title: Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany (L.W., A.H.); UMR7355, INEM, CNRS and University of Orleans, Orleans, France (I.M., V.Q., B.R.); and IIDMM, University of Cape Town, Cape Town, Republic of South Africa (B.R.).
authors.forename: Lutz
authors.initials: L
authors.lastname: Wollin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.forename: Valérie
authors.initials: V
authors.lastname: Quesniaux
authors.forename: Alexander
authors.initials: A
authors.lastname: Holweg
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001761:Bleomycin; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006099:Granuloma / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012822:Silicon Dioxide
chemical_list: D000893:Anti-Inflammatory Agents; D007211:Indoles; D001761:Bleomycin; D012822:Silicon Dioxide; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C530716:nintedanib