Effects of nintedanib on the microvascular architecture in a lung fibrosis model
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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.
KeywordsIdiopathic pulmonary fibrosis Angiogenesis inhibitors Intussusceptive angiogenesis Microvascular corrosion casting Synchrotron radiation tomographic microscopy
This work is dedicated to the memory of the late Prof. Moritz A. Konerding. The authors acknowledge the skillful technical assistance of Kerstin Bahr (University Medical Center Mainz), Janine Beier, Helene Lichius, and Andrea Vögtle (all Boehringer Ingelheim, Biberach). Editorial assistance, funded by Boehringer Ingelheim, was provided by Clare Ryles of Fleishman-Hillard Fishburn. M.A., L.W., M.A.K., D.Sc., and S.J.M were involved in the conception and design. M.A., Y.O.K., W.L.W., C.D.V., S.K., D.St., and L.W. were involved in the experimental work, analysis, and interpretation. M.A., Y.O.K., W.L.W, C.D.V., D.Sc., S.J.M., S.K., D.St., and L.W. drafted the manuscript and revised it for intellectual content. M.A. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
This study was funded in part by Boehringer Ingelheim, Biberach, Germany
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