Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma
The anti-malarial drug artesunate possesses anti-inflammatory and anti-oxidative actions in experimental asthma, comparable to corticosteroid. We hypothesized that artesunate may modulate disease-relevant metabolic alterations in allergic asthma. To explore metabolic profile changes induced by artesunate in allergic airway inflammation, we analysed bronchoalveolar lavage fluid (BALF) and serum from naïve and ovalbumin-induced asthma mice treated with artesunate, using both gas and liquid chromatography-mass spectrometry metabolomics. Pharmacokinetics analyses of serum and lung tissues revealed that artesunate is rapidly converted into the active metabolite dihydroartemisinin. Artesunate effectively suppressed BALF total and differential counts, and repressed BALF Th2 cytokines, IL-17, IL-12(p40), MCP-1 and G-CSF levels. Artesunate had no effects on both BALF and serum metabolome in naïve mice. Artesunate promoted restoration of BALF sterols (cholesterol, cholic acid and cortol), phosphatidylcholines and carbohydrates (arabinose, mannose and galactose) and of serum 18-oxocortisol, galactose, glucose and glucouronic acid in asthma. Artesunate prevented OVA-induced increases in pro-inflammatory metabolites from arginine–proline metabolic pathway, particularly BALF levels of urea and alanine and serum levels of urea, proline, valine and homoserine. Multiple statistical correlation analyses revealed association between altered BALF and serum metabolites and inflammatory cytokines. Dexamethasone failed to reduce urea level and caused widespread changes in metabolites irrelevant to asthma development. Here we report the first metabolome profile of artesunate treatment in experimental asthma. Artesunate restored specific metabolic perturbations in airway inflammation, which correlated well with its anti-inflammatory actions. Our metabolomics findings further strengthen the therapeutic value of using artesunate to treat allergic asthma.
KeywordsMetabolome Artemisinins Mass spectrometry Allergic asthma Corticosteroid
- Dai, C. L., Yao, X. L., Keeran, K. J., Zywicke, G. J., Qu, X., Yu, Z. X., et al. (2012). Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. American Journal of Respiratory Cell and Molecular Biology, 47(2), 186–195.CrossRefPubMedCentralPubMedGoogle Scholar
- Ho, W. E., Xu, Y.-J., Cheng, C., Peh, H. Y., Tannenbaum, S. R., Wong, W. S. F., et al. (2014b). Metabolomics reveals inflammatory-linked pulmonary metabolic alterations in a murine model of house dust mite-induced allergic asthma. Journal of Proteome Research. doi: 10.1021/pr5003615.
- Jiang, W., Li, B., Zheng, X., Liu, X., Cen, Y., Li, J., et al. (2011). Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. International Immunopharmacology, 11(8), 1065–1073.CrossRefPubMedGoogle Scholar
- Li, B., Li, J., Pan, X., Ding, G., Cao, H., Jiang, W., et al. (2010). Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF-alpha release via inhibition TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation. International Immunopharmacology, 10(3), 344–350.CrossRefPubMedGoogle Scholar
- Li, Y., Wang, S., Wang, Y., Zhou, C., Chen, G., Shen, W., et al. (2013). Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. Translational Research, 161(2), 89–98.CrossRefPubMedGoogle Scholar
- Marescau, B., De Deyn, P. P., Lowenthal, A., Qureshi, I. A., Antonozzi, I., Bachmann, C., et al. (1990). Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: Follow-up of guanidino compound levels during therapy. Pediatric Research, 27(3), 297–303.CrossRefPubMedGoogle Scholar
- Meurs, H., McKay, S., Maarsingh, H., Hamer, M. A. M., Macic, L., Molendijk, N., et al. (2002). Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. British Journal of Pharmacology, 136(3), 391–398.CrossRefPubMedCentralPubMedGoogle Scholar
- Morris, C. A., Duparc, S., Borghini-Fuhrer, I., Jung, D., Shin, C. S., & Fleckenstein, L. (2011). Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malaria Journal, 10, 263.CrossRefPubMedCentralPubMedGoogle Scholar
- Saude, E. J., Skappak, C. D., Regush, S., Cook, K., Ben-Zvi, A., Becker, A., et al. (2011). Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy. Journal of Allergy and Clinical Immunology, 127(3), 757–764 e, 751–756.Google Scholar
- Tan, S. S. L., Ong, B., Cheng, C., Ho, W. E., Tam, J. K. C., Stewart, A. G., et al. (2013). The antimalarial drug artesunate inhibits primary human cultured airway smooth muscle cell proliferation. American Journal of Respiratory Cell and Molecular Biology, 50(2), 451–458.Google Scholar
- Teja-Isavadharm, P., Watt, G., Eamsila, C., Jongsakul, K., Li, Q., Keeratithakul, G., et al. (2001). Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene, 65(6), 717–721.PubMedGoogle Scholar
- Weeda, E., de Kort, C. A. D., & Beenakkers, A. M. T. (1980). Oxidation of proline and pyruvate by flight muscle mitochondria of the Colorado beetle, Leptinotarsa decemlineata say. Insect Biochemistry, 10(3), 305–311.Google Scholar