汉防己甲素抑制ROS介导的成纤维细胞活化治疗肺纤维化

Tetrandrine ameliorates pulmonary fibrosis by inhibiting ROS-mediated fibroblast activation

肺纤维化是一种威胁人类健康的慢性进展性肺部疾病,目前临床治疗方法有限,迫切需要研究其发病机制并开发有效治疗策略。汉防己甲素(tetrandrine, TET)是一种从粉防己中提取的双苄基异喹啉生物碱,具有一定的抗炎和抗纤维化作用,但具体机制尚不明确。本研究进一步明确了TET在慢性肺纤维化疾病模型中的抗肺纤维化作用,并探索了TET抑制成纤维细胞活化的分子机制。结果显示, TET显著减轻多次博来霉素诱导的小鼠肺纤维化模型的病理改变,并有效抑制TGF-β1诱导的成纤维细胞活化;机制上, TET主要通过抑制TGF-β/SMAD信号通路以及减少细胞内活性氧水平的方式来发挥作用。通过CRISPR-Cas9文库筛选,本研究发现血管紧张素Ⅱ 1型受体相关蛋白(angiotensin Ⅱ type 1 receptor associated protein, AGTRAP)与膜棕榈酰化蛋白6 (membrane palmitoylated protein 6, MPP6)在TET抑制活性氧水平过程中发挥重要调控作用,敲除Agtrap和Mpp6基因可以抑制TET的抗成纤维细胞活化作用。本研究所有动物实验均通过中国医学科学院医药生物技术研究所伦理审查委员会批准(IMB-20230406D507)。本研究不仅阐释了汉防己甲素的药理学作用机制,也为肺纤维化治疗提供了新的选择。

Pulmonary fibrosis is a chronic and progressive lung disease that poses a threat to human health.Current treatment options are limited,highlighting the urgent need for more effective therapeutic strategies.Tetrandrine(TET),a bis-benzylisoquinoline alkaloid extracted from Stephania tetrandra,has been known for its anti-inflammatory and anti-fibrotic effects,but its specific mechanisms remain unclear.This study investigated the anti-fibrotic effects of TET in a chronic model of pulmonary fibrosis,aiming to delineate the molecular mechanisms underlying TET-mediated inhibition of fibroblast activation.The results showed that TET significantly alleviated the pathological changes in a murine model of multiple bleomycin-induced pulmonary fibrosis and effectively inhibited TGF-β1-induced fibroblast activation.Mechanistically,TET predominantly inhibited the TGF-β/SMAD signaling pathway and diminished intracellular reactive oxygen species(ROS)levels.Utilizing CRISPR-Cas9 library screening,we identified that angiotensin Ⅱ type 1 receptor associated protein(AGTRAP)and membrane palmitoylated protein 6(MPP6)played important roles in TET's suppressive impact of ROS levels,with the knockout of two genes attenuating TET's antifibrotic activity.All animal treatment procedures were approved according to the Committee on the Ethics of Animal Experiments of the Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences(IMB-20230406D507).This research not only elucidates the pharmacological mechanism of TET but also provides a novel therapeutic avenue for the treatment of pulmonary fibrosis.