RUNX3-dependent oxidative epithelial-to-mesenchymal transition in methamphetamine-induced chronic lung injury
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ORIGINAL PAPER
RUNX3-dependent oxidative epithelial-to-mesenchymal transition in methamphetamine-induced chronic lung injury Lin Shi 1 & Bing-Yang Liu 2 & Xin Wang 1 & Mei-Jia Zhu 1 & Lei Chen 1 & Ming-Yuan Zhou 1 & Ying-Jian Gu 1 & Lin Cheng 1 & Yun Wang 1 Received: 18 April 2020 / Revised: 22 June 2020 / Accepted: 25 June 2020 # Cell Stress Society International 2020
Abstract Lung toxicity is the main cause of the death from methamphetamine (MA) abuse, but its mechanism has remained unclear. The purpose of our study was to investigate if MA can induce epithelial-to-mesenchymal transition (EMT) and if RUNX3 is involved in oxidative EMT in MA-induced chronic lung injury. The rats were divided into the control group and MA group. Extracted lungs were used for morphological measurements and Western blot. The alveolar epithelial cells were cultured or transfected and then treated with MA or/and N-acetyl cysteine (NAC) followed by flow cytometry, Western blot, and immunohistochemistry. Chronic exposure to MA resulted in the lower growth ratio of weight, increased right ventricular index, thickened alveolar walls, and reduced number of alveolar sacs. Long-term administration with MA caused oxidative stress and pulmonary EMT. NAC increased RUNX3 and alleviated EMT. However, after knockdown of RUNX3, reactive oxygen species (ROS) levels were significantly upregulated, indicating that RUNX3 was closely related to oxidative stress. Knockdown of RUNX3 aggravated MA-induced EMT by activating RUNX3-dependent TGF-β signaling. Therefore, RUNX3 may be the key to oxidative EMT in methamphetamine-induced chronic lung injury. Keywords RUNX3 . Epithelial-to-mesenchymal transition . Oxidative . Methamphetamine . Lung . TGF-β
Introduction The abuse of methamphetamine (MA) is a major public health issue (Wang et al. 2018). MA is an addictive drug with popularity among the young and the middle-aged adults (Orcholski et al. 2017). A study has found that when injecting MA in humans, 24–31% of the dose is absorbed by lung (Volkow et al. 2010). A higher uptake rate of MA in lungs resulted in toxicity and some lung diseases such as pulmonary hypertension and pulmonary edema (Albertson et al. 1999; Ciccarone 2011; Ramirez et al. 2018). Pulmonary dysfunction
Lin Shi and Bing-Yang Liu contributed equally to this work. * Yun Wang [email protected] 1
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning, People’s Republic of China
2
Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, People’s Republic of China
is the main cause of the death from MA toxicity, but its mechanism has remained unclear. Runt gene family members (RUNX1, RUNX2, and RUNX3) play the important roles in the normal development of tissues and carcinogenesis. RUNX1 was first recognized as a tumor suppressor in myeloid leukemia. RUNX1 is indispensable for the hematopoietic system and is one of the most commonly mutated genes
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