Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
Laboratory of Molecular Immunology, Department of Biological Applications and Technology, School of Health Sciences, University of Ioannina, Ioannina, Greece.
Front Immunol. 2024 Oct 23;15:1480594. doi: 10.3389/fimmu.2024.1480594. eCollection 2024.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a significant pulmonary complication of RA. This study tried to elucidate the mechanisms enhancing inflammation and causing lung injury in RA-ILD, focusing on the role of neutrophil extracellular traps (NETs). The study also investigated the potential benefits of nintedanib in advanced disease.
Nine RA-ILD patients and nine healthy controls were included in the study. Inflammatory markers in patients' circulation were evaluated with immunoassays. The formation of NETs was examined using a citrullinated histone H3 (CitH3) ELISA and cell immunofluorescence. Inflammatory proteins expressed in neutrophils/NETs were studied with real-time qPCR and NET ELISA. To assess the effect of nintedanib, an intracellular tyrosine kinase inhibitor with antifibrotic properties, in RA-ILD a paired study was conducted in five patients before treatment administration and 16 weeks later.
The soluble terminal complement complex sC5b-9 and the levels of CitH3 were significantly elevated in patients with RA-ILD, compared to healthy controls. In addition, neutrophils isolated from RA-ILD patients released NETs enriched with tissue factor and interleukin-17A. Inflammatory NETs had a dynamic role, increasing the fibrotic potential of human pulmonary fibroblasts (HPFs). On the other hand, nintedanib treatment decreased NETs and sC5b-9 levels in RA-ILD patients.
The findings propose an interplay between circulating NETs and HPFs, establishing the immunofibrotic aspects of RA-ILD. They also support the effectiveness of nintedanib in reducing key pathological processes of the disease. Further research is needed to fully understand these mechanisms and optimize treatment strategies for RA-ILD.
类风湿关节炎相关间质性肺疾病（RA-ILD）是类风湿关节炎的一种严重肺部并发症。本研究试图阐明增强炎症并导致 RA-ILD 肺损伤的机制，重点关注中性粒细胞胞外陷阱（NETs）的作用。该研究还探讨了尼达尼布在晚期疾病中的潜在益处。
本研究纳入了 9 名 RA-ILD 患者和 9 名健康对照者。采用免疫测定法评估患者循环中的炎症标志物。通过瓜氨酸化组蛋白 H3（CitH3）ELISA 和细胞免疫荧光法检测 NET 的形成。采用实时 qPCR 和 NET ELISA 研究中性粒细胞/NETs 中表达的炎症蛋白。为了评估具有抗纤维化特性的细胞内酪氨酸激酶抑制剂尼达尼布对 RA-ILD 的影响，对 5 名患者进行了配对研究，在治疗前和 16 周后进行。
与健康对照组相比，RA-ILD 患者的可溶性末端补体复合物 sC5b-9 和 CitH3 水平显著升高。此外，从 RA-ILD 患者分离的中性粒细胞释放富含组织因子和白细胞介素-17A 的 NETs。炎症性 NETs 具有动态作用，增加了人肺成纤维细胞（HPFs）的纤维化潜能。另一方面，尼达尼布治疗降低了 RA-ILD 患者的 NETs 和 sC5b-9 水平。
这些发现提出了循环 NETs 和 HPFs 之间的相互作用，确立了 RA-ILD 的免疫纤维化方面。它们还支持尼达尼布在降低疾病关键病理过程中的有效性。需要进一步研究以充分了解这些机制并优化 RA-ILD 的治疗策略。
