哮喘联盟

    理论基础：核因子（NF）κB 的持续活化与哮喘的发展有关。穿心莲内酯是药用植物穿心莲的主要活性成分，研究发现其能抑制NF-κB 活性。
    目的：我们认为穿心莲内酯可能通过抑制NF-κB 信号通路来治疗过敏性哮喘。
    方法：采用卵清蛋白使BALB/c小鼠致敏，制造气道炎症。收集支气管肺泡灌洗液，评价总细胞和不同细胞计数、细胞因子和趋化因子水平。同时检测血清IgE水平。取肺组织检测细胞浸润、粘液的过度分泌以及炎症性生物标记物的表达。气道高反应性通过直接气道阻力分析监测。
    检测主要结果：穿心莲内酯以剂量依赖性方式抑制卵清蛋白诱导的支气管肺泡灌洗液总细胞、嗜酸性粒细胞和IL-4, IL-5 及IL-13水平的增加，降低血清卵清蛋白特异性IgE水平。穿心莲内酯还能降低卵清蛋白诱导的肺组织嗜酸性粒细胞增多和气道粘液的产生，抑制肺组织E选择素、甲壳酶、Muc5ac和诱导型一氧化氮合成酶的mRNA表达和气道对乙酰甲胆碱的过度反应性。在正常人体支气管上皮细胞，穿心莲内酯能抑制TNF-alpha 诱导的抑制性κB (IκB)激酶β(IKKβ)的磷酸化，下调IκBα的降解，抑制NF-κB的p65亚单位磷酸化，抑制p65的核转位以及DNA结合活性。与此类似，穿心莲内酯能抑制卵清蛋白致敏小鼠肺组织的核提取物中p65的核转位和DNA结合活性。
    结论：该结果揭示了穿心莲内酯治疗哮喘的潜在机制，其在IKKβ活化水平上通过抑制NF-κB通路来发挥治疗作用。

（苏楠 审校）
Bao Z, et al. Am J Respir Crit Care Med. 2009 Feb 6. [Epub ahead of print]

A Novel Anti-inflammatory Role for Andrographolide in Asthma via Inhibition of the Nuclear Factor-{kappa}B Pathway.

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.