Prevention of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice by Paeonol.
Prevention of Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice by Paeonol.
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DOI：
10.3389/fphys.2017.00193
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发表时间：
2017
影响因子：
4
通讯作者：
Kou YR
中科院分区：
文献类型：
--
作者：
Liu MH;Lin AH;Ko HK;Perng DW;Lee TS;Kou YR
肺纤维化是一种严重的进行性疾病，其特征是细胞外基质（如胶原）的异常沉积。该疾病的发病机制可能是由纤维化刺激引起肺上皮细胞氧化损伤，导致肺部炎症，进而促进各种肺纤维化反应。转化生长因子-β1 （TGF-β1）对肺成纤维细胞的促纤维化作用对本病的发病机制至关重要。丹皮酚是芍药中主要的酚类化合物，具有抗氧化和抗炎作用。然而，丹皮酚是否对肺纤维化有治疗作用尚不清楚。通过小鼠模型，我们发现，在损伤21天后，气管内博莱霉素引起肺部炎症和纤维化，肺部组织病理学表现和各项指标均有所增加。炎症指标包括支气管肺泡灌洗液中总细胞计数、差异细胞计数和总蛋白浓度升高。纤维化指标包括肺TGF-β1、总胶原蛋白、1α1型胶原蛋白（COL1A1）、α-平滑肌肌动蛋白（α-SMA，肌成纤维细胞标志物）水平升高。博莱霉素还被发现会引起氧化应激的增加，这反映在肺部丙二醛和4-羟基壬烯醛水平的增加上。重要的是，所有这些病理生理事件都被丹皮酚日常治疗所抑制。利用人肺成纤维细胞，我们进一步证明，暴露于TGF-β1的人肺成纤维细胞增加了α-SMA和COL1A1的产生，这两种蛋白均被JNK、p38和Smad3抑制剂抑制。JNK和p38是丝裂原活化蛋白激酶（MAPKs）的两个亚家族成员，而Smad3是一个转录因子。TGF-β1暴露在α-SMA和COL1A1诱导之前，也增加了JNK、p38和Smad3的磷酸化。值得注意的是，这些TGF-β1诱导的细胞事件均被丹皮酚处理抑制。我们的研究结果表明，丹皮酚对博莱霉素诱导的小鼠肺纤维化具有抗氧化、抗炎和抗纤维化功能。丹皮酚的有益作用可能至少部分是通过抑制MAPKs/Smad3信号传导介导的。
Pulmonary fibrosis is a severe and progressive disease that is characterized by an abnormal deposition of extracellular matrix, such as collagens. The pathogenesis of this disease may be initiated by oxidative damage of lung epithelial cells by fibrogenic stimuli, leading to lung inflammation, which in turn promotes various lung fibrotic responses. The profibrogenic effect of transforming growth factor-β1 (TGF-β1) on lung fibroblasts is crucial for the pathogenesis of this disease. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has therapeutic effects against pulmonary fibrosis remains unclear. Using a murine model, we showed that 21 days after the insult, intratracheal bleomycin caused pulmonary inflammation and fibrosis, as evidenced by lung histopathological manifestations and increase in various indices. The inflammatory indices included an increase in total cell count, differential cell count, and total protein concentration in bronchoalveolar lavage fluid. The fibrotic indices included an increase in lung levels of TGF-β1, total collagen, type 1α1 collagen (COL1A1), and α-smooth muscle actin (α-SMA; a marker of myofibroblasts). Bleomycin also was found to cause an increase in oxidative stress as reflected by increased levels of malondialdehyde and 4-hydroxynonenal in the lungs. Importantly, all these pathophysiological events were suppressed by daily treatment with paeonol. Using human lung fibroblasts, we further demonstrated that exposure of human lung fibroblasts to TGF-β1 increased productions of α-SMA and COL1A1, both of which were inhibited by inhibitors of Jun N-terminal kinase (JNK), p38, and Smad3. JNK and p38 are two subfamily members of mitogen-activated protein kinases (MAPKs), whereas Smad3 is a transcription factor. TGF-β1 exposure also increased the phosphorylation of JNK, p38, and Smad3 prior to the induction of α-SMA and COL1A1. Notably, all these TGF-β1-induced cellular events were suppressed by paeonol treatment. Our findings suggest that paeonol has antioxidant, anti-inflammatory, and anti-fibrotic functions against bleomycin-induced pulmonary fibrosis in mice. The beneficial effect of paeonol may be, at least in part, mediated through the inhibition of the MAPKs/Smad3 signaling.