Ulrich Kristina, Hincks Jennifer S, Walsh Roddy, Wetterstrand E M Caroline, Fidock Mark D, Sreckovic Sasha, Lamb David J, Douglas Garry J, Yeadon Michael, Perros-Huguet Christelle, Evans Steven M
Drug Safety Research and Development, Pfizer Global Research and Development, Sandwich, Sandwich, UK.
Pulm Pharmacol Ther. 2008 Aug;21(4):637-47. doi: 10.1016/j.pupt.2008.02.006. Epub 2008 Mar 5.
Asthma affects 300 million people worldwide and continues to be a major cause of morbidity and mortality. Disease relevant animal models of asthma are required for benchmarking of novel therapeutic mechanisms in comparison to established clinical approaches. We demonstrate that chronic exposure of mice to house dust mite (HDM) extract results in allergic airway inflammation, that can be significantly attenuated by therapeutic intervention with phosphodiesterase 4 inhibition and corticosteroid treatment. Female BALB/c mice were administered intranasally with HDM (Dermatophagoides pteronyssinus) extract daily for five weeks, and therapeutic intervention with anti-inflammatory treatment (dexamethasone 1 mg/kg subcutaneous once daily, prednisolone 10mg/kg orally twice daily, fluticasone 3, 10 and 30 microg intranasally twice daily, roflumilast 10 mg/kg orally twice daily and intranasally 10 and 30 microg twice daily) was initiated after three weeks of exposure. Chronic HDM extract exposure resulted in significant airway inflammation, demonstrated by bronchoalveolar lavage cell infiltration and lung tissue inflammatory gene expression by TaqMan low density array. Chronic steroid treatment significantly inhibited these parameters. In addition, roflumilast caused a significant reduction in airway inflammatory cell infiltration. We have demonstrated that chronic HDM-induced allergic inflammation can be significantly ameliorated by steroid treatment, and that phosphodiesterase 4 inhibition modulates inflammatory cell infiltration. Therefore, the murine HDM model may be a useful tool for evaluating new targets for the treatment of asthma.
哮喘影响着全球3亿人，并且仍然是发病和死亡的主要原因。与既定的临床方法相比，需要哮喘相关的疾病动物模型来对新的治疗机制进行基准测试。我们证明，将小鼠长期暴露于屋尘螨（HDM）提取物会导致过敏性气道炎症，而磷酸二酯酶4抑制和皮质类固醇治疗的干预可以显著减轻这种炎症。雌性BALB/c小鼠每天经鼻给予HDM（粉尘螨）提取物，持续五周，在暴露三周后开始用抗炎治疗（地塞米松1mg/kg皮下注射，每日一次；泼尼松龙10mg/kg口服，每日两次；氟替卡松3、10和30μg经鼻给药，每日两次；罗氟司特10mg/kg口服，每日两次，经鼻给药10和30μg，每日两次）进行治疗干预。长期暴露于HDM提取物导致显著的气道炎症，通过支气管肺泡灌洗细胞浸润和TaqMan低密度阵列检测肺组织炎症基因表达得以证明。长期使用类固醇治疗可显著抑制这些指标。此外，罗氟司特可显著减少气道炎症细胞浸润。我们已经证明，类固醇治疗可以显著改善长期HDM诱导的过敏性炎症，并且磷酸二酯酶4抑制可调节炎症细胞浸润。因此，小鼠HDM模型可能是评估哮喘治疗新靶点的有用工具。
