Elsevier

Toxicology in Vitro

Volume 62, February 2020, 104668
Toxicology in Vitro

Chronic toxicity of methamphetamine: Oxidative remodeling of pulmonary arteries

https://doi.org/10.1016/j.tiv.2019.104668Get rights and content
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Highlights

  • Chronic exposure to MA induced the hypertrophy of pulmonary arterial walls of rats.

  • Nrf2 affected the response of oxidative stress to MA in PASMCs.

  • Silence of Nrf2 enhanced the proliferation of PASMCs responding to MA.

  • MA-induced proliferation of PASMCs was associated with Nrf2-mediated redox imbalance.

Abstract

Methamphetamine (MA) has a high uptake in lung, but the precise mechanism of MA-induced lung toxicity remains unclear. The aim of this study is to investigate the role of MA abuse in remodeling of pulmonary arteries and to explore the possible correlation of the association of the remodeling with the redox imbalance in pulmonary arterial smooth muscle cells (PASMCs). Wistar rats were randomly divided into control group and MA group for the experimental study. We employed H&E staining, western blot, immunofluorescence, knockdown, flow in our experimental approach. Our studies shows that chronic exposure to MA led to weight loss, increased pulmonary arterial pressure, hypertrophy of right ventricle and remodeling of pulmonary arterial wall of rats. Our cell culture study with PASMCs indicates that MA significantly induced the imbalance between proliferation and apoptosis by upregulating the level of PCNA, Bcl-2 and reduction in the expression of BAX and Caspase 3. MA markedly prevented the nuclear translocation of Nrf2 to inhibit antioxidation. The knockdown of Nrf2 expression using siRNA significantly elevated the expression of SOD2/GCS and the production of ROS in PASMCs and even scaled up the amount of PASMCs induced by MA. Linear regression analysis showed that knockdown of Nrf2 promoted the positive correlation of relative ROS level with proliferation of PASMCs. Therefore, chronic exposure to MA induces pulmonary arterial remodeling by Nrf2-mediated imbalance of redox system to aggravate oxidative stress, and Nrf2 is a possible target for the treatment of MA-lung toxicity.

Keywords

Methamphetamine
Remodeling
Pulmonary artery
Oxidative
Nrf2
Proliferation
Apoptosis

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Equal contribution to this work.