Loss of Interferon Regulatory Factor-1 Prevents Lung Fibrosis by Upregulation of Pon1 Expression

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2024 Nov 2

PMID 39487505

Authors

Aiyuan Zhou

Xiyan Zhang

Xinyue Hu

Tiao Li

Wenzhong Peng

Hang Yang

Dingding Deng

Chunheng Mo

Rongli Lu

Pinhua Pan

Affiliations

Soon will be listed here.

Abstract

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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