Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones. PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using precision-cut lung slices. Our results identified PRRX1 as a mesenchymal transcription factor driving lung fibrogenesis.

中文翻译：

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配对相关的同源盒蛋白1的鉴定作为特发性肺纤维化的关键间质转录因子

基质重塑是特发性肺纤维化（IPF）的显着特征。靶向细胞驱动基质重塑可能是IPF治疗的有希望的途径。转录组数据库分析确定间充质转录因子PRRX1在IPF中上调。肺成纤维细胞强烈表达的PRRX1在体外受对照和IPF成纤维细胞的TGF-β/ PGE2平衡调节，而IPF成纤维细胞衍生的基质在对照组中以PDGFR依赖性方式增加PRRX1表达。PRRX1抑制通过下调S期细胞周期蛋白的表达来减少成纤维细胞增殖。PRRX1的抑制作用还通过抑制磷酸酶PPM1A上调和TGFBR2的下调来抑制SMAD2 / 3磷酸化，从而影响TGF-β驱动的肌纤维母细胞分化，从而导致TGF-β响应总体下降。最后，在肺纤维化博莱霉素小鼠模型中和使用精密切割肺切片离体时，通过气管内反义寡核苷酸靶向抑制Prrx1体内的纤维化重构减弱。我们的结果确定PRRX1是驱动肺纤维化的间质转录因子。