Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthma.
Oxidative stress is a critical pathophysiological factor in the development of allergic airway inflammation, resulting in oxidative damage to lipids, proteins, and DNA. Our recent report revealed potent anti-inflammatory effects of the antimalarial drug artesunate in experimental allergic asthma. The present study investigated potential antioxidative effects of artesunate in a murine model of allergic asthma in comparison with dexamethasone, a potent corticosteroid. Mice were sensitized and challenged with ovalbumin and developed airway inflammation and oxidative lung damage. Artesunate markedly suppressed ovalbumin-induced increases in total cell, eosinophil, and neutrophil counts. In contrast, dexamethasone failed to inhibit neutrophil recruitment. Levels of the oxidative damage markers 8-isoprostane, 8-hydroxy-2-deoxyguanosine, and 3-nitrotyrosine were potently repressed by artesunate. However, dexamethasone showed weaker inhibitory effects on 3-nitrotyrosine production. Ovalbumin-induced increases in the expression of the pro-oxidants iNOS and NADPH oxidase (NOX1, 2, 3, and 4) were significantly abated by artesunate. Gene expression of regulatory subunits of NOX, p22phox and p67phox, was also reduced by artesunate. The expression and activities of the antioxidants superoxide dismutase and catalase were substantially reversed with artesunate in ovalbumin-challenged mice. Artesunate significantly enhanced nuclear levels of nuclear factor erythroid-2-related factor 2 (Nrf2) in lung tissues from ovalbumin-challenged mice and in TNF-α-stimulated human bronchial epithelial cells. Our findings implicate a potential therapeutic value for artesunate in the treatment of asthma via the amelioration of oxidative damage in allergic airways, and it may act by suppressing pro-oxidants and restoring the activities and expression of antioxidants via activation of Nrf2. Artesunate may be a potential novel anti-asthma drug capable of controlling both inflammation and oxidative damage in chronic severe asthma.
Saw Swee Hock School of Public Health, National University Health System, Singapore.
Wanxing Eugene
WE
Ho
Chang
C
Cheng
Hong Yong
HY
Peh
Fengguo
F
Xu
Steven R
SR
Tannenbaum
Choon Nam
CN
Ong
W S Fred
WS
Wong
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D055745:Bronchioles / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007962:Leukocytes / Q000276:immunology / Q000473:pathology; D055370:Lung Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D020556:Neutrophil Infiltration; D010047:Ovalbumin / Q000276:immunology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D000962:Antimalarials; D000975:Antioxidants; D037621:Artemisinins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D000077332:Artesunate; D003907:Dexamethasone; D010047:Ovalbumin; D010088:Oxidoreductases