Impact of soluble epoxide hydrolase inhibition on silica-induced pulmonary fibrosis, ectopic lymphoid neogenesis, and autoantibody production in lupus-prone mice.

Objective: Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO₂) 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 cSiO₂ 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 cSiO₂ or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO₂ instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies. Results: cSiO₂-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 cSiO₂-induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers. Discussion: cSiO₂ 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 cSiO₂-induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO₂-triggered lung inflammation, fibrosis, and early autoimmunity in our model. [ABSTRACT FROM AUTHOR]