Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase
- Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030 (United States)
Highlights: • Leflunomide decreases oxidative stress in fetal human lung endothelial cells. • Leflunomide induces catalase, NQO1, and SOD2 enzymes in fetal human lung cells. • Leflunomide effects on oxidative stress, catalase, and SOD2 are AhR-independent. • AhR deficiency abrogates leflunomide-mediated induction of NQO1 enzyme. Hyperoxia-induced oxidative stress contributes to the pathogenesis of bronchopulmonary dysplasia (BPD), the most common respiratory morbidity of preterm infants. Importantly, the disease lack specific therapies and is associated with long-term cardio-pulmonary and neurodevelopmental morbidities, signifying the need to discover novel therapies and decrease the disease burden. We and others have demonstrated that leflunomide, a food and drug administration approved drug to treat humans with rheumatoid arthritis, increases the expression of the anti-oxidant enzymes, NAD(P)H quinone dehydrogenase 1 (NQO1), catalase, and superoxide dismutase (SOD). However, whether this drug can decrease oxidative stress in fetal human pulmonary arterial endothelial cells (HPAECs) is unknown. Therefore, we tested the hypothesis that leflunomide will decrease hyperoxia-induced oxidative stress by upregulating these anti-oxidant enzymes in HPAECs. Leflunomide decreased hydrogen peroxide (H{sub 2}O{sub 2}) levels and increased the mRNA and protein levels of catalase, NQO1, and SOD2 in HPAECs at basal conditions. Further, leflunomide-treated cells continued to have decreased H{sub 2}O{sub 2} and increased SOD2 levels upon hyperoxia exposure. Leflunomide did not affect the expression of other anti-oxidant enzymes, including hemoxygenase-1 and SOD1. AhR-knockdown experiments suggested that leflunomide regulated NQO1 levels via AhR-dependent mechanisms and H{sub 2}O{sub 2}, catalase, and SOD2 levels via AhR-independent mechanisms. Collectively, the results support the hypothesis that leflunomide decreases oxidative stress in HPAECs via SOD2-and catalase-dependent, but AhR- and NQO1-independent mechanisms. Our findings indicate that leflunomide is a potential drug for the management of BPD in preterm infants.
- OSTI ID:
- 23105571
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 3; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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