Abstract
OBJECTIVE: Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO(2)) triggers robust lung inflammation that drives autoimmunity. Prior studies in other preclinical models show that soluble epoxide hydrolase (sEH) inhibition upregulates pro-resolving lipid metabolites that are protective against pulmonary inflammation. Herein, we assessed in NZBWF1 mice how acute IN cSiO(2) exposure with or without the selective sEH inhibitor TPPU influences lipidomic, transcriptomic, proteomic, and histopathological biomarkers of inflammation, fibrosis, and autoimmunity. METHODS: Female 6-week-old NZBWF1 mice were fed control or TPPU-supplemented diets for 2 weeks then IN instilled with 2.5 mg cSiO(2) or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO(2) instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies. RESULTS: cSiO(2)-treatment induced prostaglandins, cytokines/chemokine, proinflammatory gene expression, CD206(+) monocytes, Ly6B.2(+) neutrophils, CD3(+) T cells, CD45R(+) B cells, centriacinar inflammation, collagen deposition, ectopic lymphoid structure neogenesis, and autoantibodies. While TPPU effectively inhibited sEH as reflected by skewed lipidomic profile in lung and decreased cSiO(2)-induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers. DISCUSSION: cSiO(2) evoked robust pulmonary inflammation and fibrosis in NZBWF1 mice that was evident at 7 days PI and progressed to ELS development and autoimmunity by 28 days PI. sEH inhibition by TPPU modestly suppressed cSiO(2)-induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO(2)-triggered lung inflammation, fibrosis, and early autoimmunity in our model.