RETRACTED: NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice

Abstract

Emphysema is currently a leading cause of mortality with no known effective therapy to attenuate progressive loss of lung function. Previous work support that activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is protective to the lung through induction of hundreds of antioxidant genes. In models of lung injury, the expression of NAD(P)H:quinine oxidoreductase 1 (NQO1) is upregulated in a manner dependent on Nrf2 and human emphysema is associated with reduced levels of NQO1. However, the functional role of NQO1 in emphysema remains unknown. In this study, we demonstrate the protective role of NQO1 in the development of emphysema using mouse models. NQO1 deficient animals demonstrate premature age-related emphysema and were more susceptible to both elastase and inhaled lipopolysaccharide (LPS) models of emphysema. The absence of NQO1 was associated with enhanced markers of oxidant stress. Treatment of NQO1 deficient animals with the antioxidant N-acetyl cysteine reversed the NQO1-dependent emphysematous changes. In vitro studies utilizing either inhibition or induction of NQO1 demonstrate a potent antioxidant role of NQO1 in macrophages, suggesting a role of macrophage-derived oxidants in the pathogenesis of emphysema. These novel findings support a functional role of NQO1 in protecting the lung from development of emphysema.

Innate Immune Activation by Inhaled Lipopolysaccharide, Independent of Oxidative Stress, Exacerbates Silica-Induced Pulmonary Fibrosis in Mice

“…Saline-Saline first received the vehicle control for silica via oropharyngeal aspiration followed 28 days later by the aerosolized saline control for LPS; Saline-LPS first received the vehicle control for silica via oropharyngeal aspiration followed 28 days later by aerosolized LPS; Silica-Saline first received 0.2 g/kg silica via oropharyngeal aspiration followed 28 days later by the aerosolized saline control for LPS, and; Silica-LPS first received 0.2 g/kg silica via oropharyngeal aspiration followed 28 days later by aerosolized LPS. Mice treated with N-acetylcysteine (NAC) were provided with drinking water supplemented with 2 mg/ml NAC as described previously [18] for the period beginning three days prior to the start of LPS inhalation and lasting until phenotyping (n = 8/group). All animal procedures were approved by the Duke University Institutional Animal Care and Use Committee.…”

Dietary Iron Controls Circadian Hepatic Glucose Metabolism Through Heme Synthesis

“…The animals were maintained on a 12-h light/dark cycle. Treatment of mice with 2 mg/mL aminolevulinic acid (ALA) ( 15 ) (#A167; Frontier Scientific), 1 mg/mL isonicotinylhydrazine (INH) ( 16 ) (#I3377; Sigma-Aldrich), or 6.5 mg/mL N -acetylcysteine (NAC) ( 17 ) (#A9165; Sigma-Aldrich) in their drinking water and adjusted to pH 7. Water intake was monitored to ensure there were no variations.…”

Distinct activation mechanisms trigger the trypanocidal activity of DNA damaging prodrugs

“…However, this is accompanied by toxicity against macrophage (‐like) mammalian cells, a trait previously noted in primary mouse splenocytes (Miliukiene et al ., ). This unwanted activity may be because such immune cells have the ability to constitutively express or to upregulate quinone oxidoreductases including NQO1 and NQO1‐independent activities that promote oxidative stress and/or DNA damage (Tudor et al ., ; Potts‐Kant et al ., ; Miliukiene et al ., ). Although these cytotoxicity issues may preclude the use of these ABQs as therapies for the treatment of systemic infections, understanding how they mediate their trypanocidal activities can inform drug development.…”