Oridonin attenuates LPS-induced early pulmonary fibrosis by regulating impaired autophagy, oxidative stress, inflammation and EMT.
Oridonin attenuates LPS-induced early pulmonary fibrosis by regulating impaired autophagy, oxidative stress, inflammation and EMT.
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DOI：
10.1016/j.ejphar.2022.174931
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发表时间：
2022-04
影响因子：
5
通讯作者：
Huahong Yang;Lidong Wang;Manshi Yang;Jianqiang Hu;Erli Zhang;Liping Peng
中科院分区：
文献类型：
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作者：
Huahong Yang;Lidong Wang;Manshi Yang;Jianqiang Hu;Erli Zhang;Liping Peng
冬凌草甲素（Ori）具有抗炎、抗氧化和抗肿瘤特性。本实验采用小鼠肺纤维化模型，观察Ori对LPS（1 mg/kg）和Ori（20 mg/kg）诱导的小鼠肺纤维化的保护作用。取左肺组织行HE、免疫组化和Masson染色，右肺组织行羟脯氨酸测定和westernblot实验。支气管肺泡灌洗液收集Giemsa染色。结果Ori治疗降低了LPS诱导的高水平羟脯氨酸。免疫组化染色和western blot分析显示，Ori可抑制纤维化相关蛋白（α-平滑肌肌动蛋白、转化生长因子-β、Ⅰ型胶原和磷酸化smad）的表达。此外，Ori治疗增加了E-钙粘蛋白水平，并降低了Snail和Slug水平。此外，Ori可抑制LPS诱导的中性粒细胞浸润和NLRP 3炎性小体的激活。此外，LPS引起NADPH氧化酶4上调，加重肺纤维化。Ori作为NF-E2相关因子-2的激活剂，在该动物模型中具有保护作用。结论Ori通过抑制NLRP 3依赖的炎症反应、NADPH氧化酶4依赖的氧化应激反应、自噬受损和上皮间质转化，对LPS诱导的早期肺纤维化具有保护作用。
ContextOridonin (Ori) possesses anti-inflammatory, antioxidant and antitumor properties. However, the effects of Ori on Lipopolysaccharide (LPS)-induced early pulmonary fibrosis remain unclear.ObjectiveWe evaluated the protective effects of Ori on the mice model of pulmonary fibrosis.Materials and methodsThe BALB/C mice were given LPS (1 mg/kg) or Ori (20 mg/kg) according to experimental grouping. Then the left lung tissues were used for HE, immunohistochemical and Masson staining, and the right lung tissues were used for hydroxyproline measurement and western blot experiments. Bronchoalveolar lavage fluid was collected for Giemsa staining.ResultsThe high levels of hydroxyproline induced by LPS were reduced by Ori treatment. Immunohistochemical staining and western blot analysis showed that Ori inhibited the increased levels of fibrosis-related proteins (α-smooth muscle actin, transforming growth factor-β, Collagen Ⅰ and phosphorylated-smad). Additionally, Ori treatment increased E-cadherin levels and decreased in Snail and Slug levels. Besides, Ori could suppress LPS-induced the infiltration of neutrophils and activation of the NLRP3 inflammasome. In addition, LPS caused the upregulation of NADPH oxidase 4 and exacerbated lung fibrosis. As the activator of NF-E2 related factor-2, Ori exerted protective effects in this animal model. Moreover, Ori reversed the LPS-triggered increases in Beclin-1, P62/sequestosome 1, autophagy related 3 and LC3.ConclusionsThese findings suggested that Ori protected against LPS-induced early pulmonary fibrosis by inhibiting NLRP3-dependent inflammation, NADPH oxidase 4-dependent oxidative stress, the impaired autophagy and epithelial mesenchymal transformation.