Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by the extensive accumulation of myofibroblasts and collagens. However, the exact mechanism that underlies this condition is unclear. Growing evidence suggests that NADPH oxidases (NOXs), especially NOX4-derived oxidative stress, play an important role in the development of lung fibrosis. Bleomycin (BLM) is a tumor chemotherapeutic agent, which has been widely employed to establish IPF animal models. Osthole (OST) is an active constituent of the fruit of Cnidium ninidium. Here, we used an in vivo mouse model and found that OST suppressed BLM-induced body weight loss, lung injury, pulmonary index increase, fibroblast differentiation, and pulmonary fibrosis. OST also significantly downregulated BLM-induced NOX4 expression and oxidative stress in the lungs. In vitro, OST could inhibit TGF-β1-induced Smad3 phosphorylation, differentiation, proliferation, collagen synthesis, NOX4 expression, and ROS generation in human lung fibroblasts in a concentration-dependent manner. Moreover, NOX4 overexpression could prevent the above effects of OST. We came to the conclusion that OST could significantly attenuate BLM-induced pulmonary fibrosis in mice, via the mechanism that involved downregulating TGF-β1/NOX4-mediated oxidative stress in lung fibroblasts.

中文翻译：

---

蛇床子素通过调节 NADPH 氧化酶 4 衍生的氧化应激来减轻小鼠博莱霉素诱导的肺纤维化


特发性肺纤维化（IPF）是一种慢性进行性肺部疾病，其特征是肌成纤维细胞和胶原蛋白的广泛积累。然而，造成这种情况的确切机制尚不清楚。越来越多的证据表明 NADPH 氧化酶 (NOX)，尤其是 NOX4 衍生的氧化应激，在肺纤维化的发展中发挥重要作用。博莱霉素（BLM）是一种肿瘤化疗药物，已广泛用于建立IPF动物模型。蛇床子素 (OST) 是蛇床子果实的活性成分。在这里，我们使用体内小鼠模型，发现 OST 抑制 BLM 引起的体重减轻、肺损伤、肺指数增加、成纤维细胞分化和肺纤维化。 OST 还显着下调 BLM 诱导的 NOX4 表达和肺部氧化应激。在体外，OST可以浓度依赖性方式抑制人肺成纤维细胞中TGF- β1诱导的Smad3磷酸化、分化、增殖、胶原合成、NOX4表达和ROS生成。此外，NOX4过表达可以阻止OST的上述作用。我们得出的结论是，OST 可以通过下调肺成纤维细胞中 TGF- β1 /NOX4 介导的氧化应激的机制，显着减轻 BLM 诱导的肺纤维化。