Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Dose-response Effects of Bleomycin on Inflammation and Pulmonary Fibrosis in Mice

  • Kim, Soo-Nam (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Lee, Jin-Soo (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Yang, Hyo-Seon (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Cho, Jae-Woo (Division of Toxicologic Pathology, Korea Institute of Toxicology) ;
  • Kwon, Soon-Jin (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Kim, Young-Beom (Division of Toxicologic Pathology, Korea Institute of Toxicology) ;
  • Her, Jeong-Doo (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Cho, Kyu-Hyuk (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Song, Chang-Woo (Inhalation Toxicology Center, KIT Jeongeup Campus) ;
  • Lee, Kyu-Hong (Inhalation Toxicology Center, KIT Jeongeup Campus)
  • Received : 2010.07.11
  • Accepted : 2010.08.11
  • Published : 2010.09.01
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Abstract

Many studies have reported that bleomycin, anti-cancer drug, induces pulmonary fibrosis as a side effect. However, few investigations have focused on the dose-response effects of bleomycin on pulmonary fibrosis. Therefore, in the present study, we investigated the effects of different doses of bleomycin in male mice. ICR mice were given 3 consecutive doses of bleomycin: 1, 2, or 4 mg/kg in bleomycin-treated (BT) groups and saline only in vehicle control (VC) groups. The animals were sacrificed at 7 and 24 days postinstillation. The severity of pulmonary fibrosis was evaluated according to inflammatory cell count and lactate dehydrogenase (LDH) activity in the broncho alveolar lavage fluid (BALF), and lung tissues were histologically evaluated after hematoxylin and eosin (H&E), and Masson's trichrome staining. BT groups exhibited changed cellular profiles in BAL fluid compared to the VC group, which had an increased number of total cells, neutrophils, and lymphocytes and a modest increase in the number of macrophages at 7 days post-bleomycin instillation. Moreover, BT groups showed a dose-dependent increase in LDH levels and inflammatory cell counts. However, at 24 days after treatment, collagen deposition, interstitial thickening, and granulomatous lesions were observed in the alveolar spaces in addition to a decrease in inflammatory cells. These results indicate that pulmonary fibrosis induced by 4 mg/kg bleomycin was more severe than that induced by 1 or 2 mg/kg. These data will be utilized in experimental animal models and as basic data to evaluate therapeutic candidates through non-invasive monitoring using the pulmonary fibrosis mouse model established in this study.

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References

  1. Antje, M., Juan Carlos, R.L., Lingqiao, W., Jack, G. and Martin, K. (2006). Models of pulmonary fibrosis. J. Ddmod., 3, 243-249.
  2. Bethany, B.M. and Cory, M.H. (2008). Murine models of pulmonaryfibrosis. Am J Physiol. Lung Cell Mol Physiol., 294, 152-160. https://doi.org/10.1152/ajplung.00313.2007
  3. Bonniaud, P., Kolb, M., Galt, T., Robertson, J., Robbins, C.,Stampfli, M., Lavery, C., Margetts, P.J., Roberts, A.B. and Gauldie, J. (2004). Smad3 null mice develop airspace enlargement and are resistant to TGF-beta-mediated pulmonary fibrosis. J. Immunol., 173, 2099-2108. https://doi.org/10.4049/jimmunol.173.3.2099
  4. Briggs, A.D., Chandler, D.B., Jackson, R.M. and Fulmer, J.D.(1985). The effect of endotoxin on bleomycin-induced lung fibrosis in the rat. Toxicol Lett., 27, 91-96. https://doi.org/10.1016/0378-4274(85)90124-9
  5. Brown, R.F., Drawbaugh, R.B. and Marrs, T.C. (1988). An investigation of possible models for the production of progressive pulmonary fibrosis in the rat. The effects of repeated intratracheal instillation of bleomycin. Toxicol., 51, 101-110. https://doi.org/10.1016/0300-483X(88)90084-4
  6. Hemmati, A.A., Nazari, Z., Motlagh, M.E. and Goldasteh, S. (2002). The role of sodium cromolyn in treatment of paraquatinduced pulmonary fibrosis in rat. Pharmacol. Res., 46, 229-234. https://doi.org/10.1016/S1043-6618(02)00122-6
  7. Higashiyama, H., Yoshimoto, D., Kaise, T., Matsubara, S., Fujiwara, M., Kikkawa, H., Asano, S. and Kinoshita, M. (2007).Inhibition of activin receptor-like kinase 5 attenuates Bleomy-cin-induced pulmonary fibrosis. Exp Mol Pathol., 83, 39-46. https://doi.org/10.1016/j.yexmp.2006.12.003
  8. Jack, G., Martin, K., Kjetil, A., Gail, M., Philippe, B. and David, W. (2006). Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac. Soc., 3, 696-702. https://doi.org/10.1513/pats.200605-125SF
  9. John, S.L., et al. (1990). BLEOMYCIN: A pharmacologic tool inthe study of the pathogenesis of interstitial pulmonary fibrosis. Pharmac. Ther., 47, 347-358.
  10. Manoury, B., Nenan, S., Guenon, I., Lagente, V. and Boichot, E.(2007) Influence of early neutrophil depletion on MMPs/TIMP-1 balance in bleomycin-induced lung fibrosis. Int Immunopharmacol., 7, 900-911. https://doi.org/10.1016/j.intimp.2007.02.009
  11. 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. https://doi.org/10.1016/j.biocel.2007.08.011
  12. Oku, H., Shimizu, T., Kawabata, T., Nagira, M., Hikita, I.,Ueyama, A., Matsushima, S., Torii, M. and Arimura, A. (2008).Antifibrotic action of pirfenidone and prednisolone: Differenteffects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J. Pharmacol.,590, 400-408. https://doi.org/10.1016/j.ejphar.2008.06.046
  13. Ou, X.-M., Li, W.-C., Liu, D.-S., Li, Y.-P., Wen, F.-Q., Feng, Y.-L.,Zhang, S.-F., Huang, X.-Y., Wang, T., Wang, K., Wang, X. and Chen, L. (2009). VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice. Int. Immunopharmacol.,9, 70-79. https://doi.org/10.1016/j.intimp.2008.10.002
  14. Ouchi, H., Fujita, M., Ikegame, S., Ye, Q., Inoshima, I., Harada, E., Kuwano, K. and Nakanishi, Y. (2008). The role of collagenases in experimental pulmonary fibrosis. Pulm Pharmacol. Ther., 21, 401-408. https://doi.org/10.1016/j.pupt.2007.10.006
  15. Saito, F., Tasaka, S., Inoue, K., Miyamoto, K., Nakano, Y., Ogawa,Y., Yamada, W., Shiraishi, Y., Hasegawa, N., Fujishima, S., Takano, H. and Ishizaka, A. (2008). Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. Am. J.Respir. Cell. Mol. Biol., 38, 566-571. https://doi.org/10.1165/rcmb.2007-0299OC
  16. Steven, E.M., Robin, J.M., Geoffrey, J.L. and Darryl, A.K. (2004). Evaluation of experimental models of idiopathic pulmonary fibrosis. J. Ddmod., 1, 329-336.
  17. Thomas, A.W. (2007). Common and unique mechanisms regulatefibrosis in various fibroproliferative diseases. J. Clin. Invest.,117, 524-529. https://doi.org/10.1172/JCI31487
  18. Thomas, W.H., Joan, E.G., Karen, M.R., Andrew, C.J., Carroll,E.C. and Jerold, A.L. (1981). Bleomycin-induced pulmonaryfibrosis: correlation of biochemical, physiological, and histological changes. Toxicol. Appl. Pharmacol., 60, 360-367. https://doi.org/10.1016/0041-008X(91)90239-B
  19. Tom, W.-M. and Montgomery, M.R. (1980). Biochemical and morphological assessments of bleomycin pulmonary toxicity inrats. Toxicol. Appl. Pharmacol., 53, 64-74. https://doi.org/10.1016/0041-008X(80)90382-8
  20. Zhou, X.-M., Zhang, G.-C., Li, J.-X. and Hou, J. (2007). Inhibitory effects of Hu-qi-yin on the bleomycin-induced pulmonary fibrosis in rats. J. Ethnopharmacol., 111, 255-264. https://doi.org/10.1016/j.jep.2006.11.029

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