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A new humanized mouse model for idiopathic pulmonary fibrosis and effects of nintedanib treatment

: Prasse, Antje; Jäger, Benedikt; Plappert, Linda; Kraus, Kim; Wollin, Lutz


European Respiratory Journal 52 (2018), Supplement 62, Abstract OA5363
ISSN: 0903-1936
ISSN: 1399-3003
European Respiratory Society (ERS International Congress) <2018, Paris>
Fraunhofer ITEM ()

Background: The widely used mouse bleomycin model does not resemble idiopathic pulmonary fibrosis (IPF) adequately. In particular, the spontaneous resolution of fibrotic lesions and the lack of honeycombing are major pitfalls. To confirm a role of airway basal cells (ABC) in IPF we established a humanized mouse model using primary cell lines derived from IPF patients.
Objectives: To test the evolution of pulmonary fibrosis after i.t. instillation of primary cell lines derived from IPF patients and the effect of nintedanib treatment.
Methods: At day 0 a small dose of bleomycin was instilled i.t. to C57/B6N Rag2 KO mice and 3 days later ABCs or fibroblasts derived from IPF patients were injected i.t.. GFP expression was used to track cells in some experiments. 22 mice were treated with nintedanib b.i.d.. Lung tissues were used for Masson trichrome staining and Ashcroft scoring and lung function and hydroxyproline levels were assessed.
Results: Only administration of ABCs from IPF patients resulted in the evolution of cystic changes and vast bronchiolization resembling honeycombing. IPF lung fibroblasts resulted in severe fibrotic changes but without any evolution of cysts. Fibrotic lesions did not resolve with both human cell types and were tracked in the murine lungs for > 6 weeks. If mice challenged with ABCs from IPF were treated with nintedanib the histomorphological analysis showed a statistically significant decrease in fibrotic lesions (p=0.019) and lower hydroxyproline levels (p=0.039).
Conclusion: This new humanized mouse model resembles IPF better than the commonly used bleomycin model. Nintedanib treatment attenuated pulmonary fibrosis in the humanized mouse model.