Lauren K Heine, Tasha Scarlett, James G Wagner, Ryan P Lewandowski, Abby D Benninghoff, Ashleigh N Tindle, Anna E Skedel, Jack R Harkema, James J Pestka
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Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset.</p><p><strong>Results: </strong>VEH/CON mice showed no pathology. cSiO<sub>2</sub>/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO<sub>2</sub>/CON lungs exhibited elevated cellularity, chemokines, CD3<sup>+</sup> T-cells, CD45R <sup>+</sup> B-cells, IgG <sup>+</sup> plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects.</p><p><strong>Discussion: </strong>The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO<sub>2</sub>-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO<sub>2</sub>-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice.</p><p><strong>Conclusion: </strong>These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.</p>","PeriodicalId":13561,"journal":{"name":"Inhalation Toxicology","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378324/pdf/","citationCount":"0","resultStr":"{\"title\":\"Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.\",\"authors\":\"Lauren K Heine, Tasha Scarlett, James G Wagner, Ryan P Lewandowski, Abby D Benninghoff, Ashleigh N Tindle, Anna E Skedel, Jack R Harkema, James J Pestka\",\"doi\":\"10.1080/08958378.2024.2318378\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Occupational exposure to respirable crystalline silica (cSiO<sub>2</sub>) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO<sub>2</sub> exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO<sub>2</sub> and DHA effects in mature lupus-prone adult mice, more representative of cSiO<sub>2</sub>-exposed worker age.</p><p><strong>Methods: </strong>Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO<sub>2</sub> weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset.</p><p><strong>Results: </strong>VEH/CON mice showed no pathology. cSiO<sub>2</sub>/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO<sub>2</sub>/CON lungs exhibited elevated cellularity, chemokines, CD3<sup>+</sup> T-cells, CD45R <sup>+</sup> B-cells, IgG <sup>+</sup> plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. 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引用次数: 0
摘要
目的：职业暴露于可吸入结晶二氧化硅（cSiO2）与红斑狼疮的发病有关。以前对易患红斑狼疮的幼年小鼠进行的研究表明，鼻内接触二氧化硅会引发自身免疫，而二十二碳六烯酸（DHA）可预防这种免疫。本研究探讨了 cSiO2 和 DHA 对成熟的红斑狼疮易感成年小鼠的影响，这更能代表暴露于 cSiO2 的工人年龄：方法：雌性 NZBWF1 小鼠（14 周大）喂食对照组（CON）或添加 DHA 的饲料。两周后，每周向小鼠体内灌注生理盐水（VEH）或 1 毫克二氧化硅，连续四周。然后对灌注后1周和5周的组群进行分析，以检测肺部炎症、细胞计数、趋化因子、组织病理学、B细胞和T细胞浸润、自身抗体和基因特征，结果与自身免疫性肾小球肾炎的发病相关：cSiO2/CON小鼠的肺部表现出细胞增多、趋化因子增多、CD3+ T细胞增多、CD45R + B细胞增多、IgG + 浆细胞增多、基因表达增多、IgG自身抗体增多和肾小球肥大。补充 DHA 可减轻所有这些影响：这里使用的成熟成年 NZBWF1 小鼠代表了与免疫耐受破坏相吻合的生命阶段，也更恰当地代表了暴露于二氧化硅的工人的年龄（20-30 岁）。二氧化硅在成熟成年小鼠中诱发了强烈的肺部炎症、自身抗体反应和肾小球肾炎，超过了之前在年轻成年人中观察到的影响。在成年小鼠中，等同于人体剂量的 DHA 能有效对抗二氧化硅诱导的炎症/自身免疫反应，这反映了对幼年小鼠的保护作用：这些结果凸显了临床前狼疮模型中生命阶段的重要性，并强调了欧米伽-3 脂肪酸对毒性诱发的自身免疫反应的治疗潜力。
Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.
Objective: Occupational exposure to respirable crystalline silica (cSiO2) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO2 exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO2 and DHA effects in mature lupus-prone adult mice, more representative of cSiO2-exposed worker age.
Methods: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO2 weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset.
Results: VEH/CON mice showed no pathology. cSiO2/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO2/CON lungs exhibited elevated cellularity, chemokines, CD3+ T-cells, CD45R + B-cells, IgG + plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects.
Discussion: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO2-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO2-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice.
Conclusion: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.
期刊介绍：
Inhalation Toxicology is a peer-reviewed publication providing a key forum for the latest accomplishments and advancements in concepts, approaches, and procedures presently being used to evaluate the health risk associated with airborne chemicals.
The journal publishes original research, reviews, symposia, and workshop topics involving the respiratory system’s functions in health and disease, the pathogenesis and mechanism of injury, the extrapolation of animal data to humans, the effects of inhaled substances on extra-pulmonary systems, as well as reliable and innovative models for predicting human disease.
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