Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Center of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Respir Res. 2024 Nov 1;25(1):394. doi: 10.1186/s12931-024-02987-9.
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.
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.
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.
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.
干扰素调节因子 1（IRF1）是一种转录因子，在多种生物学过程中发挥重要作用，包括炎症损伤、病毒感染、细胞死亡和免疫反应，并且在不同的肺部疾病中得到了广泛研究。然而，其在肺纤维化中的作用机制仍知之甚少。
野生型（WT）小鼠和 IRF1 全局敲除（Irf1）小鼠（Irf1）被用于博来霉素诱导的肺纤维化模型，以研究 IRF1 在肺纤维化中的作用。对用生理盐水或博来霉素处理的 WT 和 Irf1 小鼠的肺组织进行蛋白质组学分析，以探讨 IRF1 调节肺纤维化的机制。
在博来霉素诱导的纤维化小鼠模型中，观察到 IRF1 的表达增加。与 WT 小鼠相比，在用博来霉素处理后，Irf1 敲除小鼠的肺纤维化程度降低。通过肺组织的 Western blot 分析检测到纤维连接蛋白的蛋白表达下调。使用羟脯氨酸检测观察到类似的胶原蛋白含量减少。组织学检查显示，与 WT 小鼠相比，Irf1 小鼠肺部的胶原蛋白沉积较少。蛋白质组学数据表明，IRF1 可能通过调节铁死亡参与肺纤维化。我们确定，在暴露于博来霉素后，在 Irf1 小鼠中，一种在肺纤维化中表征较差的蛋白，对氧磷酶 1（PON1）上调。体外实验表明，IRF1 可以通过 PON1 调节 GSH 和 MDA 的水平。我们还确定，与健康对照组相比，IPF 患者的血浆中 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，PON1 可能是 IRF1 在肺纤维化进展中的潜在介质。
