肺纤维化
纤维化
脂质过氧化
博莱霉素
旁分泌信号
下调和上调
癌症研究
细胞生物学
成纤维细胞
免疫学
生物
医学
内分泌学
病理
内科学
氧化应激
受体
体外
生物化学
基因
化疗
作者
Jia Li,Xinqian Du,Yukui Zhang,Sheng Wang,Lian Duan,Hanxiao Zhang,Ruoyang Zhang,Yingjie Xu,Ruonan Zhou,X. Zhang,Muzhi Zhang,Jie Liu,Zhe Lv,Yan Chen,Wei Wang,Ying Sun,Ye Cui
出处
期刊:American Journal of Physiology-cell Physiology
[American Physiological Society]
日期:2024-08-26
标识
DOI:10.1152/ajpcell.00675.2023
摘要
Idiopathic pulmonary fibrosis (IPF) is a devastating condition characterized by progressive lung scarring and uncontrolled fibroblast proliferation, inevitably leading to organ dysfunction and mortality. While elevated iron levels have been observed in patients and animal models of lung fibrosis, the mechanisms linking iron dysregulation to lung fibrosis pathogenesis, particularly the role of macrophages in orchestrating this process, remain poorly elucidated. Here we evaluate iron metabolism in macrophages during pulmonary fibrosis using both in vivo and in vitro approaches. In murine bleomycin- and amiodarone-induced pulmonary fibrosis models, we observed significant iron deposition and lipid peroxidation in pulmonary macrophages. Intriguingly, the ferroptosis regulator glutathione peroxidase 4 (GPX4) was upregulated in pulmonary macrophages following bleomycin instillation, a finding corroborated by single-cell RNA sequencing analysis. Moreover, macrophages isolated from fibrotic mouse lungs exhibited increased transforming growth factor (TGF)-β1 expression that correlated with lipid peroxidation. In vitro, iron overload in bone marrow-derived macrophages triggered lipid peroxidation and TGF-β1 upregulation, which was effectively suppressed by ferroptosis inhibitors. When co-cultured with iron-overloaded macrophages, lung fibroblasts exhibited heightened activation, evidenced by increased α-smooth muscle actin and fibronectin expression. Importantly, this pro-fibrotic effect was attenuated by treating macrophages with a ferroptosis inhibitor or blocking TGF-β receptor signaling in fibroblasts. Collectively, our study elucidates a novel mechanistic paradigm in which the accumulation of iron within macrophages initiates lipid peroxidation, thereby amplifying TGF-β1 production, subsequently instigating fibroblast activation through paracrine signaling. Thus, inhibiting iron overload and lipid peroxidation warrants further exploration as a strategy to suppress fibrotic stimulation by disease-associated macrophages.
科研通智能强力驱动
Strongly Powered by AbleSci AI