Effects of nintedanib on the microvascular architecture in a lung fibrosis model

• Published in: Angiogenesis (London) Vol. 20; no. 3; pp. 359 - 372
• Main Authors: Ackermann, Maximilian, Kim, Yong Ook, Wagner, Willi L., Schuppan, Detlef, Valenzuela, Cristian D., Mentzer, Steven J., Kreuz, Sebastian, Stiller, Detlef, Wollin, Lutz, Konerding, Moritz A.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.08.2017; Springer Nature B.V
• Subjects: Alveoli; Angiogenesis; Animals; Architecture; Attenuation; Biomedical and Life Sciences; Biomedicine; Bleomycin; Bronchus; Cancer Research; Cardiology; Casts; Cell Biology; Cell Proliferation - drug effects; Collagen - metabolism; Computation; Computed tomography; Corrosion; Corrosion inhibitors; Disease Models, Animal; Distortion; Electron microscopy; Enzyme inhibitors; Fibrosis; Idiopathic Pulmonary Fibrosis - diagnostic imaging; Idiopathic Pulmonary Fibrosis - drug therapy; Idiopathic Pulmonary Fibrosis - pathology; Idiopathic Pulmonary Fibrosis - physiopathology; Imaging, Three-Dimensional; Indoles - therapeutic use; Inflammation; Inhibitors; Interferon; Lung diseases; Lungs; Mice; Mice, Inbred C57BL; Microvasculature; Microvessels - diagnostic imaging; Microvessels - drug effects; Microvessels - ultrastructure; Mode of action; Neovascularization, Physiologic - drug effects; Oncology; Ophthalmology; Original Paper; Pneumonia - complications; Pneumonia - diagnostic imaging; Pneumonia - pathology; Pneumonia - physiopathology; Protein-tyrosine kinase; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - pathology; Pulmonary Alveoli - ultrastructure; Pulmonary fibrosis; Radiation; Respiratory function; Respiratory Function Tests; Rodents; Scanning electron microscopy; Synchrotron radiation; Tomography; Trachea; Tyrosine; X-Ray Microtomography; Angiogenesis inhibitors; Microvascular corrosion casting; Idiopathic pulmonary fibrosis; Intussusceptive angiogenesis; Synchrotron radiation tomographic microscopy
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-017-9543-z

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.