The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Center for Global Health, Nanjing Medical University, Nanjing 211166, Jiangsu, PR China.
School of Public Health, Baotou Medical College, Baotou 014030, Inner Mongolia, PR China.
Toxicol Sci. 2023 Dec 21;197(1):27-37. doi: 10.1093/toxsci/kfad107.
Some rare earth elements are occupational and environmental toxicants and can cause organ and systemic damage; therefore, they have attracted global attention. Neodymium oxide (Nd2O3) is a rare earth element that is refined and significantly utilized in China. The long noncoding RNA (lncRNA) H19 is encoded by the H19/IGF2 imprinted gene cluster located on human chromosome 11p15.5. H19 has become a research focus due to its ectopic expression leading to the promotion of fibrosis. However, the mechanisms by which it causes pulmonary fibrosis are elusive. This investigation indicates that biologically active Nd2O3 increases H19, SNIP1, and c-myc, decreases miR-29a-3p, accelerates macrophage M2 polarization, and causes pulmonary fibrosis in mice lung tissues. In macrophage-differentiated THP-1 cells, Nd2O3 (25 μg/ml) enhanced H19, SNIP1, and c-myc, reduced miR-29a-3p, accelerated macrophages M2 polarization, and stimulated fibrogenic cytokine (TGF-β1) secretion. Furthermore, the coculturing of Nd2O3-treated macrophage-differentiated THP-1 cells. And human embryonic lung fibroblast cells activated lung fibroblast, which increases the levels of collagen I, α-SMA, p-Smad2/3, and Smad4, whereas H19 knockdown or miR-29a-3p upregulation in macrophages had opposite effects. Moreover, it was revealed that H19/miR-29a-3p/SNIP1/c-myc regulatory axis is involved in pulmonary fibrosis induced by Nd2O3. Therefore, this study provides new molecular insights into the mechanism of pulmonary fibrosis by Nd2O3.
一些稀土元素是职业和环境毒物，会导致器官和全身损伤；因此，它们引起了全球关注。氧化钕（Nd2O3）是一种经过精炼并在中国得到广泛应用的稀土元素。长链非编码 RNA（lncRNA）H19 由位于人类 11p15.5 染色体上的 H19/IGF2 印记基因簇编码。由于其异位表达导致纤维化的促进，H19 已成为研究的焦点。然而，其导致肺纤维化的机制尚不清楚。本研究表明，生物活性 Nd2O3 增加 H19、SNIP1 和 c-myc，减少 miR-29a-3p，加速巨噬细胞 M2 极化，并导致小鼠肺组织纤维化。在巨噬细胞分化的 THP-1 细胞中，Nd2O3（25μg/ml）增强了 H19、SNIP1 和 c-myc，减少了 miR-29a-3p，加速了巨噬细胞 M2 极化，并刺激了成纤维细胞因子（TGF-β1）的分泌。此外，Nd2O3 处理的巨噬细胞分化的 THP-1 细胞和人胚胎肺成纤维细胞共培养激活了肺成纤维细胞，增加了胶原 I、α-SMA、p-Smad2/3 和 Smad4 的水平，而巨噬细胞中的 H19 敲低或 miR-29a-3p 上调则产生相反的效果。此外，研究表明 H19/miR-29a-3p/SNIP1/c-myc 调控轴参与了 Nd2O3 诱导的肺纤维化。因此，本研究为 Nd2O3 诱导的肺纤维化机制提供了新的分子见解。
