Novel mechanisms for the antifibrotic action of nintedanib
Open accessAbstract
Idiopathic pulmonary fibrosis (IPF) is a disease with relentless course and limited therapeutic options. Nintedanib (BIBF-1120) is a multiple tyrosine kinase inhibitor recently approved by the U.S. Food and Drug Administration for the treatment of IPF. The precise antifibrotic mechanism(s) of action of nintedanib, however, is not known. Therefore, we studied the effects of nintedanib on fibroblasts isolated from the lungs of patients with IPF. Protein and gene expression of profibrotic markers were assessed by Western immunoblotting and real-time PCR. Autophagy markers and signaling events were monitored by biochemical assays, Western immunoblotting, microscopy, and immunofluorescence staining. Silencing of autophagy effector proteins was achieved with small interfering RNAs. Nintedanib down-regulated protein and mRNA expression of extracellular matrix (ECM) proteins, fibronectin, and collagen 1a1 while inhibiting transforming growth factor (TGF)-β1–induced myofibroblast differentiation. Nintedanib also induced beclin-1–dependent, ATG7-independent autophagy. Nintedanib’s ECM-suppressive actions were not mediated by canonical autophagy. Nintedanib inhibited early events in TGF-β signaling, specifically tyrosine phosphorylation of the type II TGF-β receptor, activation of SMAD3, and p38 mitogen-activated protein kinase. Nintedanib down-regulates ECM production and induces noncanonical autophagy in IPF fibroblasts while inhibiting TGF-β signaling. These mechanisms appear to be uncoupled and function independently to mediate its putative antifibrotic effects.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nintedanib is an intracellular triple tyrosine kinase inhibitor of PDGFR α and β, FGFR 1, 2, and 3, and VEGFR 1, 2, and 3, and exerts a variety of antifibrotic effects.
“The second approved anti-fibrotic agent, nintedanib is an intracellular triple tyrosine kinase inhibitor of platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1, 2, and 3, and vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, and also exerts a variety of antifibrotic effects (Rangarajan et al., 2016).”
From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Rangarajan et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis
Richeldi, L., du Bois, R. M., Raghu, G., Azuma, A., Brown, K. K., Costabel, U., Cottin, V., Flaherty, K. R., Hansell, D. M., Inoue, Y., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1402584 · Cited by 4,654 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · cited 1× · see citing works
“To determine if this is related to a block in autophagy or an increase in autophagic flux, we tested the effect of adding chloroquine, an autophagy inhibitor that interferes with lysosomal degradation (15, 16).”
Self-citationTransforming Growth Factor β in Tissue Fibrosis
Epstein, F. H., Border, W. A., & Noble, N. A. (1994) · New England Journal of Medicine · doi:10.1056/nejm199411103311907 · Cited by 3,044 · see citing works
How to Interpret LC3 Immunoblotting
Mizushima, N., & Yoshimori, T. (2007) · Autophagy · doi:10.4161/auto.4600 · Cited by 2,595 · cited 1× · see citing works
“To determine if this is related to a block in autophagy or an increase in autophagic flux, we tested the effect of adding chloroquine, an autophagy inhibitor that interferes with lysosomal degradation (15, 16).”
Autophagy in Human Health and Disease
Choi, A. M. K., Ryter, S. W., & Levine, B. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1205406 · Cited by 2,583 · see citing works
Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011) · Cell · doi:10.1016/j.cell.2011.07.030 · Cited by 2,107 · see citing works
Massagué, J. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043051 · Cited by 1,882 · see citing works
Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Richeldi, L., Costabel, U., Selman, M., Kim, D. S., Hansell, D. M., Nicholson, A. G., Brown, K. K., Flaherty, K. R., Noble, P. W., Raghu, G., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103690 · Cited by 1,157 · see citing works
BIBF 1120: Triple Angiokinase Inhibitor with Sustained Receptor Blockade and Good Antitumor Efficacy
Hilberg, F., Roth, G. J., Krssak, M., Kautschitsch, S., Sommergruber, W., Tontsch-Grunt, U., Garin-Chesa, P., Bader, G., Zoephel, A., Quant, J., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6307 · Cited by 1,056 · see citing works
Mechanisms of Pulmonary Fibrosis
Thannickal, V. J., Toews, G. B., White, E. S., Lynch, J. P., & Martínez, F. J. (2004) · Annual Review of Medicine · doi:10.1146/annurev.med.55.091902.103810 · Cited by 806 · see citing works
Self-citationBroekelmann, T. J., Limper, A. H., Colby, T. V., & McDonald, J. A. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.15.6642 · Cited by 794 · see citing works
Wollin, L., Maillet, I., Quesniaux, V., Holweg, A., & Ryffel, B. (2014) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.208223 · Cited by 633 · see citing works
Canonical and non-canonical autophagy: variations on a common theme of self-eating?
Codogno, P., Mehrpour, M., & Proikas‐Cezanne, T. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3249 · Cited by 545 · see citing works
Khalil, N., O'Connor, R. N., Unruh, H. W., Warren, P. W., Flanders, K. C., Kemp, A., Bereznay, O. H., & Greenberg, A. H. (1991) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/ajrcmb/5.2.155 · Cited by 519 · see citing works
Zhou, Y., Huang, X., Hecker, L., Kurundkar, D., Kurundkar, A., Liu, H., Jin, T. H., Desai, L. P., Bernard, K. F., & Thannickal, V. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66700 · Cited by 452 · see citing works
Self-citationInhibition of PDGF, VEGF and FGF signalling attenuates fibrosis
Chaudhary, N. I., Roth, G. J., Hilberg, F., Müller–Quernheim, J., Prasse, A., Zissel, G., Schnapp, A., & Park, J. E. (2007) · European Respiratory Journal · doi:10.1183/09031936.00152106 · Cited by 386 · see citing works
Imatinib Treatment for Idiopathic Pulmonary Fibrosis: Randomized Placebo-controlled Trial Results
Daniels, C. E., Lasky, J. A., Limper, A. H., Mieras, K., Gabor, E., & Schroeder, D. R. (2010) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200906-0964oc · Cited by 373 · see citing works
Autophagy in Idiopathic Pulmonary Fibrosis
Patel, A. S., Lin, L., Geyer, A. I., Haspel, J. A., An, C. H., Cao, J., Rosas, I. O., & Morse, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041394 · Cited by 371 · see citing works
Hayashida, T., deCaestecker, M. P., & Schnaper, H. W. (2003) · The FASEB Journal · doi:10.1096/fj.03-0037fje · Cited by 364 · see citing works
Insufficient autophagy in idiopathic pulmonary fibrosis
Araya, J., Kojima, J., Takasaka, N., Ito, S., Fujii, S., Hara, H., Yanagisawa, H., Kobayashi, K., Tsurushige, C., Kawaishi, M., et al. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00213.2012 · Cited by 326 · see citing works
Han, W., Pan, H., Chen, Y., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018691 · Cited by 256 · see citing works
Galliher, A. J., & Schiemann, W. P. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3851 · Cited by 249 · see citing works
Ahluwalia, N., Shea, B. S., & Tager, A. M. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201403-0509pp · Cited by 233 · see citing works
Imatinib as a Novel Antifibrotic Agent in Bleomycin-induced Pulmonary Fibrosis in Mice
Aono, Y., Nishioka, Y., Inayama, M., Ugai, M., Kishi, J., Uehara, H., Izumi, K., & Sone, S. (2005) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200404-531oc · Cited by 228 · see citing works
Reversible differentiation of myofibroblasts by MyoD
Hecker, L., JAGIRDAR, R. M., Jin, T., & Thannickal, V. J. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.03.016 · Cited by 153 · see citing works
Self-citationTherapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis
Hu, M., Che, P., Han, X., Cai, G., Liu, G., Antony, V. B., Luckhardt, T., Siegal, G. P., Zhou, Y., Liu, R.-M., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.216044 · Cited by 106 · see citing works
Self-citationDecreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts
Rícci, A., Cherubini, E., Scozzi, D., Pietrangeli, V., Tabbì, L., Raffa, S., Leone, L., Visco, V., Torrisi, M. R., Bruno, P., et al. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24307 · Cited by 79 · see citing works
Chen, X., Wang, H., Liao, H., Hu, W., Gewin, L. S., Mernaugh, G., Zhang, S., Zhang, Z., Vega‐Montoto, L., Vanacore, R., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71668 · Cited by 76 · see citing works
Calabretta, B., & Salomoni, P. (2011) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2010.546913 · Cited by 71 · see citing works
Vittal, R., Zhang, H., Han, M. K., Moore, B. B., Horowitz, J. C., & Thannickal, V. J. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.113407 · Cited by 59 · see citing works
Self-citationAlternative Macroautophagic Pathways
Juenemann, K., & Reits, E. A. (2012) · International Journal of Cell Biology · doi:10.1155/2012/189794 · Cited by 58 · see citing works
Negative Regulation of NADPH Oxidase 4 by Hydrogen Peroxide-inducible Clone 5 (Hic-5) Protein
Desai, L. P., Zhou, Y., Venado, A. E., Ding, Q., Cheng, G., Collawn, J. F., & Thannickal, V. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.562249 · Cited by 53 · see citing works
Self-citationYu, J. J., Parkhitko, A. A., & Henske, E. P. (2011) · Autophagy · doi:10.4161/auto.7.11.17652 · Cited by 38 · see citing works
Michaelson, J. E., Ritzenthaler, J. D., & Roman, J. (2002) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00445.2000 · Cited by 38 · see citing works
Sui, X., Kong, N., Zhu, M., et al. (2013) · Molecular and Clinical Oncology · doi:10.3892/mco.2013.187 · Cited by 31 · see citing works
Autophagic action of new targeting agents in head and neck oncology
Rikiishi, H. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.21079 · Cited by 24 · see citing works
Regulation of fibrotic signalling by TGF-β receptor tyrosine phosphorylation
Allison, S. J. (2014) · Nature Reviews Nephrology · doi:10.1038/nrneph.2014.127 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [7]Rangarajan S, Dodson M, Zhang J, Thannickal V. Enhanced autophagy as a potential mechanism for the anti-fibrotic effects of BIBF-1120 in IPF [abstract] Am J Respir Crit Care Med. 2013;187:A5162. [Google Scholar]
- [8]Rangarajan S, Kurundkar A, Zhang J, Thannickal V. Non-canonical autophagy and the anti-fibrotic effects of BIBF-1120 in IPF [abstract] Am J Respir Crit Care Med. 2014;189:A5395. [Google Scholar]
Cited by
Sorted by citations
The myofibroblast, a key cell in normal and pathological tissue repair
Darby, I. A., Zakuan, N., Billet, F., & Desmoulière, A. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2110-0 · Cited by 328 · see citing works
Lehtonen, S. T., Veijola, A., Karvonen, H., Lappi-Blanco, E., Sormunen, R., Korpela, S., Zagai, U., Sköld, M. C., & Kaarteenaho, R. (2016) · Respiratory Research · doi:10.1186/s12931-016-0328-5 · Cited by 133 · see citing works
Lambers, C., Roth, M., Jaksch, P., Muraközy, G., Tamm, M., Klepetko, W., Ghanim, B., & Zhao, F. (2018) · Scientific Reports · doi:10.1038/s41598-018-19294-1 · Cited by 61 · see citing works
Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies
Selvarajah, B., Platé, M., & Chambers, R. C. (2023) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2023.101227 · Cited by 57 · see citing works
De Biasi, S., Cerri, S., Bianchini, E., Gibellini, L., Persiani, E., Montanari, G., Luppi, F., Carbonelli, C. M., Zucchi, L., Bocchino, M., et al. (2015) · BMC Medicine · doi:10.1186/s12916-015-0515-0 · Cited by 28 · see citing works
- Authors
- Rangarajan, S., Kurundkar, A., Kurundkar, D., Bernard, K., Sanders, Y. Y., Ding, Q., Antony, V. B., Zhang, J., Zmijewski, J., & Thannickal, V. J.
- Affiliations
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and
- University of Alabama at Birmingham (US)
- Corresponding author
- Thannickal, Victor J.
- ORCID
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-01-01
- Volume
- 54
- Issue
- 1
- Pages
- 51-59
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- PMC
- PMC4742925
- OpenAlex
- W1894287559
- Cited by
- 238
- References
- 37
- Citations by year
- 2026: 20 · 2025: 27 · 2024: 32 · 2023: 21 · 2022: 27 · 2021: 20 · 2020: 21 · 2019: 18 · 2018: 13 · 2017: 18 · 2016: 17 · 2015: 4
- FWCI
- 13.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG046210)
- National Heart, Lung, and Blood Institute (R01HL085324, R01HL127338, P01HL114470, T32HL105346)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- nintedanib, idiopathic pulmonary fibrosis, antifibrotic mechanism, autophagy, TGF-beta signaling, extracellular matrix, fibronectin, type I collagen, myofibroblast differentiation, Beclin-1, ATG7, Smad3, p38 MAPK, TGFBR2, lung fibroblasts, tyrosine kinase inhibitors
- MeSH terms
- Beclin-1, Autophagy-Related Protein 7, Receptor, Transforming Growth Factor-beta Type II, Collagen Type I, alpha 1 Chain, Cells, Cultured, Dose-Response Relationship, Drug, Fibronectins, Humans, Indoles, Lung, Membrane Proteins, Phosphorylation, RNA, Messenger, Time Factors, Transfection, Signal Transduction, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Collagen Type I, RNA Interference, Ubiquitin-Activating Enzymes, p38 Mitogen-Activated Protein Kinases, Apoptosis Regulatory Proteins, Smad3 Protein, Transforming Growth Factor beta1, Idiopathic Pulmonary Fibrosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
