Department of Toxicology, School of public Health, Lanzhou University, Lanzhou, China.
Lanzhou Municipal Center for Disease Control, Lanzhou, China.
Environ Toxicol. 2019 Jun;34(6):719-727. doi: 10.1002/tox.22738. Epub 2019 Feb 27.
Nickel oxide nanoparticles (Nano NiO) could induce pulmonary fibrosis, however, the mechanisms are still unknown. The aim of the present study was to explore the roles of transforming growth factor-β1 (TGF-β1), mitogen-activated protein kinase (MAPK) pathway and MMPs/TIMPs balance in Nano NiO-induced pulmonary fibrosis. For that purpose, we first established Nano NiO-induced human lung adenocarcinoma epithelial cells (A549 cells) model of collagen excessive formation through detecting the levels of hydroxyproline (Hyp) and type I collagen (Col-I). Then the protein levels of TGF-β1, MAPKs, and MMPs/TIMPs were assessed by Western blot. The results showed that Nano NiO resulted in the increased contents of Hyp, Col-I, and TGF-β1, the MAPK pathway activation and MMPs/TIMPs imbalance with a dose-dependent manner. In addition, to investigate whether TGF-β1 mediated MAPK signaling pathway, A549 cells were treated by 100 μg/mL Nano NiO combined with TGF-β1, p38 MAPK, and ERK1/2 inhibitors (10 μM SB431542, 10 μM SB203580, and 10 μM U0126), respectively. We found that MAPK signal pathway was suppressed by TGF-β1 inhibitor. Meanwhile, the increased contents of Hyp and Col-I, and MMPs/TIMPs imbalance were alleviated by the p38 MAPK and ERK1/2 inhibitors, respectively. These findings indicated that the MAPK pathway and MMPs/TIMPs imbalance were involved in collagen excessive formation induced by Nano NiO.
氧化镍纳米颗粒（Nano NiO）可诱导肺纤维化，但具体机制尚不清楚。本研究旨在探讨转化生长因子-β1（TGF-β1）、丝裂原活化蛋白激酶（MAPK）通路和 MMPs/TIMPs 平衡在 Nano NiO 诱导的肺纤维化中的作用。为此，我们首先通过检测羟脯氨酸（Hyp）和 I 型胶原（Col-I）的水平，建立了 Nano NiO 诱导的人肺腺癌细胞（A549 细胞）胶原过度形成模型。然后通过 Western blot 检测 TGF-β1、MAPKs 和 MMPs/TIMPs 的蛋白水平。结果表明，Nano NiO 以剂量依赖的方式导致 Hyp、Col-I 和 TGF-β1 的含量增加，MAPK 通路激活和 MMPs/TIMPs 失衡。此外，为了研究 TGF-β1 是否介导 MAPK 信号通路，我们用 100μg/mL Nano NiO 联合 TGF-β1、p38 MAPK 和 ERK1/2 抑制剂（10μM SB431542、10μM SB203580 和 10μM U0126）处理 A549 细胞。结果发现，TGF-β1 抑制剂可抑制 MAPK 信号通路。同时，p38 MAPK 和 ERK1/2 抑制剂分别减轻了 Hyp 和 Col-I 含量的增加以及 MMPs/TIMPs 失衡。这些结果表明，MAPK 通路和 MMPs/TIMPs 失衡参与了 Nano NiO 诱导的胶原过度形成。
