Abstract：
The mechanisms of fibrosis onset and development remain to be elucidated. However, it has been reported that mechanical stretch promotes fibrosis in various organs and cells, and may be involved in the pathogenesis of pulmonary fibrosis. We demonstrated that ventilator-induced lung hyperextension stimulation in mice increased the expression of connective tissue growth factor (CTGF), a profibrotic cytokine, in lung tissue. Increased CTGF expression induced by cyclic mechanical stretch (CMS) was also observed in vitro using A549 human alveolar epithelial cells. Pathway analysis revealed that the induction of CTGF expression by CMS involved MEK phosphorylation. Furthermore, early growth response 1 (Egr-1) was identified as a transcription factor associated with CTGF expression. Finally, the antifibrotic drug pirfenidone significantly reduced CTGF expression, MEK phosphorylation, and Egr-1 levels induced by CMS. Thus, our results demonstrated that profibrotic cytokine CTGF induced by CMS may be a therapeutic target of pirfenidone.
摘要：
纤维化发生和发展的机制仍有待阐明。然而,据报道，机械拉伸促进各种器官和细胞的纤维化，并可能参与了肺纤维化的发病机制。我们证明了呼吸机诱导的小鼠肺过伸性刺激增加了结缔组织生长因子（CTGF）的表达，促纤维化细胞因子，在肺组织中。使用A549人肺泡上皮细胞在体外也观察到由循环机械拉伸（CMS）诱导的CTGF表达增加。通路分析表明，CMS诱导CTGF表达涉及MEK磷酸化。此外，早期生长反应1（Egr-1）被鉴定为与CTGF表达相关的转录因子。最后,抗纤维化药物吡非尼酮显著降低CTGF表达，MEK磷酸化，和CMS诱导的Egr-1水平。因此，我们的结果表明，CMS诱导的促纤维化细胞因子CTGF可能是吡非尼酮的治疗靶点。
