Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/29521
Title: NOVEL ANTI-INFLAMMATORY ACTIONS OF THE ANTI-MALARIAL DRUG ARTESUNATE IN ALLERGIC RESPONSES AND INFLAMMATORY DISEASES
Authors: CHENG CHANG
Keywords: Artemisinin, Allergy, Respiratory, Anaphylaxis, Type I hypersensitivity
Issue Date: 15-Dec-2010
Source: CHENG CHANG (2010-12-15). NOVEL ANTI-INFLAMMATORY ACTIONS OF THE ANTI-MALARIAL DRUG ARTESUNATE IN ALLERGIC RESPONSES AND INFLAMMATORY DISEASES. ScholarBank@NUS Repository.
Abstract: The purpose of this thesis is to investigate the therapeutic potential of artesunate, an anti-malaria drug, on allergy and allergic asthma. Firstly, we studied the anti-inflammatory effects of artesunate on allergic asthma by employing a murine asthma model. In this study, female Balb/c mice were actively sensitized and challenged by ovalbumin to induce airway inflammation, mucus hypersecretion and airway hyperresponsiveness. Artesunate (3, 10, 30 mg/kg, given intraperitoneally) markly inhibited OVA-induced increases in total cell counts and eosinophil counts and IL-4, IL-5, IL-13 and eotaxin levels in bronchoalveolar lavage fluid in a dose dependent manner. Artesunate also substantially (P<0.05) reduced serum levels of OVA-IgE and IgG1; whereas the levels of OVA-specific IgG2a were not significantly affected. In addition, artesunate was shown to restore the levels of Th1 related cytokines such as IFN-gamma and IL-12 back to basal level in a dose dependent manner. Histological analysis further showed that artesunate potently inhibited OVA-induced lung tissue eosinophilia and mucus hypersecretion. Furthermore, artesunate was shown to significantly (P<0.05) suppress OVA-induced airway hyperresponsiveness when challenged with methacholine. Western blot results show that pretreatment of artesunate (10 uM) attenuated EGF-induced activation of PI3K/Akt signaling cascade in primary human bronchial epithelial cells. Secondly, we investigated the anti-allergic properties of artesunate on animal anaphylaxis models. In this particular study, we established two in vivo models, passive cutaneous anaphylaxis and systemic anaphylaxis; as well as two in vitro models, the Schulz-Dale reaction and RBL-2H3 releasing assay. For the in vivo models, female Balb/c mice were passively sensitized with IgE and challenged by an intravenous injection of an allergen (Human Serum Albumin, HSA). Upon allergen challenge, significant increase of plasma extravasation, drop of body temperature and mast cell degranulation were observed in IgE-sensitized mice. Mice treated with artesunate (3, 10, 30 mg/kg given intravenously) could markedly attenuate IgE-induced anaphylactic symptoms and prevent mast cells from degranulating in a dose-dependent manner. For the in vitro model, guinea pigs were actively sensitized by intraperitoneal injections of ovalbumin. Bronchial rings were harvested and prepared for the contractile study. Artesunate (30uM) significantly inhibited OVA-induced but not histamine or LT4-induced anaphylactic contraction. We further demonstrated that artesunate could dose dependently (3, 10, 30 uM) suppress the release of beta-hexosaminidase in RBL-2H3 mast cells which were sensitized and challenged with IgE or HSA, respectively. Regulation of calcium concentration plays a pivotal role in mast cell degranualation and also involves in regulating of mast cell activation. Syk kinase plays an essential role in IgE-dependent mast cell activation and provides docking sites for other signaling molecules to ensure further signal transduction. Such signals phosphorylate and activate PLC-gamma which generates critical signals (calcium and IP3) for mast cell degranulation. In our findings, we observed that artesunate could inhibit phosphorylation of Syk kinase as well as its downstream signaling molecule PLC-gamma mediated calcium influx in RBL-2H3 cells. Our study further suggests that these potent anti-inflammatory and anti-allergic effects exhibited by artesunate are mediated via the negative regulation at the level of PI3K/Akt and FceRI-mediated signaling involving Syk/PLCgamma. Despite so, it is still unclear how artesunate interacts with these molecule targets to achieve its therapeutic effects. Taken together, our findings indicate that artesunate possess novel therapeutic capabilities in experimental allergic disorders such as asthma and anaphylaxis.
URI: http://scholarbank.nus.edu.sg/handle/10635/29521
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