1. MDA5 expression is associated with TGF-β-induced fibrosis: potential mechanism of interstitial lung disease in anti-MDA5 dermatomyositis.
- Author
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Shen, Ning, Zhou, Xiaopeng, Jin, Xuexiao, Lu, Ci, Hu, Xiuhua, Zhang, Yichi, Jiang, Yu, Xu, Qin, Xu, Xiayan, Liu, Minghao, Lu, Linrong, and Han, Yongmei
- Subjects
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RNA analysis , *TRANSFORMING growth factors-beta , *IN vitro studies , *COLLAGEN , *DERMATOMYOSITIS , *SEQUENCE analysis , *FIBROBLASTS , *CONNECTIVE tissue growth factor , *CELL culture , *ANTISYNTHETASE syndrome , *INTERSTITIAL lung diseases , *CYTOSKELETAL proteins , *CELLULAR signal transduction , *DESCRIPTIVE statistics , *GENES , *PULMONARY fibrosis , *COMPUTED tomography , *ANTIGENS , *DISEASE risk factors , *SYMPTOMS , *DISEASE complications , *METABOLISM - Abstract
Objectives This study aimed to investigate the high-resolution CT (HRCT) characteristics of anti-melanoma differentiation-associated gene 5 (MDA5) antibody positive dermatomyositis-associated interstitial lung disease (anti-MDA5 DM-ILD), and to clarify the underlying mechanisms of the clinical phenomenon. Methods Clinical data and HRCT patterns were compared between anti-MDA5 DM-ILD (n = 32) and antisynthetase syndrome-associated ILD (ASS-ILD) (n = 29). RNA sequencing of whole-blood samples from the two groups, and in vitro experiments using human embryonic lung fibroblasts (HELFs) were conducted to explore the potential mechanisms of the clinical findings. Results The anti-MDA5 DM-ILD subset had a significantly higher incidence of rapidly progressive ILD (RPILD) than ASS-ILD (65.6% vs 37.9%; P = 0.031). The relative percentage of the lung fibrosis HRCT pattern was significantly lower in the anti-MDA5 DM-ILD group, especially the RPILD subgroup (P = 0.013 and 0.003, respectively). RNA sequencing detected the upregulated genes including interferon-induced helicase C domain 1 (encoding MDA5), and a trend towards downregulated expression of TGF-β signalling components in anti-MDA5 DM-ILD. In vitro culture of HELFs revealed that upregulated expression of MDA5 in HELFs was correlated with the downregulated expression of alpha smooth muscle actin, connective tissue growth factor, collagen I and collagen III by suppressing the TGF-β signalling pathway. Conclusions Anti-MDA5 DM-ILD patients have significantly less lung fibrosis and elevated MDA5 expression. The upregulated expression of MDA5 has relations with the suppression of the pro-fibrotic function of fibroblasts via the TGF-β signalling pathway, which may partially explain the mechanism of the clinical phenomenon. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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