Pirfenidone alleviates interstitial lung disease in mice by inhibiting neutrophil extracellular trap formation and NLRP3 inflammasome activation.

IF 3.4 3区医学 Q3 IMMUNOLOGY

Clinical and experimental immunology Pub Date : 2025-03-21 DOI:10.1093/cei/uxaf019

Qiyan Su, Yingyue Feng, Jin Guo, Xi Cui, Jiarui Zhu, Jumei Yang, Sigong Zhang

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引用次数: 0

Abstract

Background: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.

Methods: A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of IL-1β, IL-6 and TNF-α were detected by ELISA. PFD was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of CitH3 and MPO in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot was utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NLRP3 inflammasome markers.

Results: PFD treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. PFD intervention reduced NETs formation in vitro. PFD treatment significantly reduce NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD down-regulated EMT and NLRP3-related proteins in vivo. PFD treatment also notably reduced serum levels of IL-1β, IL-6 and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. PFD attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.

Conclusion: PFD alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.

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背景：特发性炎症性肌病（IIM）是一种以间质性肺病（ILD）为特征的进行性自身免疫性疾病，治疗方法有限。吡非尼酮（PFD）是一种用于治疗特发性肺纤维化的药物，具有显著的抗氧化、抗炎和抑制胶原合成的作用。本研究旨在阐明其治疗 IIM-ILD 的疗效和机制：方法：采用小鼠肌炎相关间质性肺病（MAILD）模型评估 PFD 的治疗效果。用酶联免疫吸附法检测血清中IL-1β、IL-6和TNF-α的水平。利用 PFD 在体外破坏中性粒细胞胞外捕获物（NETs）的形成，并通过小鼠肺组织中 CitH3 和 MPO 的免疫组化以及血清 cfDNA 水平评估其对 NETs 的抑制作用。免疫组化和免疫印迹法检测了上皮-间质转化（EMT）和NLRP3炎性体标记物的变化：结果：PFD治疗抑制了MAILD模型中的肺部炎症和纤维化。PFD干预减少了体外NETs的形成。PFD 治疗明显降低了小鼠肺组织中 NETs 的浸润和血清中 cfDNA 的水平。此外，PFD 还能在体内下调 EMT 和 NLRP3 相关蛋白。PFD 还能显著降低血清中 IL-1β、IL-6 和 TNF-α 的水平。刺激 NETs 后，A549 细胞表现出 EMT 和 NLRP3 炎性体的活化。PFD减轻了A549细胞的EMT，抑制了NLRP3炎性体的活化：结论：PFD 通过抑制 NETs 的形成和 NLRP3 炎性体的激活，缓解了小鼠 MAILD 模型中的 ILD，这表明 PFD 可能是 IIM-ILD 的潜在治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and experimental immunology 医学-免疫学

CiteScore

8.40

自引率

2.20%

发文量

101

审稿时长

3-8 weeks

期刊介绍： Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.