Clin Sci (Lond). 2014 Jan 1;126(1):55-65. doi: 10.1042/CS20130174.
Severe asthma and viral-induced asthma exacerbations represent a high unmet medical need as no therapy is currently available for these patients. HRV (human rhinovirus) is prominently associated with asthma exacerbations in humans. The aim of the present study was to establish a mouse model of severe asthma with additional rhinovirus infection to investigate the interplay between chronic allergic airway inflammation and acute respiratory viral infection. Balb/c mice were sensitized with HDM (house dust mite) extract (25 μg in 50 μl of saline) by i.n. (intranasal) delivery to the lung over 7 weeks. HRV1B (HRV serotype 1B) inoculation was performed i.n. on the last 3 days. Therapeutic treatment with FP (fluticasone propionate) was performed to assess steroid efficacy. Lung resistance was measured invasively to assess AHR (airway hyper-responsiveness). BAL (bronchoalveolar lavage) differential cell count, cytokines, lung histology and the proliferative and cytokine response of MLN (mediastinal lymph node) cells upon in vitro restimulation were analysed. Chronic HDM application induced a strong Th2-skewed eosinophilic airway inflammation and AHR, which was not exacerbated by superimposed HRV1B infection. Therapeutic steroid intervention in the chronic HDM model reduced BAL eosinophil cell counts, cytokine levels and AHR, while neutrophil numbers were unaffected. Steroid efficacy against inflammatory readouts was maintained during additional HRV1B infection. Animals with chronic allergic airway inflammation exhibited a diminished immune response towards superimposed HRV1B infection compared with HRV1B alone, as induction of the anti-viral and pro-inflammatory cytokines IFN (interferon)-α, IFN-γ and IL (interleukin)-12 were suppressed. Although superimposed HRV1B infection did not provoke asthma exacerbation in this severe model, a deficient anti-viral immune response to HRV1B was present under chronic allergic airway inflammatory conditions. Thus, this model is able to reflect some aspects of the complex interplay of respiratory virus infection in chronic allergic asthma.
严重哮喘和病毒引起的哮喘恶化代表着未满足的高医疗需求，因为目前尚无针对这些患者的治疗方法。HRV（人鼻病毒）与人哮喘恶化密切相关。本研究旨在建立一种伴有鼻病毒感染的严重哮喘小鼠模型，以研究慢性过敏性气道炎症与急性呼吸道病毒感染之间的相互作用。Balb/c 小鼠通过鼻内（鼻腔内）给药在 7 周内用 HDM（屋尘螨）提取物（50μl 中的 25μg）致敏。在最后 3 天进行 HRV1B（鼻病毒血清型 1B）接种。进行 FP（丙酸氟替卡松）治疗以评估皮质类固醇的疗效。通过侵入性测量肺阻力来评估 AHR（气道高反应性）。分析 BAL（支气管肺泡灌洗）差异细胞计数、细胞因子、肺组织学以及 MLN（纵隔淋巴结）细胞在体外再刺激时的增殖和细胞因子反应。慢性 HDM 应用诱导强烈的 Th2 偏向嗜酸性气道炎症和 AHR，叠加 HRV1B 感染不会加重。慢性 HDM 模型中的治疗性皮质类固醇干预降低了 BAL 嗜酸性粒细胞计数、细胞因子水平和 AHR，而中性粒细胞数量不受影响。在叠加 HRV1B 感染期间，皮质类固醇对炎症指标的疗效得以维持。与单独 HRV1B 感染相比，具有慢性过敏性气道炎症的动物对叠加 HRV1B 感染的免疫反应减弱，因为诱导抗病毒和促炎细胞因子 IFN（干扰素）-α、IFN-γ 和 IL（白细胞介素）-12 受到抑制。尽管在这个严重的模型中叠加 HRV1B 感染没有引发哮喘恶化，但在慢性过敏性气道炎症条件下存在对 HRV1B 的缺陷抗病毒免疫反应。因此，该模型能够反映呼吸道病毒感染在慢性过敏性哮喘中的复杂相互作用的某些方面。
