Bao Z, Guan S, Cheng C, Wu S, Wong SH, Kemeny DM, Leung BP, Wong WS.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore; Division of Respiratory Medicine, The First Affiliated-Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
RATIONALE: Persistent activation of nuclear factor (NF)-kappaB has been associated with the development of asthma. Andrographolide, the principal active component of a medicinal plant Andrographis paniculata, has been shown to inhibit NF-kappaB activity. OBJECTIVES: We hypothesized that andrographolide may attenuate allergic asthma via inhibition of the NF-kappaB signaling pathway. METHODS: BALB/c mice sensitized and challenged with ovalbumin developed airway inflammation. Bronchoalveolar lavage fluid was assessed for total and differential cell counts, and cytokine and chemokine levels. Serum IgE levels were also determined. Lung tissues were examined for cell infiltration and mucus hypersecretion, and the expression of inflammatory biomarkers. Airway hyperresponsiveness was monitored by direct airway resistance analysis. MEASUREMENTS AND MAIN RESULTS: Andrographolide dose-dependently inhibited ovalbumin-induced increases in total cell count, eosinophil count, and IL-4, IL-5 and IL-13 levels recovered in bronchoalveolar lavage fluid, and reduced serum level of ovalbumin-specific IgE. It attenuated ovalbumin-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, chitinases, Muc5ac and inducible nitric oxide synthase in lung tissues, and airway hyperresponsiveness to methacholine. In normal human bronchial epithelial cells, andrographolide blocked TNF-alpha-induced phosphorylation of inhibitory kappaB (IkappaB) kinase-beta (IKKbeta), and downstream IkappaBalpha degradation, p65 subunit of NF-kappaB phosphorylation, and p65 nuclear translocation and DNA-binding activity. Similarly, andrographolide blocked p65 nuclear translocation and DNA-binding activity in the nuclear extracts from lung tissues of ovalbumin-challenged mice. CONCLUSIONS: Our findings implicate a potential therapeutic value of andrographolide in the treatment of asthma and it may act by inhibiting NF-kappaB pathway at the level of IKKbeta activation.
PMID: 19201922 [PubMed - as supplied by publisher]
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