miR-21 mediates nickel nanoparticle-induced pulmonary injury and fibrosis

Abstract

We and other groups have demonstrated that exposure to nickel nanoparticles (Nano-Ni) results in severe and persistent lung inflammation and fibrosis, but the underlying mechanisms remain unclear. Here, we propose that miR-21 may play an important role in Nano-Ni-induced lung inflammation, injury, and fibrosis. Our dose-and time-response studies demonstrated that exposure of C57BL/6J (WT) mice to Nano-Ni resulted in upregulation of miR-21, proinflammatory cytokines, and profibrotic mediators. Histologically, exposure to Nano-Ni caused severe pulmonary inflammation and fibrosis. Based on the dose-and time-response studies, we chose a dose of 50 μg of Nano-Ni per mouse to compare the effects of Nano-Ni on WT with those on miR-21 KO mouse lungs. At day 3 post-exposure, Nano-Ni caused severe acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, total protein concentration, MMP-2/9 protein levels and activities, and proinflammatory cytokines in the BALF or lung tissues from WT mice, which were confirmed histologically. Although Nano-Ni had similar effects on miR-21 KO mice, the above mentioned levels were significantly lower than those in WT mice. Histologically, lungs from WT mice exposed to Nano-Ni had infiltration of a large number of polymorphonuclear (PMN) cells and macrophages in the alveolar space and interstitial tissues. However, exposure of miR-21 KO mice to Nano-Ni only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive pulmonary fibrosis and chronic inflammation in the WT mouse lungs. However, exposure of miR-21 KO mice to Nano-Ni only caused mild lung fibrosis and chronic lung

MicroRNA expression in lung tissues of asbestos-exposed mice: Upregulation of miR-21 and downregulation of tumor suppressor genes Pdcd4 and Reck

“…37 In this study, we used relatively short asbestos fibers, which induced only mild histopathological changes and macrophage infiltration. A recent study using miR-21 knockout mice has demonstrated that miR-21 plays a critical role in nickel nanoparticle-induced pulmonary inflammation and fibrosis, 38 suggesting that miR-21 precedes asbestosinduced histopathological changes. In this study, fluorescent immunohistochemistry showed that PDCD4 and RECK expression was reduced in bronchial and alveolar cells throughout the lung tissues, even where no histopathological changes occurred.…”

“…Extensive studies have been conducted to examine molecular events and histopathological changes in mice exposed to particulate matters, including asbestos. 37,38 However, it has been reported that intratracheal administration of asbestos induces lung tumor in rats and hamsters, but not in mice. 1 Although we employed a mouse model with subacute asbestos exposure in this study, further studies using different animal species with long-term asbestos exposure are needed to understand the role of miRNA and target genes in the pathogenesis of asbestos-induced diseases.…”

Comprehensive analysis of the alteration of plasma miRNA expression level in mice exposed to diesel exhaust

“…Many studies have shown that abnormal expression levels of miRNAs are closely related to diseases such as cancer, diabetes, stroke, and Alzheimer's disease (Hironaka-Mitsuhashi et al, 2017;Kumar et al, 2017;Liang et al, 2020;Vijayan et al, 2018). Furthermore, several reports indicated that exposure to environmental pollutants and particulate matter such as arsenic, lead, cadmium, cigarette smoke, PM 2.5 , and nickel nanoparticles affect the expression levels of miRNAs (An et al, 2014;Chao et al, 2017;Hassan et al, 2012;Mo et al, 2020;Ren et al, 2015). These reports suggest that dysregulation of miRNA expression is associated with detrimental effects caused by exposure to environmental chemicals.…”

Assessing Risks Caused by Nickel-Containing Nanomaterials: Hazard Characterization in Vivo

“…Three types of Ni NPs (with non-modified surface, oxide-passivated, and protected with monomolecular carbon layers) were introduced through single intratracheal instillation into common mice and mice with knocked-out micro-RNA (miR)-21 gene; the experiments revealed that expression of Reck gene (tumor dissemination inhibitor) that was a direct target for effects produced by miR-21 was inhibited only in wild mice under exposure to the first two types of NPs. These data highlight an important role played by miR-21 in inflammatory response induction in vivo and probably carcinogenicity of nickel NPs [21,22]. There was a comparative study performed on mice who were exposed to 3 types of Ni-containing NPs through a single intratracheal instillation in doses varying from 10 to 100 µg; the exposure resulted in dose-dependent development of acute lung inflammation with elevated contents of neutrophils, CXCL1/KC, total proteins and greater LDG activity in BAL.…”