小鼠早期病毒感染和过敏原暴露两者相互作用诱导哮喘表现型
2010/07/05
背景：早期呼吸道感染，特别是呼吸道合胞病毒（RSV）感染，能增加儿童期哮喘发生的风险。本实验采用RSV种属特异性模型研究早期感染和随后过敏原暴露是否能预测哮喘特征。
方法：新生小鼠感染小鼠肺炎病毒（PVM，该模型模拟新生儿严重RSV感染），随后经鼻腔给予卵清蛋白致敏。然后动物给予持续4周的雾化抗原刺激，使其产生慢性哮喘，随后采用单次中度水平刺激，诱导炎症恶化。我们对气道炎症、与气道重构相关的上皮改变、气道高反应性（AHR）及宿主免疫反应进行评价。
结果：过敏性气道炎症包括嗜酸性粒细胞聚集，在PVM感染后恢复期给予致敏及慢性抗原处理后的小鼠非常明显。此外，这些小鼠Th2细胞免疫反应增加，其中包括血清抗卵清蛋白IgE和IgG1水平增加、Th2相关细胞因子（IL-4、IL-5和 IL-13）表达增加。通过比较，AHR和粘膜细胞改变与PVM感染相关，不管是否随后有过敏原刺激。PVM感染后肺内IL-25表达增加，可能诱导Th2反应。IL-4受体α链相关信号对于过敏性炎症、粘膜细胞改变和AHR至关重要，因为在IL-4受体缺陷小鼠未见上述变化。相反，对于慢性过敏原刺激的小鼠，不管是否存在早期PVM感染，气道重构均较明显，而且不依赖于IL-4受体信号。
结论：在本文小鼠模型中，早期病毒感染和过敏原致敏/刺激两者相互作用，对儿童期出现哮喘特征性表现至关重要，这些特征包括过敏性炎症和Th2免疫反应。
(刘国梁 审校)
Siegle JS, et al. Respir Res. 2010 Feb 3;11(1):14. [Epub ahead of print]
Early-life viral infection and allergen exposure interact to induce an asthmatic phenotype in mice.
Siegle JS, Hansbro N, Herbert C, Rosenberg HF, Domachowske JB, Asquith KL, Foster PS, Kumar RK.
BACKGROUND: Early-life respiratory viral infections, notably with respiratory syncytial virus (RSV), increase the risk of subsequent development of childhood asthma. The purpose of this study was to assess whether early-life infection with a species-specific model of RSV and subsequent allergen exposure predisposed to the development of features of asthma.
METHODS: We employed a unique combination of animal models in which BALB/c mice were neonatally infected with pneumonia virus of mice (PVM, which replicates severe RSV disease in human infants) and following recovery, were intranasally sensitised with ovalbumin. Animals received low-level challenge with aerosolised antigen for 4 weeks to elicit changes of chronic asthma, followed by a single moderate-level challenge to induce an exacerbation of inflammation. We then assessed airway inflammation, epithelial changes characteristic of remodelling, airway hyperresponsiveness (AHR) and host immunological responses.
RESULTS: Allergic airway inflammation, including recruitment of eosinophils, was prominent only in animals that had recovered from neonatal infection with PVM and then been sensitised and chronically challenged with antigen. Furthermore, only these mice exhibited an augmented Th2-biased immune response, including elevated serum levels of anti ovalbumin IgE and IgG1 as well as increased relative expression of Th2-associated cytokines IL-4, IL-5 and IL-13. By comparison, development of AHR and mucous cell change were associated with recovery from PVM infection, regardless of subsequent allergen challenge. Increased expression of IL-25, which could contribute to induction of a Th2 response, was demonstrable in the lung following PVM infection. Signalling via the IL-4 receptor alpha chain was crucial to the development of allergic inflammation, mucous cell change and AHR, because all of these were absent in receptor-deficient mice. In contrast, changes of remodelling were evident in mice that received chronic allergen challenge, regardless of neonatal PVM infection, and were not dependent on signalling via the IL-4 receptor.
CONCLUSION: In this mouse model, interaction between early-life viral infection and allergen sensitisation/challenge is essential for development of the characteristic features of childhood asthma, including allergic inflammation and a Th2-biased immune response.
