs）有望预防和改善慢性炎症性疾病，包括自身免疫性肾炎。本研究的具体目的是验证一种假设，即摄入n-3 PUFAs会抑制易患狼疮小鼠的硅加速肾炎，这将与肾脏中白细胞募集和炎症相关基因表达的减少相对应。本研究将有两个目的。在Aim 1中，将确定n-3 PUFA消耗及其如何影响二氧化硅加速狼疮性肾炎的潜伏期和严重程度。在Aim 2中，将测试n-3 PUFA如何调节现有硅加速狼疮性肾炎的进展。与NIEHS的使命一致，这些目标的预期结果将是增加对n-3 PUFAs如何影响二氧化硅触发和自身免疫性肾炎恶化的理解。这些发现将产生积极的影响，因为它将是预测n-3 PUFA摄入如何预防或改善二氧化硅和其他有毒物质加速自身免疫的第一步。这项研究的贡献有望提高对n-3 PUFA消耗如何抵消二氧化硅引发和加剧狼疮性肾炎的理解。这一贡献意义重大，因为它将是营养学研究连续体的第一步

DESCRIPTION (provided by applicant): Autoimmune diseases, a constellation of chronic, disabling illnesses that result from the immune system attacking the body's own tissues, are estimated to adversely affect up to 25 million persons in the U.S. The prevalence of autoimmune diseases is markedly impacted by environmental factors (e.g. toxicant exposures) and lifestyle choices (e.g. diet). Notably, the risk of developing systemic lupus erythematosus (lupus), a prototypical autoimmune disease affecting 300,000 Americans and often associated with glomerulonephritis and kidney failure, is increased by occupational exposure (e.g. mining, construction, custodial and manufacturing industries) to silica. Research studies reveal that consumption of n-3 polyunsaturated fatty acids (PUFAs) found in fish oil holds promise for preventing and ameliorating chronic inflammatory diseases including autoimmune nephritis. The specific objective here is to test the hypothesis that consumption of n-3 PUFAs will suppress silica-accelerated nephritis in lupus-prone mice and that this will correspond with decreased leukocyte recruitment and inflammation-associated gene expression in the kidney. This research will be accomplished in two aims. In Aim 1, n-3 PUFA consumption and how it affects latency and severity of silica-accelerated lupus nephritis will be established. In Aim 2, a determination of how n-3 PUFA modulates progression of existing silica-accelerated lupus nephritis will be tested. Consistent with the NIEHS mission, the expected outcomes of these aims will be an increased understanding of how n-3 PUFAs impact silica triggering and exacerbation of autoimmune nephritis. These findings will have a positive impact, because it will be an initial step in the path to predicting how n-3 PUFA consumption might prevent or ameliorate acceleration of autoimmunity by silica and other toxicants. The contribution of this research is expected to be an improved understanding of how n-3 PUFA consumption counteracts the triggering and exacerbation of lupus nephritis by silica. This contribution is significant because it will be the first step in a research continuum that will lead to nutritional strategies to mitigate environmental triggering and exacerbation of autoimmunity. Availability of such preventative and ameliorative strategies would enable individuals who are occupationally exposed to silica to 1) reduce their risk for developing lupus and other autoimmune disease and 2) delay progression of existing autoimmunity by increasing n-3 PUFA consumption via diet and/or supplementation. Furthermore, n-3 PUFA chemoprevention and chemointervention might similarly be applied to workers who are at increased risk of autoimmunity from exposures to toxicants such as asbestos, heavy metals, trichloroethylene, and pesticides. Finally, it is expected that these studies will reveal additional potential benefits of n-3 PUFA consumption on silica-induced lung disease and fibrosis, another understudied area.