Leflunomide attenuates oxidative stress in fetal human lung endothelial cells via superoxide dismutase 2 and catalase

Abstract

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 (HO) 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 HO 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 HO, 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.

The Mitochondria-Independent Cytotoxic Effect of Leflunomide on RPMI-8226 Multiple Myeloma Cell Line

“…However, there were no symptoms of oxidative stress in teriflunomide treated cells. Despite this fact, there have been several reports of oxidative stress reduction—e.g., in fetal human pulmonary arterial endothelial cells due teriflunomide treatment [ 34 ]—and its ability to preserve peripheral nerve mitochondria from oxidative stress [ 35 ].…”

Research Progress on Association between Early-Life Exposure to Phthalates and Childhood Asthma

“…Oxidative stress response: More and more population studies have shown that oxidative stress plays an important role in the pathogenesis of asthma, and the oxidative stress level is mainly refl ected in the levels of various antioxidant enzymes [23][24][25]. I-Jen W, et al [20] found that individuals with Superoxide Dismutase 2 (SOD2) (rs5746136) TT genotype had higher risk of asthma and higher level of MEHHP in vivo than those with CC genotype.…”