Wang Yun, Gu Yu-Han, Liu Ming, Bai Yang, Wang Huai-Liang
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Department of Drug Control, China Criminal Police University, Shenyang, Liaoning 110035, P.R. China.
Mol Med Rep. 2017 Feb;15(2):673-680. doi: 10.3892/mmr.2016.6072. Epub 2016 Dec 23.
Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA‑induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine‑treated groups. Rats in the MA and the two fluoxetine‑treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine‑treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin‑6 and tumor necrosis factor‑α in rat lungs. Fluoxetine inhibited MA‑induced increases in the expression levels of serotonin transporter (SERT) and p‑p38 mitogen‑activated protein kinase (MAPK), and reversed the MA‑induced decrease in nuclear Nrf2 and human heme oxygenase‑1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.
甲基苯丙胺（MA）滥用是全球主要的公共卫生和安全问题，且医疗成本负担日益加重。本研究的目的是探讨氟西汀对MA诱导的慢性肺部炎症的保护作用，并评估核因子红细胞2相关因子2（Nrf2）介导的抗氧化应激的潜在作用。将Wistar大鼠分为对照组、MA组和两个氟西汀治疗组。MA组和两个氟西汀治疗组的大鼠每天腹腔注射10mg/kg MA，每日两次。两个氟西汀治疗组的大鼠分别每天灌胃注射氟西汀（2mg/kg和10mg/kg）一次。5周后，将大鼠安乐死并进行苏木精-伊红染色、免疫组织化学、蛋白质印迹分析和氧化还原测定。结果表明，长期暴露于MA可诱导大鼠肺部炎症，出现炎症细胞浸润、肺实质拥挤、隔膜增厚和肺泡囊数量减少等症状。氟西汀减轻了大鼠肺部炎症以及白细胞介素-6和肿瘤坏死因子-α的表达。氟西汀抑制了MA诱导的血清素转运体（SERT）和p-p38丝裂原活化蛋白激酶（MAPK）表达水平的升高，并逆转了MA诱导的肺组织中核Nrf2和人血红素加氧酶-1的降低。10mg/kg的氟西汀显著逆转了MA组大鼠肺组织中还原型谷胱甘肽（GSH）水平、GSH/氧化型谷胱甘肽比值和活性氧水平的降低。这些发现表明，作为一种SERT抑制剂，氟西汀通过SERT/p38 MAPK/Nrf2途径抑制氧化应激，对MA诱导的肺部炎症具有保护作用。
