Kim Suji, Han Jung-Hwa, Kim Sujin, Lee Heejung, Kim Jae-Ryong, Lim Jae Hyang, Woo Chang-Hoon
Department of Pharmacology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
Smart-Ageing Convergence Research Center, Yeungnam University College of Medicine, Daegu, Republic of Korea.
Cell Physiol Biochem. 2020 Feb 22;54(2):195-210. doi: 10.33594/000000214.
BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-β1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-β1 signaling and the pathogenesis of pulmonary fibrosis remain unknown.
We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies.
Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-β1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-β1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis.
These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.
背景/目的：特发性肺纤维化（IPF）是一种病因不明的进行性慢性间质性肺病的特殊形式。IPF的特征是细胞外基质（ECM）过度沉积以及由于上皮-间质转化（EMT）导致的破坏性病理重塑。最终，肺间质增厚变硬，呼吸变得困难。转化生长因子-β1（TGF-β1）/Smad信号通路在肺纤维化发病机制中起关键作用已得到充分证实。TGF-β1介导的丝裂原活化蛋白激酶（MAPK）家族激活会影响Smad信号。p90RSK是一种丝氨酸/苏氨酸激酶，由细胞外信号调节激酶（ERK）信号通路激活。然而，p90RSK在TGF-β1信号传导和肺纤维化发病机制中的作用仍不清楚。
我们使用体外和体内系统以及蛋白质免疫印迹、实时定量PCR、转录活性测定和免疫荧光研究，调查p90RSK是否调节肺纤维化的发病机制。
FMK对p90RSK的药理学抑制或用编码p90RSK显性阴性形式的腺病毒载体抑制p90RSK，可抑制TGF-β1诱导的肺上皮细胞和成纤维细胞中的ECM积累和EMT。有趣的是，FMK显著抑制TGF-β1诱导的Smad3核转位和Smad结合元件依赖性转录活性，但不抑制Smad3磷酸化。此外，在博来霉素诱导的肺纤维化小鼠模型中，FMK改善了肺纤维化。
这些发现表明p90RSK在肺纤维化中起关键作用，这表明它可被视为治疗肺纤维化的新治疗靶点。
