The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?
Open accessAbstract
Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 240 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. 222 of those used a preventive regimen (drug given < or =7 days after last bleomycin application), only 13 were therapeutic trials (>7 days after last bleomycin application). In 5 studies we did not find enough details about the timing of drug application to allow inter-study comparison. It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin-induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Histological features observed in bleomycin-challenged rodents, including fibroblastic foci, fibrous collagen bands and thickening of alveolar walls, closely resemble histopathological hallmarks of human IPF.
“The histological features observed in the bleomycin-challenged rodents, including the formation of fibroblastic foci, fibrous collagen bands and thickening of alveolar walls, closely resemble the histopathological hallmarks of human IPF (Moeller et al., 2008).”
From PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells (2024) · cites this paper as Moeller et al., 2008
Development of fibrotic tissue in the bleomycin rat model is partially reversible, independent of any intervention.
“The development of fibrotic tissue in this model is partially reversible, independent of any intervention (Moeller et al., 2008).”
From PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells (2024) · cites this paper as Moeller et al., 2008
Cites
High-Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis
Demedts, M., Behr, J., Buhl, R., Costabel, U., Dekhuijzen, R., Jansen, H. M., MacNee, W., Thomeer, M., Wallaert, B., Laurent, F., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa042976 · Cited by 964 · see citing works
Piguet, P. F., Vesin, C., Grau, G. E., & Thompson, R. C. (1993) · Cytokine · doi:10.1016/1043-4666(93)90024-y · Cited by 215 · see citing works
IL-12 attenuates bleomycin-induced pulmonary fibrosis
Keane, M. P., Belperio, J. A., Burdick, M. D., & Strieter, R. M. (2001) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2001.281.1.l92 · Cited by 146 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Barry-Hamilton, V., Spangler, R., Marshall, D., McCauley, S., Rodriguez, H. M., Oyasu, M., Mikels, A., Vaysberg, M., Ghermazien, H., Wai, C., et al. (2010) · Nature Medicine · doi:10.1038/nm.2208 · Cited by 870 · see citing works
Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance
Hecker, L., Logsdon, N. J., Kurundkar, D., Kurundkar, A., Bernard, K., Hock, T., Meldrum, E., Sanders, Y. Y., & Thannickal, V. J. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008182 · Cited by 686 · 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
Evolution of nadph oxidase inhibitors: Selectivity and mechanisms for target engagement
Altenhöfer, S., Radermacher, K. A., Kleikers, P. W. M., Wingler, K., & Schmidt, H. H. H. W. (2015) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5814 · Cited by 521 · see citing works
Antifibrotic activities of pirfenidone in animal models
Schaefer, C. J., Ruhrmund, D. W., Pan, L., Seiwert, S. D., & Kossen, K. (2011) · European Respiratory Review · doi:10.1183/09059180.00001111 · Cited by 454 · see citing works
Cai, Y., Zhou, H., Zhu, Y., Sun, Q., Ji, Y., Xue, A., Wang, Y., Chen, W., Yu, X., Wang, L., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0314-9 · Cited by 397 · see citing works
Animal to human translation: a systematic scoping review of reported concordance rates
Leenaars, C. H. C., Kouwenaar, C., Stafleu, F. R., Bleich, A., Ritskes-Hoitinga, M., De Vries, R. B. M., & Meijboom, F. L. B. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1976-2 · Cited by 310 · see citing works
A key role for nox4 in epithelial cell death during development of lung fibrosis
Carnesecchi, S., Deffert, C., Donati, Y., Basset, O., Hinz, B., Preynat-Seauve, O., Guichard, C., Arbiser, J. L., Banfi, B., Pache, J.-C., et al. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3829 · Cited by 290 · see citing works
Raghu, G., Brown, K. K., Collard, H. R., Cottin, V., Gibson, K. F., Kaner, R. J., Lederer, D. J., Martinez, F. J., Noble, P. W., Song, J. W., et al. (2017) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(16)30421-0 · Cited by 278 · see citing works
Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells
Strikoudis, A., Cieślak, A., Loffredo, L., Chen, Y.-W., Patel, N., Saqi, A., Lederer, D. J., & Snoeck, H.-W. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.077 · Cited by 242 · see citing works
Defining the Activated Fibroblast Population in Lung Fibrosis Using Single-Cell Sequencing
Peyser, R., MacDonnell, S., Gao, Y., Cheng, L., Kim, Y., Kaplan, T., Ruan, Q., Wei, Y., Ni, M., Adler, C., et al. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0313oc · Cited by 210 · see citing works
Hsu, H.-S., Liu, C.-C., Lin, J.-H., Hsu, T.-W., Hsu, J.-W., Su, K., & Hung, S.-C. (2017) · Scientific Reports · doi:10.1038/s41598-017-14612-5 · Cited by 205 · see citing works
Use of precision cut lung slices as a translational model for the study of lung biology
Liu, G., Betts, C., Cunoosamy, D. M., Åberg, P. M., Hornberg, J. J., Sivars, K. B., & Cohen, T. S. (2019) · Respiratory Research · doi:10.1186/s12931-019-1131-x · Cited by 206 · see citing works
Hohmann, M. S., Habiel, D. M., Coelho, A. L., Verri, W. A., & Hogaboam, C. M. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0289oc · Cited by 202 · see citing works
Pedroza, M., Le, T. T., Lewis, K., Karmouty‐Quintana, H., To, S., George, A. T., Blackburn, M. R., Tweardy, D. J., & Agarwal, S. K. (2016) · The FASEB Journal · doi:10.1096/fj.15-273953 · Cited by 193 · see citing works
Wilkinson, D. C., Alva-Ornelas, J. A., Sucre, J. M. S., Vijayaraj, P., Durra, A., Richardson, W., Jonas, S. J., Paul, M. K., Karumbayaram, S., Dunn, B., et al. (2017) · Stem Cells Translational Medicine · doi:10.5966/sctm.2016-0192 · Cited by 165 · see citing works
Yang, H.-Z., Wang, J.-P., Mi, S., Liu, H.-Z., Cui, B., Yan, H.-M., Yan, J., Li, Z., Liu, H., Hua, F., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2011.09.019 · Cited by 155 · see citing works
TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis
Sun, T., Huang, Z., Liang, W.-C., Yin, J., Lin, W. Y., Wu, J., Vernes, J.-M., Lutman, J., Caplazi, P., Jeet, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe0407 · Cited by 134 · 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
Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis
Singh, A., Chakraborty, S., Wong, S. W., Hefner, N. A., Stuart, A., Qadir, A. S., Mukhopadhyay, A., Bachmaier, K., Shin, J.-W., Rehman, J., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2121098119 · Cited by 107 · see citing works
Myofibroblast YAP/TAZ activation is a key step in organ fibrogenesis
He, X., Tolosa, M. F., Zhang, T., Goru, S. K., Ulloa Severino, L., Misra, P. S., McEvoy, C. M., Caldwell, L., Szeto, S. G., Gao, F., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.146243 · Cited by 106 · see citing works
Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF
Decaris, M. L., Schaub, J. R., Chen, C., Cha, J., Lee, G. G., Rexhepaj, M., Ho, S. S., Rao, V., Marlow, M. M., Kotak, P., et al. (2021) · Respiratory Research · doi:10.1186/s12931-021-01863-0 · Cited by 94 · see citing works
Screening for YAP inhibitors identifies statins as modulators of fibrosis
Santos, D. M., Pantano, L., Pronzati, G., Grasberger, P., Probst, C. K., Black, K. E., Spinney, J. J., Hariri, L. P., Nichols, R., Lin, Y., et al. (2020) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0296oc · Cited by 72 · see citing works
Reininger, D., Fundel‐Clemens, K., Mayr, C. H., Wollin, L., Laemmle, B., Quast, K., Nickolaus, P., & Herrmann, F. E. (2024) · British Journal of Pharmacology · doi:10.1111/bph.17303 · Cited by 48 · see citing works
“The histological features observed in the bleomycin-challenged rodents, including the formation of fibroblastic foci, fibrous collagen bands and thickening of alveolar walls, closely resemble the histopathological hallmarks of human IPF (Moeller et al., 2008).”
A novel phosphodiesterase 4 inhibitor, AA6216, reduces macrophage activity and fibrosis in the lung
Matsuhira, T., Nishiyama, O., Tabata, Y., Kaji, C., Kubota-Ishida, N., Chiba, Y., Sano, H., Iwanaga, T., & Tohda, Y. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173508 · Cited by 41 · see citing works
Lagares, D., Busnadiego, O., García-Fernández, R. A., Lamas, S., & Rodríguez-Pascual, F. (2012) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2011-0446oc · Cited by 40 · see citing works
Heinemann, F., Birk, G., Schoenberger, T., & Stierstorfer, B. (2018) · PLOS ONE · doi:10.1371/journal.pone.0202708 · Cited by 37 · see citing works
Anti-inflammatory effects of GLP-1 in patients with COVID-19
Sazgarnejad, S., Yazdanpanah, N., & Rezaei, N. (2022) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2021.1964955 · Cited by 21 · see citing works
Suckling, C. J., Mukherjee, S., Khalaf, A. I., Narayan, A., Scott, F. J., Khare, S., Dhakshinamoorthy, S., Harnett, M. M., & Harnett, W. (2018) · Acta Tropica · doi:10.1016/j.actatropica.2018.05.015 · Cited by 12 · see citing works
LTI-03 peptide demonstrates anti-fibrotic activity in ex vivo lung slices from patients with IPF
MacKenzie, B., Mahavadi, P., Pinho Jannini-Sa, Y. A., Creyns, B., Coelho, A. L., Espindola, M., Ruppert, C., Windsor, B., Aigner, C., Hogaboam, C. M., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113437 · Cited by 2 · see citing works
- Authors
- Moeller, A., Ask, K., Warburton, D., Gauldie, J., & Kolb, M.
- Affiliations
- University of Würzburg (DE)
- McMaster University (CA)
- University of Southern California (US)
- Corresponding author
- Kolb, Martin
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2008
- Volume
- 40
- Issue
- 3
- Pages
- 362-382
- ISSN
- 1357-2725 (ISSN-L)
- PMC
- PMC2323681
- OpenAlex
- W2065977597
- Cited by
- 1,007
- References
- 3
- Citations by year
- 2026: 58 · 2025: 77 · 2024: 74 · 2023: 71 · 2022: 69 · 2021: 82 · 2020: 52 · 2019: 61 · 2018: 50 · 2017: 73 · 2016: 55 · 2015: 53 · 2014: 47 · 2013: 49 · 2012: 43
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL060231, R01HL075773, R01HL044060, R01HL044977)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Keywords
- idiopathic pulmonary fibrosis, bleomycin-induced lung fibrosis, antifibrotic agents, drug efficacy, translational validity, timing of drug administration, fibrosis reversibility, alternative animal models
- MeSH terms
- Animals, Bleomycin, Clinical Trials as Topic, Disease Models, Animal, Humans, 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
