Animal Models of Pulmonary Fibrosis

Reliable animal disease models greatly facilitate drug development, even when the precise trigger of a disease is unknown. Since this is the case with idiopathic pulmonary fibrosis (IPF), the availability of an animal model is particularly important for successful development of antifibrotic drugs. The standard models of pulmonary fibrosis are bleomycin-treated rodents. Extensive reviews of the bleomycin model and of its use in pulmonary research were recently published (Moeller et al., 2008). A single intratracheal administration of bleomycin produces pulmonary fibrosis in rodents, with a maximal effect at between 20 to 28 days after exposure to the drug. Thereafter fibrosis slowly resolves. The cause and the spontaneous resolution of fibrosis differentiate this model from IPF in humans, although it is similar with respect to the production of cytokines and free radicals. Moeller et al. listed published studies on the prevention or treatment of bleomycin-induced fibrosis in laboratory animals. They point out that to mimic clinical situations the potential antifibrotic drugs should be administered after, and not prior to, the development of bleomycin-induced fibrosis. Antioxidants, angiotensin converting enzyme inhibitors, angiotensin antagonists, immunosuppressants, macrolide antibiotics and many other agents are reported to reduce fibrosis in bleomycin-treated animals. Most of the drugs were never tested for antifibrotic activity in humans whereas others were ineffective in clinical trials. However, the fact that pirfenidone is effective in this model, and has yielded promising clinical results in a Phase III trial, suggests the potential utility of this model in drug discovery.
Other drugs or chemicals known to produce pulmonary fibrosis in humans are also
used in the search for potential antifibrotic drugs. For example, Cantor et al. (1984) produced amiodarone-induced fibrosis in hamsters, while Leeder et al. (1994) demonstrated a reduction of amiodarone-induced pulmonary toxicity by N-acetyl cysteine (NAC). Pulmonary fibrosis can be also produced in rats by paraquat and the angiotensin converting enzyme inhibitors captopril and enalapril reduce paraquat-induced pulmonary fibrosis in rats (Ghazi-Khansari et al., 2007). Parra et al. (2008) induced pulmonary fibrosis in mice by butyl-hydroxytoluene and found it to be histologically identical to fibrosis in humans with IPF. Ask et al. (2008) have induced pulmonary fibrosis in rats by adenoviral gene transfer of transforming growth factor beta (TGFβ) and assessed progression of the disease by non-invasive techniques.
Attempts have also been made to develop in vitro models of pulmonary fibrosis. As an example, cadmium chloride in combination with TGFβ produces fibrosis in rat lung slice cultures (Lin et al., 1998).
The adequate technology for the preclinical evaluation of potential antifibrotic drugs is available, although it is obvious that neither animal models nor in vitro techniques mimic the human condition in all respects.

Ask, K., Labiris, R., Farkas, L., Moeller, A., Froese, A., Farncombe, T., McClelland, G.B., Inman, M., Gauldie, J., and Martin, R.J. (2008). Comparison between conventional and “clinical” assessment of lung fibrosis. J Transl Med 6:16.

Cantor, J.O., Osman, M., Cerreta, J.M., Suarez, R., Mandi, I., and Turino, G.M. (1984). Amiodarone-induced pulmonary fibrosis in hamsters. Exp. Lung. Res. 6:1-10.

Ghazi-Khansari, M., Mohammadi-Karakani, A., Sotoudeh, M., Mokhtary, P., Pour-Esmaeil, E., Maghsoud, S. (2007). Antifibrotic effect of captopril and enalapril on paraquat-induced fibrosis in rats. J. Appl. Toxicol. 27:342-349.

Leeder, R.G., Brien, J.F., and Massey T.E. (1994). Investigation of the role of oxidative stress in amiodarone-induced pulmonary toxicity in the hamster. Can. J. Physiol. Pharmacol. 72:613-621.

Lin, C.J., Yang, P.C., Hsu, M.T., Yew, F.H., Liu, T.Y., Shun, C., Tyan, S.W., and Lee, T.C. (1998). Induction of pulmonary fibrosis in organ-cultured rat lung by cadmium chloride and transforming factor –beta1. Toxicology 127: 157-166.

Moeller, A., Ask, K., Warburton, D., Gauldie, J., and Kolb, M. (2008). The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol. 40:362-382.

Parra, E.R., Boufelli, G., Berthanha, F., Samorano, Lde.P., Aguiar, A.C. Jr., Costa, F.M., Capelozzi, V.L., Barbas-Filho, J.V. (2008). Temporal evolution of epithelial, vascular and interstitial lung injury in an experimental model of idiopathic pulmonary fibrosis induced by butyl-hydroxytoluene. Int. J. Exp. Pathol. 89:350-357.

Alex Scriabine, MD
Guilford, CT