Anti-fibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in experi


The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis (IPF). To explore its mode of action, nintedanib was tested in human lung fibroblasts and mouse models of lung fibrosis. Human lung fibroblasts expressing PDGF-receptor-α and -β were stimulated with PDGF-BB. Receptor activation was assessed by autophosphorylation and cell proliferation by bromodeoxyuridine incorporation. TGFβ-induced fibroblast to myofibroblast transformation was determined by αSMA mRNA analysis. Lung fibrosis was induced in mice by intratracheal bleomycin or silica particle administration. Nintedanib was administered qd by gavage at 30, 60 or 100 mg/kg. Preventive nintedanib treatment started on the day that bleomycin or silica was administered, therapeutic treatment at various times after the induction of lung fibrosis. Bleomycin caused increased macrophages and lymphocytes in the bronchoalveolar lavage (BAL) and elevated IL-1β, TIMP-1 and collagen in lung tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced lung pathology additionally showed elevated BAL neutrophils, 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, IL-1β, KC, TIMP-1, and lung collagen were significantly reduced. Histological 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 anti-fibrotic 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 like IPF.

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ven 14 marzo 2014
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