Dietary Lipids and Silica-Accelerated Autoimmunity

膳食脂质和二氧化硅加速自身免疫

• 批准号: 8469038
• 负责人: James J Pestka
• 金额: $ 15.04万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469038
• 关键词: Acceleration; Adult; Affect; American; Antibody Formation; Apoptosis; Area; Asbestos; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Centers for Disease Control and Prevention (U.S.); Chemoprevention; Chemosensitization; Chronic; Clinical Research; Consumption; Development; Diet; Dietary Factors; Dietary Fats; Disease; Disease Progression; Docosahexaenoic Acids; Effectiveness; Environmental Exposure; Environmental Risk Factor; Epidemiology; Exposure to; Fibrosis; Fish Oils; Food; Foundations; Funding Opportunities; Gene Expression; Genetic Transcription; Glomerulonephritis; Goals; Health; Heavy Metals; Human; Immune system; Immunity; Immunoglobulin A; Indium; Individual; Industry; Inflammation; Inflammatory; Inhalation Exposure; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Language; Lead; Leukocytes; Life Style; Link; Lung; Lung diseases; Lupus; Lupus Nephritis; Mining; Mission; Modeling; Mus; National Institute of Allergy and Infectious Disease; National Institute of Environmental Health Sciences; Nephritis; Nutritional; Occupational Exposure; Occupations; Onset of illness; Outcome; Persons; Pesticides; Plasma Cells; Polyunsaturated Fatty Acids; Prevalence; Prevention; Production; Public Health; Recruitment Activity; Recurrence; Regimen; Renal function; Research; Resolution; Risk; Severities; Silicon Dioxide; Supplementation; Surveys; Systemic Lupus Erythematosus; Testing; Tissues; Toxicant exposure; Trichloroethylene; Trichothecenes; United States National Institutes of Health; Work; abstracting; base; cytokine; improved; insight; lupus prone mice; macrophage; mouse model; preclinical study; prevent; research study; toxicant

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.

描述（由申请人提供）：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，估计在美国对多达2500万人产生不利影响。自身免疫性疾病的患病率明显受到环境因素（例如有毒物质暴露）和生活方式选择（例如饮食）的影响。值得注意的是，发生系统性红斑狼疮（狼疮）的风险增加，这是一种影响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，职业暴露（例如采矿，建筑，保管和制造业）二氧化硅。研究表明，食用鱼油中的n-3多不饱和脂肪酸（PUFA）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检验以下假设：摄入n-3 PUFA将抑制狼疮易感小鼠的二氧化硅加速性肾炎，这将与肾脏中白细胞募集和炎症相关基因表达减少相对应。本研究将在两个目标下完成。在目标1中，将建立n-3 PUFA消耗及其如何影响二氧化硅加速的狼疮性肾炎的潜伏期和严重程度。在目标2中，将测试n-3 PUFA如何调节现有二氧化硅加速的狼疮性肾炎的进展的确定。与NIEHS的使命一致，这些目标的预期结果将是增加对n-3 PUFA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消费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。这项研究的贡献预计将是一个更好的了解如何n-3多不饱和脂肪酸的消费抵消触发和二氧化硅狼疮肾炎的恶化。这一贡献意义重大，因为这将是实现营养研究连续体的第一步 减轻环境触发和自身免疫恶化的策略。 此类预防和改善策略的可用性将使职业性接触二氧化硅的个人能够1）降低患狼疮和其他自身免疫性疾病的风险，2）通过饮食和/或补充剂增加n-3 PUFA的消耗来延迟现有自身免疫的进展。此外，n-3多不饱和脂肪酸化学预防和化学干预可能同样适用于工人谁是在暴露于有毒物质，如石棉，重金属，三氯乙烯和农药的自身免疫的风险增加。最后，预计这些研究将揭示n-3 PUFA消费对二氧化硅诱导的肺部疾病和纤维化的额外潜在益处，这是另一个未充分研究的领域。

项目成果

Silica Triggers Inflammation and Ectopic Lymphoid Neogenesis in the Lungs in Parallel with Accelerated Onset of Systemic Autoimmunity and Glomerulonephritis in the Lupus-Prone NZBWF1 Mouse.

• DOI: 10.1371/journal.pone.0125481
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bates MA;Brandenberger C;Langohr I;Kumagai K;Harkema JR;Holian A;Pestka JJ
• 通讯作者: Pestka JJ

Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption.

• DOI: 10.1371/journal.pone.0160622
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bates MA;Brandenberger C;Langohr II;Kumagai K;Lock AL;Harkema JR;Holian A;Pestka JJ
• 通讯作者: Pestka JJ