Treatment with Both Nintedanib and Steroid in Bleomycin-induced Pulmonary Fibrosis Model Mice didn’t Inhibit Lung Fibrosis

Background：In the clinical setting, the optimal timing of administration of nintedanib in the active or inactive phase of idiopathic pulmonary fibrosis （IPF） has not been clarified. Also, no consideration has been made of synergistic actions with steroids.Objectives：We used bleomycin-induced pulmonary fibrosis model mice to analyze the effects of the timing of nintedanib administration and synergistic actions in combination with steroids.Method：In the bleomycin-induced pulmonary fibrosis mouse model, nintedanib was given before or after bleomycin administration and the effects on pulmonary fibrosis and fibroblast growth factors in bronchoalveolar lavage （BAL） fluid were analyzed. Then, treatment with both steroid and nintedanib was administered in the same model and the effects of combined use on lung fibrosis were analyzed. Severity of lung fibrosis was analyzed using the Ashcroft score. Fibroblast growth factors in BAL fluid were measured using Magnetic Luminex® assay and enzyme-linked immunosorbent assay.Results：Pretreatment with nintedanib before administration of bleomycin, but not after administration of bleomycin, reduced the Ashcroft score （2.4±1.4 vs 4.9±1.3, P＜0.01） and decreased TGF-b 1 in BAL fluid （95.7±48.4 pg/mL vs 147.1±11.7 pg/mL, P＜0.05）. Conversely, pretreatment with both steroid and nintedanib did not decrease the Ashcroft score compared with pretreatment of saline as a control（ Score：3.8±1.3 vs 4.6±1.1）. There was also no synergistic effect of both steroid and nintedanib on pulmonary fibrosis.Conclusions：Nintedanib may be useful when administered early in patients with IPF. Further more, clinical administration of combined nintedanib and steroid requires caution in view of the effects on pulmonary fibrosis and side effects.