Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250000, China.
Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250000, China.
Biomed Pharmacother. 2020 Jul;127:110119. doi: 10.1016/j.biopha.2020.110119. Epub 2020 Apr 7.
Idiopathic pulmonary fibrosis (IPF), characterized by excessive collagen deposition, is a progressive and typically fatal lung disease without effective therapeutic strategies. Juglanin, as a natural product mainly isolated from green walnut husks of Juglans mandshuric, has various bioactivities, including anti-oxidative, anti-inflammatory and anti-fibrotic effects. Stimulator of interferon genes (Sting) is a signaling molecule and plays an essential role in meditating fibrosis. However, the effects of Jug and Sting on pulmonary fibrosis are not fully understood. In this study, we investigated the role of Jug in bleomycin (BLM)-induced inflammation and fibrosis mouse model, as well as the underlying molecular mechanism. The results here indicated that Jug-treated mice exhibited a definitively improved survival rate than that of the BLM-challenged mice. Jug administration significantly alleviated neutrophil alveolar infiltration, lung vascular permeability and pro-inflammatory response in BLM mice. Subsequently, the pulmonary fibrosis induced by BLM was markedly attenuated by Jug through reducing the expression of fibrotic hallmarks, including transforming growth factor-β1 (TGF-β1), fibronectin, matrix metallo-proteinase-9 (MMP-9), α-smooth muscle actin (α-SMA) and collagen I. Importantly, we found that BLM mice showed higher expression levels of Sting in lung tissues, which were notably restrained by Jug treatment. The role of Jug in suppressing Sting was confirmed in TGF-β-incubated cells. Notably, the in vitro analysis further showed that Sting knockdown could ameliorate TGF-β-triggered collagen accumulation. In contrast, TGF-β-induced fibrosis was accelerated by Sting over-expression. Therefore, BLM may induce lung fibrosis through activating Sting signaling, and Jug could be used therapeutically to improve tissue repair and attenuate the intractable disease.
特发性肺纤维化（IPF）的特征是胶原过度沉积，是一种进行性且通常致命的肺部疾病，目前尚无有效的治疗策略。 Juglanin 是一种主要从核桃绿皮中分离出来的天然产物，具有多种生物活性，包括抗氧化、抗炎和抗纤维化作用。干扰素基因刺激物（Sting）是一种信号分子，在介导纤维化中起着至关重要的作用。然而，Jug 和 Sting 对肺纤维化的影响尚未完全阐明。在这项研究中，我们研究了 Jug 在博来霉素（BLM）诱导的炎症和纤维化小鼠模型中的作用及其潜在的分子机制。结果表明，与 BLM 处理的小鼠相比，Jug 处理的小鼠具有明显提高的存活率。Jug 给药可显著减轻 BLM 小鼠中性粒细胞肺泡浸润、肺血管通透性和促炎反应。随后，Jug 通过降低纤维化标志物的表达，显著减轻 BLM 诱导的肺纤维化，包括转化生长因子-β1（TGF-β1）、纤维连接蛋白、基质金属蛋白酶-9（MMP-9）、α-平滑肌肌动蛋白（α-SMA）和胶原 I。重要的是，我们发现 BLM 小鼠肺组织中 Sting 的表达水平较高，而 Jug 处理可明显抑制其表达。在 TGF-β 孵育的细胞中证实了 Jug 抑制 Sting 的作用。值得注意的是，体外分析进一步表明，Sting 敲低可改善 TGF-β 触发的胶原积累。相反，Sting 过表达加速了 TGF-β 诱导的纤维化。因此，BLM 可能通过激活 Sting 信号通路诱导肺纤维化，而 Jug 可用于治疗以改善组织修复并减轻这种难治性疾病。
