Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms
Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: Pharmacological effects and molecular mechanisms
复制标题
DOI：
10.1016/j.biopha.2017.11.101
复制
发表时间：
2018-01-01
影响因子：
7.5
通讯作者：
Bhatia, Jagriti
中科院分区：
文献类型：
--
作者：
Gamad, Nanda;Malik, Salma;Bhatia, Jagriti
背景：二甲双胍是一种常用的口服降糖药，具有多效抗氧化、抗炎和抗纤维化作用。在这项研究中，我们评估了二甲双胍对肺纤维化的作用及其作用机制。方法：实验用博来霉素（0.035 U/g, ig）诱导肺纤维化，每周2次，连用4周。二甲双胍（125、250和500 mg/kg/天，p.o）在首次注射博来霉素前7天给予，并持续至博来霉素开始注射后28天。泼尼松龙（5mg /kg/d, p.o）为标准对照。结果：博来霉素引起大鼠肺纤维化，组织病理学表现为特征性结构改变，支气管肺泡灌洗液中炎症细胞增加，脂质过氧化标志物升高，内源性抗氧化剂减少，炎症介质（tnf - α, IL-6）增加。博莱霉素对照组tgf - β、Smad2/3、ERK1/2、p38、JNK、纤维连接蛋白、羟脯氨酸和I型胶原水平均升高。大剂量二甲双胍可改善这些变化。它恢复了结构、生化和分子的正常变化。这种保护作用可能归因于二甲双胍激活AMPK，从而降低氧化应激和tgf - β。此外，这种保护作用优于强的松龙，因为二甲双胍具有额外的抗氧化和抗纤维化特性。结论：这些数据表明二甲双胍通过激活AMPK和改善tgf - β信号通路来保护博莱霉素诱导的肺纤维化。
Background: Metformin, a commonly used oral antidiabetic agent, is known to possess pleiotropic antioxidant, anti-inflammatory and anti-fibrotic effects. In this study, we evaluated the effect of metformin on pulmonary fibrosis and the mechanism underlying its effect.Methods: Pulmonary fibrosis was induced experimentally with bleomycin (0.035 U/g, i.p.) given twice weekly for four weeks. Metformin (125, 250 and 500 mg/kg/day, p.o) was given seven days prior to first injection of bleomycin and continued till 28 days after starting bleomycin injection. Prednisolone (5 mg/kg/day, p.o) was the standard control.Results: Administration of bleomycin caused pulmonary fibrosis in rats as evidenced by characteristic structural changes in histopathology, increased inflammatory cells in bronchoalveolar lavage fluid, elevated lipid peroxidation marker, depleted endogenous antioxidants and increased inflammatory mediators (TNF-alpha, IL-6). There were also increased levels of TGF-beta, Smad2/3, ERK1/2, p38, JNK, fibronectin, hydroxyproline and type I collagen in bleomycin-control group. All these changes were ameliorated by high dose metformin. It restored structural, biochemical and molecular changes towards normal. This protective effect may be attributed to activation of AMPK by metformin, with consequent reduction in oxidative stress and TGF-beta. Moreover, this protective effect was superior to prednisolone as metformin had additional antioxidant and antifibrotic properties.Conclusion: These data suggest that metformin protects against bleomycin-induced pulmonary fibrosis through activation of AMPK and amelioration of TGF-beta signaling pathways.