The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development 
for the treatment of idiopathic pulmonary fibrosis. To explore its mode of 
action, nintedanib was tested in human lung fibroblasts and mouse models of lung 
fibrosis. Human lung fibroblasts expressing platelet-derived growth factor 
(PDGF) receptor-α and -β were stimulated with platelet-derived growth factor BB 
(homodimer) (PDGF-BB). Receptor activation was assessed by autophosphorylation 
and cell proliferation by bromodeoxyuridine incorporation. Transforming growth 
factor β (TGFβ)-induced fibroblast to myofibroblast transformation was 
determined by α-smooth muscle actin (αSMA) mRNA analysis. Lung fibrosis was 
induced in mice by intratracheal bleomycin or silica particle administration. 
Nintedanib was administered every day by gavage at 30, 60, or 100 mg/kg. 
Preventive nintedanib treatment regimen started on the day that bleomycin was 
administered. Therapeutic treatment regimen started at various times after the 
induction of lung fibrosis. Bleomycin caused increased macrophages and 
lymphocytes in the bronchoalveolar lavage (BAL) and elevated interleukin-1β 
(IL-1β), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in lung 
tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced 
lung pathology additionally showed elevated BAL neutrophils, keratinocyte 
chemoattractant (KC) levels, and granuloma formation. Nintedanib inhibited PDGF 
receptor activation, fibroblast proliferation, and fibroblast to myofibroblast 
transformation. Nintedanib significantly reduced BAL lymphocytes and neutrophils 
but not macrophages. Furthermore, interleukin-1β, KC, TIMP-1, and lung collagen 
were significantly reduced. Histologic analysis showed significantly diminished 
lung inflammation, granuloma formation, and fibrosis. The therapeutic effect was 
dependent on treatment start and duration. Nintedanib inhibited receptor 
tyrosine kinase activation and the proliferation and transformation of human 
lung fibroblasts and showed antifibrotic and anti-inflammatory activity in two 
animal models of pulmonary fibrosis. These results suggest that nintedanib may 
impact the progressive course of fibrotic lung diseases such as idiopathic 
pulmonary fibrosis.