Neotuberostemonine and tuberostemonine ameliorate pulmonary fibrosis through suppressing TGF-β and SDF-1 secreted by macrophages and fibroblasts via the PI3K-dependent AKT and ERKpathways  

作　　者：FU San SONG Xianrui HU Yingying ZHU Qingwei LV Xinmiao TANG Xiaoyan ZHANG Mian 

机构地区：[1]School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Chinese Journal of Natural Medicines》2023年第7期527-539,共13页中国天然药物（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81873075).

摘　　要：Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop.This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-β and the impacts of neotuberostemonine(NTS)and tuberostemonine(TS).Mice were intratracheally injected with 3 U·kg^(-1)bleomycin and orally administered with 30 mg·kg^(-1)NTS or TS.Primary pulmonary fibroblasts(PFBs)and MH-S cells(alveolar macrophages)were used in vitro.The animal experiments showed that NTS and TS improved fibrosis related indicators,inhibited fibroblast activation and macrophage M2 polarization,and reduced the levels of TGF-β and SDF-1 in alveolar lavage fluid.Cell experiments showed that TGF-β1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating the PI3K/AKT/HIF-1αand PI3K/PAK/RAF/ERK/HIF-1αpathways.It was also found for the first time that SDF-1 was able to directly polarize macrophages into M2 phenotype secreting TGF-β through the same pathways as mentioned above.Moreover,the results of the cell coculture confirmed that fibroblasts and macrophages actually developed a feedback loop to promote fibrosis,and the secretion of TGF-β and SDF-1 was crucial for maintaining this loop.NTS and TS may disturb this loop through inhibiting both the PI3K/AKT/HIF-1αand PI3K/PAK/RAF/ERK/HIF-1α pathways to improve pulmonary fibrosis.NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-ajazapine skeleton,and their effect on improving pulmonary fibrosis may be largely attributed to their parent nucleus.Moreover,this study found that inhibition of both the AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis.

关 键 词：FIBROBLAST Macrophage SDF-1 PI3K/AKT PI3K/PAK/RAF/ERK Pulmonary fibrosis Pyrrole[1 2-a]azapine skeleton 

分 类 号：R965[医药卫生—药理学]