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A Novel Antiinflammatory Role for Andrographolide in Asthma via Inhibition of the Nuclear Factor-B Pathway

¹ Department of Pharmacology, ² Department of Microbiology, and ³ Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, Singapore; ⁴ Immunology Program, Life Science Institute, National University of Singapore, Singapore; and ⁵ Division of Respiratory Medicine, The First Affiliated-Hospital, College of Medicine, Zhejiang University, Hangzhou, China

Correspondence and requests for reprints should be addressed to W.S. Fred Wong, Ph.D., Immunology Program, Life Science Institute, National University of Singapore, 28 Medical Drive, Center for Life Sciences, #03-05, Singapore 117456. E-mail: phcwongf{at}nus.edu.sg

Rationale: Persistent activation of nuclear factor (NF)-B has been associated with the development of asthma. Andrographolide, the principal active component of the medicinal plant Andrographis paniculata, has been shown to inhibit NF-B activity.

Objectives: We hypothesized that andrographolide may attenuate allergic asthma via inhibition of the NF-B signaling pathway.

Methods: BALB/c mice sensitized and challenged with ovalbumin (OVA) 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 OVA-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 OVA-specific IgE. It attenuated OVA-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 tumor necrosis factor-–induced phosphorylation of inhibitory B kinase-β, and downstream inhibitory B degradation, p65 subunit of NF-B 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 OVA-challenged mice.

Conclusions: Our findings implicate a potential therapeutic value of andrographolide in the treatment of asthma and it may act by inhibiting the NF-B pathway at the level of inhibitory B kinase-β activation.

Key Words: ovalbumin • inhibitory B kinase-β • inhibitory B • inducible nitric oxide synthase • chitinase • lung epithelium

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Persistent activation of nuclear factor (NF)–B is associated with asthma. Andrographolide, a principal active component of the medicinal plant Andrographis paniculata, has been shown to inhibit NF-B activity. What This Study Adds to the Field This study shows the antiinflammatory role of andrographolide in ovalbumin-induced allergic lung disease and human bronchial epithelial cells by inhibiting the NF-B activity at the level of inhibitory B kinase-B activation.

 

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