title: Effects of nintedanib on the microvascular architecture in a lung fibrosis model.
abstract: Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis, has anti-fibrotic, anti-inflammatory, and anti-angiogenic activity. We explored the impact of nintedanib on microvascular architecture in a pulmonary fibrosis model. Lung fibrosis was induced in C57Bl/6 mice by intratracheal bleomycin (0.5 mg/kg). Nintedanib was started after the onset of lung pathology (50 mg/kg twice daily, orally). Micro-computed tomography was performed via volumetric assessment. Static lung compliance and forced vital capacity were determined by invasive measurements. Mice were subjected to bronchoalveolar lavage and histologic analyses, or perfused with a casting resin. Microvascular corrosion casts were imaged by scanning electron microscopy and synchrotron radiation tomographic microscopy, and quantified morphometrically. Bleomycin administration resulted in a significant increase in higher-density areas in the lungs detected by micro-computed tomography, which was significantly attenuated by nintedanib. Nintedanib significantly reduced lung fibrosis and vascular proliferation, normalized the distorted microvascular architecture, and was associated with a trend toward improvement in lung function and inflammation. Nintedanib resulted in a prominent improvement in pulmonary microvascular architecture, which outperformed the effect of nintedanib on lung function and inflammation. These findings uncover a potential new mode of action of nintedanib that may contribute to its efficacy in idiopathic pulmonary fibrosis.
authors.affiliation: Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany. maximilian.ackermann@uni-mainz.de.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Ackermann
authors.affiliation: Institute of Translational Immunology and Research Center for Immune Therapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Yong Ook
authors.initials: YO
authors.lastname: Kim
authors.affiliation: Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany.
authors.forename: Willi L
authors.initials: WL
authors.lastname: Wagner
authors.affiliation: Institute of Translational Immunology and Research Center for Immune Therapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.|Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.affiliation: Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Cristian D
authors.initials: CD
authors.lastname: Valenzuela
authors.affiliation: Laboratory of Adaptive and Regenerative Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Mentzer
authors.affiliation: Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreuz
authors.affiliation: Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Stiller
authors.affiliation: Immunology and Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Wollin
authors.affiliation: Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg University Mainz, Johann-Joachim-Becher-Weg 13, 55128, Mainz, Germany.
authors.forename: Moritz A
authors.initials: MA
authors.lastname: Konerding
mesh_terms: D000818:Animals; D001761:Bleomycin; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D054990:Idiopathic Pulmonary Fibrosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D021621:Imaging, Three-Dimensional; D007211:Indoles / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000000981:diagnostic imaging / Q000187:drug effects / Q000648:ultrastructure*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011014:Pneumonia / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D012129:Respiratory Function Tests; D055114:X-Ray Microtomography
chemical_list: D007211:Indoles; D001761:Bleomycin; D003094:Collagen; C530716:nintedanib
keywords: Angiogenesis inhibitors; Idiopathic pulmonary fibrosis; Intussusceptive angiogenesis; Microvascular corrosion casting; Synchrotron radiation tomographic microscopy