Suppression of nuclear factor erythroid‑2‑related factor 2‑mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats.
The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid‑2‑related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2‑mediated antioxidative defense is involved in methamphetamine (MA)‑induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate‑cysteine ligase catalytic subunit C and heme oxygenase‑1), and dose‑dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2‑mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA‑induced chronic lung toxicity.
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Yang
Y
Bai
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Yun
Y
Wang
Department of Drug Control, China Criminal Police University, Shenyang, Liaoning 110035, P.R. China.
Ming
M
Liu
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Yu-Han
YH
Gu
Department of Cardiovascular Ultrasound, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China.
Bin
B
Jiang
Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Xu
X
Wu
Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Huai-Liang
HL
Wang
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001783:Blood Flow Velocity / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000032:analysis; D006339:Heart Rate / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects*; D055370:Lung Injury / Q000139:chemically induced / Q000401:mortality / Q000473:pathology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D015996:Survival Rate; D018608:Ultrasonography, Doppler
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D051547:Heme Oxygenase-1; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; D005978:Glutathione