PM2.5 暴露通过调控铁死亡 TGF-β 信号诱导肺损伤和纤维化。
PM2.5 Exposure Induces Lung Injury and Fibrosis by Regulating Ferroptosis TGF- Signaling.
机构信息
Department of Respiratory Medicine, Harbin Medical University Cancer Hospital, No. 150 Haping Road, Harbin 150081, China.
出版信息
Dis Markers. 2022 Sep 27;2022:7098463. doi: 10.1155/2022/7098463. eCollection 2022.
BACKGROUND
Lung fibrosis is a severe lung disorder featured by chronic nonspecific inflammation of the interstitial lung and deposition of collagen, leading to lung dysfunction. It has been identified that ferroptosis is involved in the progression of lung injury. Particulate matter (PM2.5) is reported to be correlated with the incidence of pulmonary fibrosis. However, mechanisms underlying ferroptosis in PM2.5-related lung fibrosis is unclear. In this study, we aimed to explore the effect of PM2.5 on ferroptosis in lung fibrosis and the related molecular mechanisms.
METHODS
PM2.5-treated mouse model and cell model were established. Fibrosis and tissue damage were measured by Masson's trichrome staining and HE staining. Fibrosis biomarkers, such as -SMA, collagen I, and collagen III, were examined by histological analysis. The ferroptosis phenotypes, including the levels of iron, Fe, MDA, and GSH, were measured by commercial kits. ROS generation was checked by DCFH-DA. The oxidative stress indicators, 3-nitro-L-tyrosine (3'-NT), 4-HNE, and protein carbonyl, were checked by enzyme linked immunosorbent assay (ELISA). The thiobarbituric acid reactive substances (TBARS) and GSH/GSSG ratio were assessed by TBARS assay kit and GSH/GSSG assay kit, respectively. TGF- signaling was detected by Western blotting.
RESULTS
PM2.5 induced the lung injury and fibrosis in the mice model, along with elevated expression of fibrosis markers. PM2.5 enhanced oxidative stress in the lung of the mice. The SOD2 expression was reduced, and NRF2 expression was enhanced in the mice by the treatment with PM2.5. PM2.5 triggered ferroptosis, manifested as suppressed expression of GPX4 and SLC7A11, decreased levels of iron, Fe, and MDA, and increased GSH level in mouse model and cell model. The TGF- and Smad3 signaling was inhibited by PM2.5. ROS inhibitor NAC reversed PM2.5-regulated ROS and ferroptosis in primary mouse lung epithelial cells.
CONCLUSIONS
Therefore, we concluded that PM2.5 exposure induced lung injury and fibrosis by inducing ferroptosis TGF- signaling.
背景
肺纤维化是一种严重的肺部疾病，其特征为肺间质的慢性非特异性炎症和胶原蛋白的沉积，导致肺功能障碍。已经确定铁死亡参与了肺损伤的进展。有报道称，颗粒物（PM2.5）与肺纤维化的发病率有关。然而，PM2.5 相关肺纤维化中铁死亡的机制尚不清楚。在这项研究中，我们旨在探讨 PM2.5 对肺纤维化中铁死亡的影响及其相关分子机制。
方法
建立了 PM2.5 处理的小鼠模型和细胞模型。通过 Masson 三色染色和 HE 染色测量纤维化和组织损伤。通过组织学分析检测纤维化生物标志物，如 -SMA、胶原 I 和胶原 III。通过商业试剂盒测量铁死亡表型，包括铁、Fe、MDA 和 GSH 的水平。通过 DCFH-DA 检测 ROS 生成。通过酶联免疫吸附试验（ELISA）检测氧化应激指标 3-硝基-L-酪氨酸（3'-NT）、4-HNE 和蛋白质羰基。通过 TBARS 测定试剂盒和 GSH/GSSG 测定试剂盒评估硫代巴比妥酸反应物质（TBARS）和 GSH/GSSG 比值。通过 Western blot 检测 TGF-信号。
结果
PM2.5 诱导小鼠模型的肺损伤和纤维化，同时纤维化标志物表达升高。PM2.5 增强了小鼠肺部的氧化应激。用 PM2.5 处理后，SOD2 表达降低，NRF2 表达增强。PM2.5 触发铁死亡，表现为 GPX4 和 SLC7A11 表达抑制，铁、Fe 和 MDA 水平降低，以及 GSH 水平升高，在小鼠模型和细胞模型中均如此。PM2.5 抑制 TGF-和 Smad3 信号。ROS 抑制剂 NAC 逆转了 PM2.5 调节的原代小鼠肺上皮细胞中的 ROS 和铁死亡。
结论
因此，我们得出结论，PM2.5 暴露通过诱导 TGF-信号诱导铁死亡导致肺损伤和纤维化。
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