Pharmacological validation of a new IPF bleomycin-induced mouse model

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Background: Drug discovery needs better animal models to mimic human features of idiopathic pulmonary fibrosis (IPF). As we previously reported1, double intratracheal (i.t.) instillation of bleomycin (BLM) produces a more severe and diffuse fibrosis compare to the single BLM instillation in mice. Aim of the study: Nintedanib, a drug approved for IPF treatment, and Macitentan, and Prednisolone, that failed in clinical trials, have been used for the pharmacological validation of the lung fibrosis model induced by double BLM treatment Methods: C57BL/6 mice were challenged i.t. at day 0 and day 4 with BLM (1 mg/kg). At day 14, once fibrosis was well established, oral therapeutic dosing with Nintedanib (30 mg/kg), Macitentan (100 mg/kg) and Prednisolone (100 mg/kg BID) was started for 2 weeks. Masson’s trichrome staining was used to stage the severity of fibrosis by Ashcroft score and to quantify % collagen content and % air area. Bronchoalveolar lavage fluid (BALF) was also sampled for cell count. Results: As expected, mice treated twice with BLM had a robust increase in the severity of fibrosis scores and collagen deposition. The Aschroft score, % collagen content and % air area were significantly lower (27%, 40%, and 40%, respectively) in the group treated therapeutically with Nintedanib . This was accompanied by a reduction of BALF inflammatory cell number (36%). Macitentan and Prednisolone did not show any effect on fibrosis nor on inflammation. Conclusions: The double BLM mouse model seems to recapitulate some of the features of human IPF and is able to respond selectively to clinically-approved drugs for IPF treatment 1-ERS London (UK) 2016. Session 559