Department of Emergency, Shanghai General Hospital of Nanjing Medical University, Shanghai 201620, China.
Department of Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 201620, China.
Life Sci. 2018 Nov 15;213:126-133. doi: 10.1016/j.lfs.2018.10.026. Epub 2018 Oct 15.
This study investigated the effects of atorvastatin (ATS) on the paraquat (PQ)-induced epithelial-mesenchymal transition (EMT) and the potential mechanism through hypoxia-inducible factor-1 alpha (HIF-1α).
Sprague-Dawley (SD) rats were randomly divided into a control group (n = 5), PQ group (n = 20), PQ + ATS L group (n = 20, ATS 20 mg/kg daily) and PQ + ATS H group (n = 20, ATS 40 mg/kg daily). All treated rats were given a 20% PQ solution (50 mg/kg) once by gavage and then sacrificed 12, 24, 72 and 168 h after PQ exposure. The A549 and RLE-6TN cell lines were treated with ATS, PQ or both for 24 h. Mesenchymal (α-SMA and vimentin) and epithelial (E-cadherin and ZO-1) cell marker expression was tested both in vivo and in vitro. The effects of ATS on HIF-1α and β‑catenin expression were also evaluated.
ATS alleviated PQ poisoning-induced lung injury and pulmonary fibrosis in vivo. This effect was dose-dependent. ATS treatment attenuated the EMT by increasing the levels of the epithelial markers E-cadherin and ZO-1 and by decreasing the expression of the mesenchymal markers α-SMA and vimentin in both lung tissues and in vitro cell culture. In addition, ATS treatment may decrease the HIF-1α and β‑catenin levels both in vivo and in vitro.
In conclusion, ATS can attenuate PQ-induced pulmonary fibrosis. The mechanism may involve the downregulation of the HIF-1α/β‑catenin pathway and the inhibition of the PQ-induced EMT by ATS. ATS may be considered as a therapeutic agent for PQ poisoning-induced pulmonary fibrosis.
本研究旨在探讨阿托伐他汀（ATS）对百草枯（PQ）诱导的上皮-间充质转化（EMT）的影响及其通过缺氧诱导因子-1α（HIF-1α）的潜在机制。
将 Sprague-Dawley（SD）大鼠随机分为对照组（n=5）、PQ 组（n=20）、PQ+ATS L 组（n=20，ATS 20mg/kg 每日）和 PQ+ATS H 组（n=20，ATS 40mg/kg 每日）。所有处理组大鼠均通过灌胃给予 20%PQ 溶液（50mg/kg）一次，然后在 PQ 暴露后 12、24、72 和 168h 处死。体外将 A549 和 RLE-6TN 细胞系用 ATS、PQ 或两者共同处理 24h。在体内和体外检测间充质（α-SMA 和波形蛋白）和上皮（E-钙黏蛋白和 ZO-1）细胞标志物的表达。还评估了 ATS 对 HIF-1α 和 β-连环蛋白表达的影响。
ATS 减轻了体内 PQ 中毒引起的肺损伤和肺纤维化。这种作用呈剂量依赖性。ATS 治疗通过增加上皮标志物 E-钙黏蛋白和 ZO-1 的水平，并降低肺组织和体外细胞培养中间充质标志物 α-SMA 和波形蛋白的表达，从而减轻 EMT。此外，ATS 治疗可能降低体内和体外的 HIF-1α 和 β-连环蛋白水平。
总之，ATS 可减轻 PQ 诱导的肺纤维化。其机制可能涉及下调 HIF-1α/β-连环蛋白通路以及 ATS 抑制 PQ 诱导的 EMT。ATS 可被视为治疗 PQ 中毒诱导的肺纤维化的一种治疗剂。
