人抗原 R 促进肺成纤维细胞分化为肌成纤维细胞并增加细胞外基质的产生,Journal of Cellular Physiology

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人抗原 R 促进肺成纤维细胞分化为肌成纤维细胞并增加细胞外基质的产生
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-04-14 , DOI: 10.1002/jcp.30380
Fatmah Al-Habeeb _{1,

2} , Noof Aloufi _{1,

3} , Hussein Traboulsi _{1,

2} , Xingxing Liu ₁ , Parameswaran Nair ₄ , Christina Haston ₅ , Ilan Azuelos _{1,

2} , Steven K Huang ₆ , Eric S White ₆ , Imed E Gallouzi _{7,

8} , Sergio Di Marco _{7,

8} , David H Eidelman ₂ , Carolyn J Baglole _{1,

2,

3,

9}

Affiliation

特发性肺纤维化 (IPF) 是一种由过度的细胞外基质 (ECM) 沉积和表达 α-SMA 的肌成纤维细胞激活引起的进行性瘢痕形成的疾病。人抗原 R (HuR) 是一种促进蛋白质翻译的 RNA 结合蛋白。在从细胞核转移到细胞质后，HuR 起到稳定信使 RNA (mRNA) 的作用，从而提高蛋白质水平。然而，HuR 在促进 ECM 产生、肌成纤维细胞分化和肺纤维化中的作用尚不清楚。用转化生长因子 β1 (TGF-β1) 处理的人肺成纤维细胞 (HLF) 显示 HuR 从细胞核到细胞质的易位显着增加。用 HuR 小干扰 RNA 转染的 TGF-β 处理的 HLF 的 α-SMA 蛋白以及 ECM 蛋白 COL1A1、COL3A 和 FN1 显着减少。ACTA2、COL1A1、COL3A1和FN。HuR 敲低影响ACTA2的 mRNA 稳定性，但不影响 ECM 基因COL1A1、COL3A1或FN的 mRNA 稳定性。在肺纤维化小鼠模型中，与对照小鼠相比，肺结构细胞中的细胞质 HuR 更高。在人类 IPF 肺中，也有更多的细胞质 HuR。这项研究首次表明肺成纤维细胞中的 HuR 控制它们向肌成纤维细胞的分化和随后的 ECM 产生。对 HuR 的进一步研究有助于为纤维化疾病（如 IPF）开发新的靶向治疗奠定基础。

"点击查看英文标题和摘要"

Human antigen R promotes lung fibroblast differentiation to myofibroblasts and increases extracellular matrix production

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive scarring caused by excessive extracellular matrix (ECM) deposition and activation of α-SMA-expressing myofibroblasts. Human antigen R (HuR) is an RNA binding protein that promotes protein translation. Upon translocation from the nucleus to the cytoplasm, HuR functions to stabilize messenger RNA (mRNA) to increase protein levels. However, the role of HuR in promoting ECM production, myofibroblast differentiation, and lung fibrosis is unknown. Human lung fibroblasts (HLFs) treated with transforming growth factor β1 (TGF-β1) showed a significant increase in translocation of HuR from the nucleus to the cytoplasm. TGF-β-treated HLFs that were transfected with HuR small interfering RNA had a significant reduction in α-SMA protein as well as the ECM proteins COL1A1, COL3A, and FN1. HuR was also bound to mRNA for ACTA2, COL1A1, COL3A1, and FN. HuR knockdown affected the mRNA stability of ACTA2 but not that of the ECM genes COL1A1, COL3A1, or FN. In mouse models of pulmonary fibrosis, there was higher cytoplasmic HuR in lung structural cells compared to control mice. In human IPF lungs, there was also more cytoplasmic HuR. This study is the first to show that HuR in lung fibroblasts controls their differentiation to myofibroblasts and consequent ECM production. Further research on HuR could assist in establishing the basis for the development of new target therapy for fibrotic diseases, such as IPF.

更新日期：2021-04-14

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