A novel antiinflammatory role for andrographolide in asthma via inhibition of the nuclear factor-kappaB pathway.
BACKGROUND
Persistent activation of nuclear factor (NF)-kappaB 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-kappaB activity.


OBJECTIVE
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 (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.


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-alpha-induced phosphorylation of inhibitory kappaB kinase-beta, and downstream inhibitory kappaB alpha 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 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-kappaB pathway at the level of inhibitory kappaB kinase-beta activation.
Bao
Zhang
Z
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
Guan
Shouping
S
Cheng
Chang
C
Wu
Songlian
S
Wong
Siew Heng
SH
Kemeny
D Michael
DM
Leung
Bernard P
BP
Wong
W S Fred
WS
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D004224:Diterpenes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D016328:NF-kappa B; C030419:andrographolide; D010047:Ovalbumin