1′-Acetoxychavicol Acetate Isolated from Alpinia galanga Ameliorates Ovalbumin-Induced Asthma in Mice

et al. (2013) 19-Acetoxychavicol Acetate Isolated from Alpinia galanga Ameliorates Ovalbumin-Induced Asthma in Mice. PLoS ONE 8(2): e56447. doi:10.1371/journal.pone.0056447 19-Acetoxychavicol Acetate Isolated from Alpinia galanga Ameliorates Ovalbumin-Induced Asthma in Mice Joung-Wook Seo 0 Soon-Chang Cho 0 Sang-Joon Park 0 Eun-Ji Lee 0 Jong-Hwa Lee 0 Sang-Seop Han 0 Byeong Sik Pyo 0 Dae-Hun Park 0 Bong-Hee Kim 0 Thomas H. Thatcher, University of Rochester Medical Center, United States of America 0 1 Korea Institute of Toxicology, Daejeon, Korea, 2 College of Pharmacy, Chungnam National University , Daejeon , Korea , 3 Center for Senior Industry, Youngdong University , Yeongdong , Korea , 4 College of Veterinary Medicine, Kyungpook National University , Daegu , Korea , 5 College of Veterinary Medicine, Chungnam National University , Daejeon , Korea , 6 Konyang University , Daejeon , Korea , 7 Dongshin University , Naju , Korea The World Health Organization reports that 235 million people are currently affected by asthma. This disease is associated with an imbalance of Th1 and Th2 cells, which results in the upregulation of cytokines that promote chronic inflammation of the respiratory system. The inflammatory response causes airway obstruction and can ultimately result in death. In this study we evaluated the effect of 19-acetoxychavicol acetate (ACA) isolated from Alpinia galanga rhizomes in a mouse model of ovalbumin (OVA)-induced asthma. To generate the mouse model, BALB/c mice were sensitized by intraperitoneal injection of OVA and then challenged with OVA inhalation for 5 days. Mice in the vehicle control group were sensitized with OVA but not challenged with OVA. Treatment groups received dexamethasone, 25 mg/kg/day ACA, or 50 mg/kg/day ACA for 5 days. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. Our results showed that ACA reduced the infiltration of white blood cells (especially eosinophils) and the level of IgE in the lungs of mice challenged with OVA and suppressed histopathological changes such as airway remodeling, goblet-cell hyperplasia, eosinophil infiltration, and glycoprotein secretion. In addition, ACA inhibited expression of the Th2 cytokines interleukin (IL)-4 and IL-13, and Th1 cytokines IL-12a and interferon-c. Because asthmatic reactions are mediated by diverse immune and inflammatory pathways, ACA shows promise as an antiasthmatic drug candidate. - Funding: This work was supported by a grant (Code No. 2009-0073116) from National Research Foundation of Korea and a grant (Code No. C0018727) from Business for Cooperative R&D between Industry, Academy, and Research Institute funded Korea Small and Medium Business Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. The World Health Organization reports that 235 million people are affected by asthma, which is the most common chronic disease among children. Triggers for asthma include indoor allergens (e.g., pet dander and dust mites in bedding, carpets, and stuffed furniture), outdoor allergens (e.g., pollens and molds), tobacco smoke, chemical irritants, and air pollution. Asthma is a serious disease that can result in death if not treated properly [1]. This chronic inflammatory lung disease causes bronchoconstriction, bronchial mucosal thickening from edema, eosinophilic infiltration, bronchial wall remodeling, and excessive mucus production, and can ultimately lead to airway obstruction [2,3]. Asthma is an immune-mediated disease in which T helper (Th) cells play an important role. Mouse Th clones can be divided into two subsets according to cytokine secretion patterns [4]: Th1 cells secret interleukin (IL)-2 and interferon (IFN)-c, and Th2 cells secrete IL-4, IL-13, and IL-5. In addition, Th2 cells promote B cell differentiation and class switching from Ig G to Ig E [5]. The cytokine IL-6 regulates the functions of CD4 T cells and mediates asthma induction [6], whereas IL-12 regulates the Th1/Th2 balance [7] and promotes IFN-c production [8]. IFN-c is related to the persistence and severity of asthma [9]. IL-4 and IL-13, which are key cytokines in the pathogenesis of asthma [10], are involved in airway remodeling, inflammatory processes, airway hyperresponsiveness, goblet-cell hyperplasia, eosinophil infiltration, mucus hypersecretion, and B cell activation [11,12,13,14]. IL-5 regulates the development, activation, migration, and survival of eosinophils, which are characteristic features of asthma [15]. Asthma is controlled with bronchodilators, corticosteroids, leukotriene modifiers, theophylline, and/or anti-IgE therapy; however, none of these treatments are curative [16]. Inhaled corticosteroids are commonly used [17], but in addition to their side effects, these drugs tend to reduce glucocorticoid receptorbinding affinity and T-cell response [18]. Therefore, alternative therapies are sought from traditional medicines or other natural products that have therapeutic effects in respiratory disorders. Alpinia galangal is a member of the ginger family but differs from Zingiber officinale, which is commonly used in Western cuisine. Alpinia galanga rhizomes have been traditionally used to treat bronchial problems in tropical areas of south and east India. This rhizome has also been reported to be useful as a carminative and as a treatment for rheumatoid arthritis, inflammation, stomatopathy, pharyngopathy, cough, asthma, hiccough, dyspepsia, stomachalgia, obesity, diabetes, cephalalgia, tubercular glands, and intermittent fevers [19]. Biological properties of A. galanga and its constituents include anticarcinogenic effects [20], chemoprevention through COX-2 suppression [21], antioxidative actions [22], and inhibition of TNF-a and IL-4 [23]. In addition, hydroxychavicol acetate, which is one of the constituents of A. galanga, increases IL-2 production and attenuates IFN-c expression [24]. Although studies have reported that A. galanga exerts various biological effects and modulates inflammation, no studies have evaluated the ability of A. galanga to cure or completely control asthma. Therefore, in this study we evaluated the effect of 19acetoxychavicol acetate (ACA; 25 or 50 mg/kg/day) isolated from A. galanga on asthma using a mouse model of ovalbumin (OVA)induced asthma. ACA reduced the number of eosinophils and other white blood cells and the level of IgE in bronchoalveolar lavage fluid In the mouse model of OVA-induced asthma, the number of white blood cells (WBCs) in bronchoalveolar lavage fluid (BALF) was significantly increased compared with that of mice treated with vehicle alone (vehicle control) (Figure 1a). In addition, ACA dose-dependently decre (...truncated)