Zhang Yinci, Liang Jiaojiao, Cao Niandie, Gao Jiafeng, Song Li, Tang Xiaolong
Joint National-Local Engineering Research Centre for Safe and Precise Coal Mining (Anhui University of Science and Technology), Huainan, 232001, China.
Institute of Environment-friendly Materials and Occupational Health of Anhui University of Science and Technology, Wuhu, 241003, China.
Cell Death Discov. 2022 Dec 29;8(1):500. doi: 10.1038/s41420-022-01291-z.
Pneumoconiosis is the most common and serious disease among coal miners. In earlier work on this subject, we documented that coal dust (CD) nanoparticles (CD-NPs) induced pulmonary fibrosis (PF) more profoundly than did CD micron particles (CD-MPs), but the mechanism has not been thoroughly studied. Based on the GEO database, jveen, STRING, and Cytoscape tools were used to screen hub genes regulating PF. Particle size distribution of CD were analyzed with Malvern nanoparticle size potentiometer. Combining 8 computational methods, we found that IGF1, POSTN, MMP7, ASPN, and CXCL14 may act as hub genes regulating PF. Based on the high score of IGF1 and its important regulatory role in various tissue fibrosis, we selected it as the target gene in this study. Activation of the IGF1/IGF1R axis promoted CD-NPs-induced PF, and inhibition of the axis activation had the opposite effect in vitro and in vivo. Furthermore, activation of the IGF1/IGF1R axis induced generation of reactive oxygen species (ROS) to promote epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) to accelerate PF. High-throughput gene sequencing based on lung tissue suggested that cytokine-cytokine receptor interaction and the NF-kB signaling pathway play a key role in PF. Also, ROS induced inflammation and EMT by the activation of the NF-kB/NLRP3 axis to accelerate PF. ROS can induce the activation of AKT/GSK3β signaling, and inhibition of it can inhibit ROS-induced inflammation and EMT by the NF-kB/NLRP3 axis, thereby inhibiting PF. CD-NPs induced PF by promoting inflammation and EMT via the NF-κB/NLRP3 pathway driven by IGF1/ROS-mediated AKT/GSK3β signals. This study provides a valuable experimental basis for the prevention and treatment of coal workers' pneumoconiosis. Illustration of the overall research idea of this study: IGF1 stimulates coal dust nanoparticles induced pulmonary fibrosis by promoting inflammation and EMT via the NF-κB/NLRP3 pathway driven by ROS-mediated AKT/GSK3β signals.
尘肺病是煤矿工人中最常见且最严重的疾病。在关于该主题的早期研究中，我们记录到煤尘（CD）纳米颗粒（CD-NPs）比CD微米颗粒（CD-MPs）更易引发肺纤维化（PF），但其机制尚未得到充分研究。基于基因表达综合数据库（GEO数据库），使用jveen、STRING和Cytoscape工具筛选调控PF的枢纽基因。用马尔文纳米粒度电位仪分析CD的粒度分布。结合8种计算方法，我们发现胰岛素样生长因子1（IGF1）、骨膜蛋白（POSTN）、基质金属蛋白酶7（MMP7）、抑瘤素M（ASPN）和趋化因子CXCL14可能作为调控PF的枢纽基因。基于IGF1的高分及其在各种组织纤维化中的重要调控作用，我们在本研究中选择其作为靶基因。IGF1/胰岛素样生长因子1受体（IGF1R）轴的激活促进了CD-NPs诱导的PF，而抑制该轴的激活在体外和体内均产生相反的效果。此外，IGF1/IGF1R轴的激活诱导活性氧（ROS）生成，以促进肺泡上皮细胞（AECs）的上皮-间质转化（EMT），从而加速PF。基于肺组织的高通量基因测序表明，细胞因子-细胞因子受体相互作用和核因子κB（NF-κB）信号通路在PF中起关键作用。此外，ROS通过激活NF-κB/NLRP3轴诱导炎症和EMT，从而加速PF。ROS可诱导蛋白激酶B（AKT）/糖原合成酶激酶3β（GSK3β）信号的激活，抑制该信号可通过NF-κB/NLRP3轴抑制ROS诱导的炎症和EMT，进而抑制PF。CD-NPs通过由IGF1/ROS介导的AKT/GSK3β信号驱动的NF-κB/NLRP3途径促进炎症和EMT，从而诱导PF。本研究为煤工尘肺的防治提供了有价值的实验依据。本研究总体研究思路示意图：IGF1通过由ROS介导的AKT/GSK3β信号驱动的NF-κB/NLRP3途径促进炎症和EMT，从而刺激煤尘纳米颗粒诱导的肺纤维化。
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