title: Anti-malarial drug artesunate protects against cigarette smoke-induced lung injury in mice.
abstract: Cigarette smoking is the primary cause of chronic obstructive pulmonary disease (COPD), which is mediated by lung infiltration with inflammatory cells, enhanced oxidative stress, and tissue destruction. Anti-malarial drug artesunate has been shown to possess anti-inflammatory and anti-oxidative actions in mouse asthma models. We hypothesized that artesunate can protect against cigarette smoke-induced acute lung injury via its anti-inflammatory and anti-oxidative properties. Artesunate was given by oral gavage to BALB/c mice daily 2h before 4% cigarette smoke exposure for 1h over five consecutive days. Bronchoalveolar lavage (BAL) fluid and lungs were collected for analyses of cytokines, oxidative damage and antioxidant activities. Bronchial epithelial cell BEAS-2B was exposed to cigarette smoke extract (CSE) and used to study the mechanisms of action of artesunate. Artesunate suppressed cigarette smoke-induced increases in BAL fluid total and differential cell counts; levels of IL-1β, MCP-1, IP-10 and KC; and levels of oxidative biomarkers 8-isoprostane, 8-OHdG and 3-nitrotyrosine in a dose-dependent manner. Artesunate promoted anti-oxidant catalase activity and reduced NADPH oxidase 2 (NOX2) protein level in the lungs from cigarette smoke-exposed mice. In BEAS-2B cells, artesunate suppressed pro-inflammatory PI3K/Akt and p44/42 MAPK signaling pathways, and increased nuclear Nrf2 accumulation in response to CSE. Artesunate possesses anti-inflammatory and anti-oxidative properties against cigarette smoke-induced lung injury, probably via inhibition of PI3K and p42/22 MAPK signaling pathways, augmentation of Nrf2 and catalase activities, and reduction of NOX2 level. Our data suggest that artesunate may have therapeutic potential for treating COPD.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: David S W
authors.initials: DS
authors.lastname: Ng
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: Wupeng
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: W S Daniel
authors.initials: WS
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: Tze Khee
authors.initials: TK
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
authors.forename: Xin Yi
authors.initials: XY
authors.lastname: Loh
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore; Immunology Program, Life Science Institute; National University of Singapore, Singapore, Singapore. Electronic address: phcwongf@nus.edu.sg.
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D037621:Artemisinins; D016207:Cytokines; D008562:Membrane Glycoproteins; D020011:Protective Agents; D000077332:Artesunate; D002374:Catalase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Artemisinins; BEAS-2B cells; Chronic obstructive pulmonary disease; NOX2; Nrf-2