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首页> 外文期刊>Journal of cellular physiology. >Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts
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Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts

机译：抑制RUNX1街区的分化肺成纤维细胞myofibroblasts

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Abstract Pathological fibrosis contributes to progression of various diseases, for which the therapeutic options are limited. Idiopathic pulmonary fibrosis (IPF) is one such progressive and fatal interstitial fibrotic disease that is often characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to stiff lung tissue and impaired gas exchange. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined the role of Runt‐related transcription factor 1 (RUNX1), an evolutionarily conserved transcription factor, in the differentiation of human lung fibroblasts (HLFs) in vitro and in an animal model of bleomycin (BLM)‐induced lung fibrosis. We observed that the expression of RUNX1 was significantly increased in the lungs of BLM‐injected mice as compared to saline‐treated mice. Furthermore, HLFs stimulated with transforming growth factor β (TGF‐β) showed significantly higher RUNX1 expression at both mRNA and protein levels, and compartmentalization in the nucleus. Inhibition of RUNX1 in HLFs (using siRNA) showed a significant reduction in the differentiation of fibroblasts into myofibroblasts as evidenced by reduced expression of alpha‐smooth muscle actin (α‐SMA), TGF‐β and ECM proteins such as fibronectin 1 (FN1), and collagen 1A1 (COL1A1). Mechanistic studies revealed that the increased expression of RUNX1 in TGF‐β‐stimulated lung fibroblasts is due to enhanced mRNA stability of RUNX1 through selective interaction with the RNA‐binding profibrotic protein, human antigen R (HuR). Collectively, our data demonstrate that increased expression of RUNX1 augments processes involved in lung fibrosis including the differentiation of fibroblasts into collagen‐synthesizing myofibroblasts. Our study suggests that targeting RUNX1 could limit the progression of organ fibrosis in diseases characterized by abnormal collagen deposition.
机译：抽象的病理纤维化导致各种疾病的进展的治疗的选择是有限的。肺纤维化(IPF)就是这样的一个进步和致命的间质纤维化疾病通常表现为过度积累导致细胞外基质(ECM)的蛋白质肺组织僵硬和受损的气体交换。然而,IPF的分子机制发展在很大程度上仍未知。研究中,我们确定了小牛的作用相关转录因子1 (RUNX1),一个进化守恒的转录因子,在分化的人类肺成纤维细胞(HLFs)博来霉素的体外和动物模型(BLM)诱导的肺纤维化。表达RUNX1显著增加在BLM所致的肺注射小鼠相比生理盐水治疗组。转化生长因子β(TGFβ应承担的)在明显高于RUNX1表达式信使rna和蛋白质水平和划分在细胞核中。(使用核显示显著减少成纤维细胞的分化myofibroblasts就是明证表达减少α平滑肌肌动蛋白(αSMA)应承担的,应承担的TGFβ和ECM蛋白质如纤连蛋白1 (FN1)胶原蛋白1 a1 (COL1A1)。表明RUNX1表达的增加进入TGFβ刺激肺成纤维细胞是由于增强的mRNA RUNX1通过的稳定选择性与RNA的绑定profibrotic蛋白质,人体抗原R(虚)。总的来说,我们的数据表明,增加表达RUNX1增加过程在肺纤维化的分化成纤维细胞在胶原蛋白的合成myofibroblasts。RUNX1可能会限制器官的进展纤维化疾病的特点是不正常的胶原蛋白沉积。

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