干扰素调节因子-1的缺失可通过上调pon1的表达防止肺纤维化。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-11-01 DOI:10.1186/s12931-024-02987-9
Aiyuan Zhou, Xiyan Zhang, Xinyue Hu, Tiao Li, Wenzhong Peng, Hang Yang, Dingding Deng, Chunheng Mo, Rongli Lu, Pinhua Pan
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引用次数: 0

摘要

背景:干扰素调节因子-1(IRF1)是一种转录因子,在炎症损伤、病毒感染、细胞死亡和免疫反应等多种生物过程中发挥着重要作用,它在不同肺部疾病中的作用已被广泛研究。然而,它参与肺纤维化的机制在很大程度上仍然未知:方法:将野生型(WT)小鼠和IRF1全基因缺失小鼠(Irf1-/-)置于博莱霉素诱导的肺纤维化模型中,以研究IRF1在肺纤维化中的作用。对用生理盐水或博莱霉素处理的WT小鼠和Irf1-/-小鼠的肺组织进行了蛋白质组学分析,以探索IRF1调控肺纤维化的机制:结果:在博莱霉素诱导的肺纤维化小鼠模型中,观察到IRF1的表达增加。与WT小鼠相比,IRF1基因敲除小鼠在博莱霉素治疗后肺纤维化程度降低。通过对肺组织的 Western 印迹分析评估,Irf1-/-小鼠的纤维连接蛋白的蛋白表达下调。通过羟脯氨酸检测,我们观察到胶原蛋白含量也有类似的减少。从组织学角度看,与 WT 小鼠相比,Irf1-/- 小鼠肺部的胶原沉积较少。蛋白质组学数据显示,IRF1 可能通过调节铁氧化酶参与肺纤维化。我们发现,在暴露于博莱霉素后,Irf1-/-小鼠体内的对氧磷(paraoxonase)1(PON1)上调,而对氧磷(paraoxonase)1是一种在肺纤维化中特征不明显的蛋白质。体外实验显示,IRF1可通过PON1调节GSH和MDA的水平。我们还发现,与健康对照组相比,IPF 患者血浆中的 PON1 水平较低:我们的数据强调了IRF1在纤维化过程中的重要性,而PON1可能是IRF1在肺纤维化进展过程中的潜在介质。
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Loss of interferon regulatory factor-1 prevents lung fibrosis by upregulation of pon1 expression.

Background: Interferon regulatory factor-1 (IRF1) is a transcription factor that plays a significant role in various biological processes, including inflammatory injury, viral infection, cell death, and immune responses, and it has been extensively studied in the context of different lung diseases. However, the mechanism underlying its involvement in lung fibrosis remains largely unknown.

Methods: Wild type (WT) mice, IRF1 global-null mice (Irf1-/-) were subjected to a bleomycin-induced lung fibrosis model to enable examination of the role of IRF1 in lung fibrosis. Proteomic analysis of lung tissue from WT and Irf1-/- mice treated with saline or bleomycin was performed to explore the mechanism of IRF1 in regulating lung fibrosis.

Results: In the bleomycin-induced fibrosis mouse model, increased expression of IRF1 was observed. Irf1 knockout mice displayed decreased lung fibrosis relative to WT mice following treatment with bleomycin. The protein expression of fibronectin, as assessed by the Western blot analysis of lung tissues, was downregulated in Irf1-/- mice. We observed a similar reduction in collagen content using hydroxyproline detection. Histologically, there was less collagen deposition in the lungs of Irf1-/- mice compared with WT mice. Proteomics data revealed that IRF1 may be involved in lung fibrosis via the regulation of ferroptosis. We determined that paraoxonase 1(PON1), a poorly characterized protein in lung fibrosis, was upregulated in Irf1-/- mice following exposure to bleomycin. In vitro experiments revealed that IRF1 could regulate the level of GSH and MDA through PON1. We also determined that PON1 levels were lower in the plasma of IPF patients compared with healthy controls.

Conclusion: Our data highlight the importance of IRF1 in the fibrotic process, and PON1 may be a potential mediator of IRF1 in the progression of lung fibrosis.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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