1. Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.
- Author
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Heine, Lauren K., Scarlett, Tasha, Wagner, James G., Lewandowski, Ryan P., Benninghoff, Abby D., Tindle, Ashleigh N., Skedel, Anna E., Harkema, Jack R., and Pestka, James J.
- Subjects
OMEGA-3 fatty acids ,AUTOANTIBODIES ,LUNGS ,LYMPHOID tissue ,ECTOPIC tissue ,AUTOIMMUNITY ,IMMUNOLOGICAL tolerance ,T cell receptors - Abstract
Occupational exposure to respirable crystalline silica (cSiO
2 ) 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. 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. 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. 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. These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses. [ABSTRACT FROM AUTHOR]- Published
- 2024
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