可溶性环氧化物水解酶抑制剂对二氧化硅诱导的红斑狼疮小鼠肺纤维化、异位淋巴新生和自身抗体产生的影响

IF 2 4区 医学 Q4 TOXICOLOGY
Inhalation Toxicology Pub Date : 2024-08-01 Epub Date: 2024-10-17 DOI:10.1080/08958378.2024.2413373
Olivia F McDonald, James G Wagner, Ryan P Lewandowski, Lauren K Heine, Vanessa Estrada, Elham Pourmand, Megha Singhal, Jack R Harkema, Kin Sing Stephen Lee, James J Pestka
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引用次数: 0

摘要

目的:给狼疮易感基因 NZBWF1 小鼠急性鼻内灌注结晶二氧化硅(cSiO2)会引发强烈的肺部炎症,从而导致自身免疫。之前在其他临床前模型中进行的研究表明,抑制可溶性环氧化物水解酶(sEH)会上调促进缓解的脂质代谢物,从而对肺部炎症起到保护作用。在此,我们在 NZBWF1 小鼠中评估了急性 IN cSiO2 暴露与选择性环氧化物水解酶抑制剂 TPPU 的作用如何影响炎症、纤维化和自身免疫的脂质组、转录物组、蛋白质组和组织病理学生物标志物:6周大的雌性NZBWF1小鼠被喂食对照组或添加TPPU的饲料2周,然后IN灌注2.5 mg cSiO2或生理盐水载体。结果:二氧化硅处理诱导前列腺素、细胞因子/凝血因子、促炎基因表达、CD206+单核细胞、Ly6B.2+中性粒细胞、CD3+中性粒细胞、CD4+中性粒细胞、CD5+中性粒细胞、CD7+中性粒细胞、CD8+中性粒细胞和CD9+中性粒细胞。+中性粒细胞、CD3+ T 细胞、CD45R+ B 细胞、中心炎、胶原沉积、异位淋巴结构新生和自身抗体。TPPU能有效抑制sEH,这体现在肺部脂质体谱的偏斜上,并能减少cSiO2诱导的肺灌洗液中的单核细胞、中性粒细胞和淋巴细胞,但对其他生物标志物没有显著影响。讨论:cSiO2诱发了NZBWF1小鼠严重的肺部炎症和纤维化,这种炎症和纤维化在7天PI时就很明显,到28天PI时发展为ELS和自身免疫。然而,TPPU并不影响ELS的形成或自身抗体反应,这表明在我们的模型中,sEH对cSiO2诱发的肺部炎症、纤维化和早期自身免疫的影响微乎其微。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
Inhalation Toxicology
Inhalation Toxicology 医学-毒理学
CiteScore
4.10
自引率
4.80%
发文量
38
审稿时长
6-12 weeks
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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