Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma
Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma
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DOI：
10.1038/labinvest.3780068
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发表时间：
2000-05-01
影响因子：
5
通讯作者：
Kumar, RK
中科院分区：
文献类型：
--
作者：
Foster, PS;Ming, Y;Kumar, RK
为了研究慢性哮喘的发病机制，我们采用了一种新的实验模型，复制了人类疾病的特征。系统致敏的BALB/c小鼠反复暴露于低质量浓度的雾化卵白蛋白6周后，可诱发慢性炎症和上皮细胞病变，尤其局限于呼吸道。在细胞因子缺陷小鼠中，评估了Th2细胞因子驱动的炎症在呼吸道损伤和高反应性发展中的作用。在白介素5缺乏的动物中，呼吸道固有层的上皮内嗜酸性粒细胞和慢性炎症细胞显著减少，但这些动物出现了与致敏野生型小鼠相似的上皮肥大和上皮下纤维化。吸入乙酰甲胆碱的呼吸道高反应性在白细胞介素5缺乏的小鼠中没有出现。相比之下，白介素4缺乏的小鼠没有表现出呼吸道炎症的减少，但有显著的上皮肥大和上皮下纤维化，以及对乙酰甲胆碱的过度反应。我们得出结论，白介素5，而不是白介素4，在慢性呼吸道炎症的发展和诱导呼吸道高反应性中起核心作用。此外，慢性上皮细胞和纤维化改变独立于白介素5而发生，并且不是发展呼吸道高反应性所必需的。气道壁重构和气道高反应性之间的分离对于慢性哮喘的治疗具有重要的意义。
To study pathogenetic mechanisms in chronic asthma, we employed a novel experimental model that replicates characteristic features of the human disease. Chronic inflammation and epithelial changes, specifically localized to the airways, were induced by repeated exposure of systemically sensitized BALB/c mice to low mass concentrations of aerosolized ovalbumin for 6 weeks. The contribution of Th2 cytokine-driven inflammation to the development of airway lesions and hyperreactivity was assessed in cytokine-deficient mice. In interleukin-5-deficient animals, intraepithelial eosinophils and chronic inflammatory cells in the lamina propria of the airways were markedly decreased; however, these animals developed epithelial hypertrophy and subepithelial fibrosis comparable with that observed in sensitized wild type mice. Airway hyperreactivity to inhaled methacholine did not develop in interleukin-5-deficient mice. In contrast, interleukin-4-deficient mice exhibited no decrease in airway inflammation, but had significantly greater epithelial hypertrophy and subepithelial fibrosis, as well as exaggerated hyperreactivity to methacholine. We conclude that interleukin-5, but not Interleukin-4, plays a central role in the development of chronic inflammation of the airways and the induction of airway hyperreactivity. Furthermore, chronic epithelial and fibrotic changes occur independently of interleukin-5 and are not required for the development of airway hyperreactivity. The dissociation between airway wall remodeling and airway hyperreactivity has important implications for therapeutic approaches to chronic asthma.