Carbon black nanoparticles induce pulmonary fibrosis through NLRP3 inflammasome pathway modulated by miR-96 targeted FOXO3a
Carbon black nanoparticles induce pulmonary fibrosis through NLRP3 inflammasome pathway modulated by miR-96 targeted FOXO3a
复制标题
炭黑纳米颗粒通过 miR-96 靶向 FOXO3a 调节的 NLRP3 炎症小体途径诱导肺纤维化
DOI：
10.1016/j.chemosphere.2019.125075
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Rong Zhang
中科院分区：
文献类型：
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作者：
Lixiao Zhou;Peiyuan Li;Mengyue Zhang;Bin Han;Chen Chu;Xuan Su;Binghua Li;Hui Kang;Jie Ning;Boyuan Zhang;Shitao Ma;Dong Su;Yaxian Pang;Yujie Niu;Rong Zhang
炭黑纳米粒子（CBNP）是细颗粒物（PM2.5）等空气污染物的核心成分，也是一种常见的制造材料。它被证明会对肺功能产生不良影响，甚至引起肺纤维化。然而，CBNP诱导的肺纤维化的潜在机制仍不清楚。本研究旨在探讨CBNPs在大鼠肺和人支气管上皮（16 HBE）细胞中引起纤维化作用的机制。将49只雄性大鼠随机分为7组，分别为染毒14 d组（30 mg/m3）、染毒28 d组（5 mg/m3和30 mg/m3）、染毒90 d组（30 mg/m3）及相应对照组。大鼠仅鼻吸入CBNP。分别用0、50、100和200 μg/mL CBNPs处理16 HBE细胞24 h。此外，还建立了Forkhead转录因子O类（FOXO）3a和miR-96过表达或抑制的16 HBE细胞，以揭示相关机制。我们的研究结果表明CBNPs诱导肺纤维化的时间和剂量依赖性的方式。CBNP诱导大鼠肺中的持续炎症，如通过全肺灌洗液（WLL）中的组织病理学和细胞学分析所观察到的。在体内和体外，CBNPs暴露显著增加NLRP 3炎性体的表达，伴随着活性氧（ROS）的增加，miR-96的减少和FOXO 3a的表达的增加，并呈剂量和时间依赖性。miR-96过表达或FOXO 3a抑制可通过抑制NLRP 3炎性体部分挽救纤维化效应。总之，我们的研究表明CBNPs诱导的肺纤维化至少部分依赖于NLRP 3炎性体的激活，而NLRP 3炎性体的激活受靶向FOXO 3a的miR-96的调控。
Carbon black nanoparticle (CBNP) is a core constituent of air pollutants like fine particulate matter (PM2.5) as well as a common manufactural material. It was proved to pose adverse effects on lung function and even provoke pulmonary fibrosis. However, the underlying mechanisms of CBNPs-induced pulmonary fibrosis remain unclear. The present study aimed to investigate the mechanism of fibrotic effects caused by CBNPs in rat lung and human bronchial epithelial (16HBE) cells. Forty-nine male rats were randomly subjected to 7 groups, means the 14-day exposure group (30 mg/m3), the 28-day exposure groups (5 mg/m3and 30 mg/m3), the 90-day exposure group (30 mg/m3) and their respective controls. Rats were nose-only-inhaled CBNPs. 16HBE cells were treated with 0, 50, 100 and 200 μg/mL CBNPs respectively for 24 h. Besides, Forkhead transcription factor class O (FOXO)3a and miR-96 overexpression or suppression 16HBE cells were established to reveal relative mechanisms. Our results suggested CBNPs induced pulmonary fibrosis in time- and dose-dependent manners. CBNPs induced persisting inflammation in rat lung as observed by histopathology and cytology analyses in whole lung lavage fluid (WLL). Both in vivo and in vitro, CBNPs exposure significantly increased the expression of NLRP3 inflammasome, accompanied by the increased reactive oxygen species (ROS), decreased miR-96 and increased FOXO3a expressions dose -and time-dependently. MiR-96 overexpression or FOXO3a suppression could partially rescue the fibrotic effects through inhibiting NLRP3 inflammasome. Conclusively, our research show that CBNPs-induced pulmonary fibrosis was at least partially depended on activation of NLRP3 inflammasome which modulated by miR-96 targeting FOXO3a.