Pulmonary fibrosis is a prototypic chronic progressive lung disease with high morbidity and mortality worldwide. Novel effective therapeutic agents are urgently needed owing to the limited treatment options in clinic. Herein, nagilactone D (NLD), a natural dinorditerpenoid obtained from Podocarpus nagi, was found to suppress transforming growth factor-β1 (TGF-β1)-mediated fibrotic process in vitro and bleomycin (BLM)-induced pulmonary fibrosis in vivo. NLD attenuated TGF-β1-induced expression of fibrotic markers including type I and III collagen, fibronectin, α-SMA, and CTGF in human pulmonary fibroblasts (WI-38 VA-13 and HLF-1 cells). Mechanism study indicated that NLD suppressed TGF-β1-induced up-regulation of TβR I, and Smad2 phosphorylation, nuclear translocation, and transcriptional activation. Moreover, NLD ameliorated BLM-induced histopathological abnormalities in the lungs of experimental fibrotic mice, suppressed synthesis of relative fibrotic markers and fibroblast-to-myofibroblast transition, as well as BLM-induced up-regulation of TβR I expression and Smad signaling in mouse lungs. These data collectively support NLD to be a potential therapeutic agent for pulmonary fibrosis.

中文翻译：

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Nagilactone D通过调节TGF-β/ Smad信号通路改善体内和体外实验性肺纤维化。

肺纤维化是一种典型的慢性进行性肺部疾病，在全球范围内具有较高的发病率和死亡率。由于临床上治疗方案的限制，迫切需要新型有效的治疗剂。在本文中，发现纳吉内酯D（NLD）是从罗汉松（Podocarpus nagi）获得的天然二去二萜类化合物，在体外可抑制转化生长因子-β1（TGF-β1）介导的纤维化过程，而在博莱霉素（BLM）诱导的体内可抑制肺纤维化。NLD减弱了人肺成纤维细胞（WI-38 VA-13和HLF-1细胞）中TGF-β1诱导的纤维化标记物的表达，包括I型和III型胶原蛋白，纤连蛋白，α-SMA和CTGF。机制研究表明，NLD抑制TGF-β1诱导的TβRI的上调以及Smad2的磷酸化，核易位和转录激活。此外，NLD改善了实验性纤维化小鼠肺中BLM诱导的组织病理学异常，抑制了相关纤维化标记物的合成以及成纤维细胞向成肌纤维细胞的转化，以及BLM诱导了小鼠肺中TβRI表达的上调和Smad信号传导。这些数据共同支持NLD成为潜在的肺纤维化治疗剂。