Arctiin-encapsulated DSPE-PEG bubble-like nanoparticles inhibit alveolar epithelial type 2 cell senescence to alleviate pulmonary fibrosis via the p38/p53/p21 pathway

作者全名："Xiong, Dian; Gao, Fei; Shao, Jingbo; Pan, Yueyun; Wang, Song; Wei, Dong; Ye, Shugao; Chen, Yuan; Chen, Rui; Yue, Bingqing; Li, Juan; Chen, Jingyu"

作者地址："[Xiong, Dian; Shao, Jingbo; Pan, Yueyun; Wei, Dong; Ye, Shugao; Chen, Yuan; Chen, Jingyu] Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Lung Transplantat Ctr, Dept Thorac Surg, Wuxi, Peoples R China; [Gao, Fei] Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Dept Emergency, Wuxi, Peoples R China; [Gao, Fei] Nanjing Gen Hosp Nanjing Mil Reg, Dept Emergency, Nanjing, Peoples R China; [Wang, Song] Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Dept Intens Care Med, Wuxi, Peoples R China; [Chen, Rui; Chen, Jingyu] Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing, Peoples R China; [Yue, Bingqing] Zhejiang Univ, Affiliated Hosp 2, Dept Lung Transplantat, Sch Med, Hangzhou, Peoples R China; [Li, Juan] Fudan Univ, Dept Chem, Shanghai, Peoples R China"

通信作者："Chen, JY (通讯作者)，Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Lung Transplantat Ctr, Dept Thorac Surg, Wuxi, Peoples R China.; Chen, JY (通讯作者)，Chongqing Med Univ, Coll Lab Med, Key Lab Clin Lab Diagnost, Minist Educ, Chongqing, Peoples R China.; Li, J (通讯作者)，Fudan Univ, Dept Chem, Shanghai, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000957033100001

JCR分区：Q1

影响因子：4.4

年份：2023

卷号：14

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：idiopathic pulmonary fibrosis; alveolar epithelial type 2 cells; cellular senescence; arctiin; nanoparticle; DSPE-PEG; p38/p53/p21 signaling axis; traditional Chinese medicine

摘要："Background: Idiopathic pulmonary fibrosis is a severe and deadly form of diffuse parenchymal lung disease and treatment options are few. Alveolar epithelial type 2 (AEC2) cell senescence is implicated in the pathogenies of IPF. A major bioactive compound from the traditional Chinese medicine Fructus arctii, arctiin (ARC) has robust anti-inflammatory, anti-senescence, and anti-fibrosis functions. However, the potential therapeutic effects of ARC on IPF and the underlying mechanisms involved are still unknown.Methods: First of all, ARC was identified as an active ingredient by network pharmacology analysis and enrichment analysis of F. arctii in treating IPF. We developed ARC-encapsulated DSPE-PEG bubble-like nanoparticles (ARC@DPBNPs) to increase ARC hydrophilicity and achieve high pulmonary delivery efficiency. C57BL/6 mice were used to establish a bleomycin (BLM)-induced pulmonary fibrosis model for assessing the treatment effect of ARC@DPBNPs on lung fibrosis and the anti-senescence properties of AEC2. Meanwhile, p38/p53 signaling in AEC2 was detected in IPF lungs, BLM-induced mice, and an A549 senescence model. The effects of ARC@DPBNPs on p38/p53/p21 were assessed in vivo and in vitro.Results: Pulmonary route of administration of ARC@DPBNPs protected mice against BLM-induced pulmonary fibrosis without causing significant damage to the heart, liver, spleen, or kidney. ARC@DPBNPs blocked BLM-induced AEC2 senescence in vivo and in vitro. The p38/p53/p21 signaling axis was significantly activated in the lung tissues of patients with IPF, senescent AEC2, and BLM-induced lung fibrosis. ARC@DPBNPs attenuated AEC2 senescence and pulmonary fibrosis by inhibiting the p38/p53/p21 pathway.Conclusion: Our data suggest that the p38/p53/p21 signaling axis plays a pivotal role in AEC2 senescence in pulmonary fibrosis. The p38/p53/p21 signaling axis inhibition by ARC@DPBNPs provides an innovative approach to treating pulmonary fibrosis in clinical settings."

基金机构：National Natural Science Foundation of China [82070059]; Natural Science Foundation Youth Project of China of Jiangsu Province [BK20220224]; Youth Project of Wuxi Health and Family Planning Commission [Q202127]

基金资助正文："Funding This study was supported by the National Natural Science Foundation of China (No. 82070059, China), Natural Science Foundation Youth Project of China of Jiangsu Province (No. BK20220224, China), and Youth Project of Wuxi Health and Family Planning Commission (No. Q202127, China)."