Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, 05029, Republic of Korea.
Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul, 05029, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul, 05029, Republic of Korea.
Biochem Biophys Res Commun. 2024 Dec 20;739:150567. doi: 10.1016/j.bbrc.2024.150567. Epub 2024 Aug 20.
Pulmonary fibrosis is a severe and progressive lung disease characterized by lung tissue scarring. Transforming growth factor beta 1 (TGFβ1) is crucial in causing pulmonary fibrosis by promoting the activation of fibroblasts and their differentiation into myofibroblasts, which are responsible for excessive extracellular matrix deposition. This study aimed to identify genes activated by TGFβ1 that promote fibrosis and to understand the regulatory pathway controlling myofibroblast. Endothelin-1 (ET-1) was identified as the top-ranking gene in the fibrosis-related gene set using quantitative PCR array analysis. TGFβ1 upregulated EGR1 expression through the ERK1/2 and JNK1/2 MAPK pathways. EGR1 and p-SMAD2 proteins interacted with the ET-1 gene promoter region to regulate TGFβ1-induced ET-1 expression in IMR-90 pulmonary fibroblasts. Mice lacking the Egr1 gene showed reduced ET-1 levels in a model of pulmonary fibrosis induced by intratracheal administration of bleomycin. These findings suggest that targeting EGR1 is a promising approach for treating pulmonary fibrosis, especially idiopathic pulmonary fibrosis, by affecting ET-1 expression and profibrotic reactions.
肺纤维化是一种严重且进行性的肺部疾病，其特征是肺组织瘢痕形成。转化生长因子β 1（TGFβ1）通过促进成纤维细胞的激活及其分化为肌成纤维细胞，从而导致肺纤维化，肌成纤维细胞是导致细胞外基质过度沉积的主要原因。本研究旨在鉴定 TGFβ1 激活的促进纤维化的基因，并了解调控肌成纤维细胞的调节途径。采用定量 PCR 阵列分析，内皮素-1（ET-1）被鉴定为纤维化相关基因集中排名最高的基因。TGFβ1 通过 ERK1/2 和 JNK1/2 MAPK 通路上调 EGR1 的表达。EGR1 和 p-SMAD2 蛋白与 ET-1 基因启动子区域相互作用，调节 TGFβ1 诱导的 IMR-90 肺成纤维细胞中 ET-1 的表达。在博来霉素气管内给药诱导的肺纤维化模型中，缺乏 Egr1 基因的小鼠 ET-1 水平降低。这些发现表明，通过影响 ET-1 表达和致纤维化反应，靶向 EGR1 可能是治疗肺纤维化（尤其是特发性肺纤维化）的一种有前途的方法。
