Small Animal Models Of Pulmonary Fibrosis

small animal pulmonary fibrosis modelsPulmonary fibrosis (interstitial lung fibrosis) has a varied etiology; including inflammatory diseases and injury, aging, environmental exposures (e.g. asbestos, silica, radiation, etc.); drug administration (e.g. bleomycin, amidarone, isothiocyanate, etc.), and idiopathic origins.

For researchers, pre-clinical pulmonary fibrosis model selection requires an assessment of the most appropriate model for the recapitulation of the fibrosis form under study, balanced with considerations around the advantages and disadvantages of each particular model.

Read more about the most common small animal fibrosis models, along with a brief description of their modes of induction, advantages, and disadvantages.

The Bleomycin Model of Fibrosis

Bleomycin-induced fibrosis is by far the best characterised and most widely used pre-clinical pulmonary fibrosis model. Indeed, bleomycin has been recommended in the ATS (American Thoracic Society) workshop report for initial pre-clinical therapy assessments5. Bleomycin is an antineoplastic glycopeptide, originating from Streptomyces verticillus, and toxicity occurs in tissues with relative under expression of the bleomycin hydrolase, such as the lung6.

Several guides to bleomycin model development are available, providing in depth discussion on experimental design, considerations and expected pathological outcomes.

Endotracheal bleomycin delivery (often performed, with the now unavailable, Penn Century Microsprayer), intravenous or intraperitoneal administration are possible, whether that be via single or repeated administrations. Systemic delivery causes more diffuse fibrosis with a longer time course, and endotracheal delivery is the more common approach. More recently, ventilator-assisted drug delivery is emerging as a potential methodology for bleomycin delivery, possibly limiting some of the heterogeneity of endotracheal instillation7

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References

  1.         Moore BB, Lawson WE, Oury TD, Sisson TH, Raghavendran K, Hogaboam CM. Animal models of fibrotic lung disease. American Journal of Respiratory Cell and Molecular Biology. 2013;49(2):167-179. doi:10.1165/rcmb.2013-0094TR
  2.         Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. American Journal of Physiology – Lung Cellular and Molecular Physiology. 2008;294(2):152-160. doi:10.1152/ajplung.00313.2007
  3.         Tashiro J, Rubio GA, Limper AH, et al. Exploring animal models that resemble idiopathic pulmonary fibrosis. Frontiers in Medicine. 2017;4(JUL):1-11. doi:10.3389/fmed.2017.00118
  4.         Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: Searching for model answers. American Journal of Respiratory Cell and Molecular Biology. 2005;33(1):9-13. doi:10.1165/rcmb.2005-0062TR
  5.         Jenkins RG, Moore BB, Chambers RC, et al. An official American thoracic society workshop report: Use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. American Journal of Respiratory Cell and Molecular Biology. 2017;56(5):667-679. doi:10.1165/rcmb.2017-0096ST
  6.         Liu T, de Los Santos FG, Phan SH. The bleomycin model of pulmonary fibrosis. In: Methods in Molecular Biology. Vol 1627. Humana Press Inc.; 2017:27-42. doi:10.1007/978-1-4939-7113-8_2
  7.         Yang L, Feuchtinger A, Möller W, et al. Three-Dimensional Quantitative Co-Mapping of Pulmonary Morphology and Nanoparticle Distribution with Cellular Resolution in Nondissected Murine Lungs. ACS Nano. January 2019:acsnano.8b07524. doi:10.1021/acsnano.8b07524