Abstract
Elastase (PPE) is usually used for emphysema models, whereas bleomycin (BLM) is used for fibrosis models. The aim of this study was to investigate the effect of BLM in PPE-induced emphysema, as well as the effect of PPE in BLM-induced fibrosis. C57BL/6 mice were divided into five groups: control, PPE, BLM, PPE + BLM, and BLM + PPE. Mice received saline, PPE (3 U/mouse), or BLM (20 U/kg) by intranasal instillation. Mice from the BLM and BLM + PPE groups received BLM on day 0 and saline or PPE on day 21, respectively. Those in the PPE and PPE + BLM groups received PPE on day 0 and saline or BLM on day 21, respectively. Mice were euthanized on day 42. We performed histology, morphometry in lung sections and ELISA, zymography and western blotting in BAL samples or lung homogenates. In the lungs of PPE + BLM and BLM + PPE groups, we observed inflammation, oxidative stress and expression of MMP-2 and MMP-9. The alveolar enlargement was reduced in the PPE + BLM group, suggesting that the BLM could participate in the alveolar remodeling process. The significance of this result supports future therapeutic approaches targeting extracellular-matrix deposition in patients with emphysema as a way to repair the enlargement of alveoli and airspaces.
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Arizmendi, N., L. Puttagunta, K.L. Chung, C. Davidson, J. Rey-Parra, D.V. Chao, B. Thebaud, P. Lacy, and H. Vliagoftis. 2014. Rac2 is involved in bleomycin-induced lung inflammation leading to pulmonary fibrosis. Respiratory Research 15: 71. doi:10.1186/1465-9921-15-71.
Bannister, J.V., and L. Calabrese. 1987. Assays for superoxide dismutase. Methods of Biochemical Analysis 32: 279–312.
Cheng, T.O. 2003. Cigarette smoking, asthma, and emphysema. Chest 124 (6): 2408.
Cheresh, P., S.J. Kim, S. Tulasiram, and D.W. Kamp. 2013. Oxidative stress and pulmonary fibrosis. Biochimica et Biophysica Acta 1832 (7): 1028–1040. doi:10.1016/j.bbadis.2012.11.021.
Chitra, P., G. Saiprasad, R. Manikandan, and G. Sudhandiran. 2013. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappaB dependant TGF-beta activation: a biphasic experimental study. Toxicology Letters 219 (2): 178–193. doi:10.1016/j.toxlet.2013.03.009.
Churg, A., D.D. Sin, and J.L. Wright. 2011. Everything prevents emphysema: are animal models of cigarette smoke-induced chronic obstructive pulmonary disease any use? American journal of respiratory cell and molecular biology 45 (6): 1111–1115. doi:10.1165/rcmb.2011-0087PS.
Draper, H.H., E.J. Squires, H. Mahmoodi, J. Wu, S. Agarwal, and M. Hadley. 1993. A comparative evaluation of thiobarbituric acid methods for the determination of malondialdehyde in biological materials. Free radical biology & medicine 15 (4): 353–363.
Evans, M.D., and W.A. Pryor. 1994. Cigarette smoking, emphysema, and damage to alpha 1-proteinase inhibitor. The American journal of physiology 266 (6 Pt 1): L593–L611.
Iraz, M., H. Erdogan, M. Kotuk, M. Yagmurca, T. Kilic, H. Ermis, E. Fadillioglu, and Z. Yildirim. 2006. Ginkgo biloba Inhibits bleomycin-induced lung fibrosis in rats. Pharmacological research 53 (3): 310–316. doi:10.1016/j.phrs.2005.12.009.
Ishii, Y., K. Itoh, Y. Morishima, T. Kimura, T. Kiwamoto, T. Iizuka, A.E. Hegab, et al. 2005. Transcription factor Nrf2 plays a pivotal role in protection against elastase-induced pulmonary inflammation and emphysema. Journal of immunology 175 (10): 6968–6975.
Kemp, S.V., M.I. Polkey, and P.L. Shah. 2009. The epidemiology, etiology, clinical features, and natural history of emphysema. Thoracic surgery clinics 19 (2): 149–158. doi:10.1016/j.thorsurg.2009.03.003.
Kim, Y.S., J.Y. Kim, J.W. Huh, S.W. Lee, S.J. Choi, and Y.M. Oh. 2015. The therapeutic effects of optimal dose of mesenchymal stem cells in a murine model of an elastase induced-emphysema. Tuberc Respir Dis (Seoul) 78 (3): 239–245. doi:10.4046/trd.2015.78.3.239.
Kuebler, W.M., C. Abels, L. Schuerer, and A.E. Goetz. 1996. Measurement of neutrophil content in brain and lung tissue by a modified myeloperoxidase assay. International Journal of Microcirculation, Clinical and Experimental 16 (2): 89–97.
Lanzetti, M., C.A. da Costa, R.T. Nesi, M.V. Barroso, V. Martins, T. Victoni, V. Lagente, et al. 2012. Oxidative stress and nitrosative stress are involved in different stages of proteolytic pulmonary emphysema. Free Radical Biology & Medicine 53 (11): 1993–2001. doi:10.1016/j.freeradbiomed.2012.09.015.
Lee, P., Gildea, T. R, and Stoller, J. K. 2002. Emphysema in nonsmokers: alpha 1-antitrypsin deficiency and other causes. Cleve Clin J Med 69 (12):928–929, 933, 936 passim.
Liu, R.M., and K.A. Gaston Pravia. 2010. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free radical biology & medicine 48 (1): 1–15. doi:10.1016/j.freeradbiomed.2009.09.026.
Moeller, A., K. Ask, D. Warburton, J. Gauldie, and M. Kolb. 2008. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? The international journal of biochemistry & cell biology 40 (3): 362–382. doi:10.1016/j.biocel.2007.08.011.
Niu, R., T. Okamoto, K. Iwase, S. Nomura, and S. Mizutani. 2000. Quantitative analysis of matrix metalloproteinases-2 and -9, and their tissue inhibitors-1 and -2 in human placenta throughout gestation. Life Sciences 66 (12): 1127–1137.
Owen, C.A. 2008. Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease. International Journal of Chronic Obstructive Pulmonary Disease 3 (2): 253–268.
Pannier, R. 1986. Socio-economic causes and consequences of chronic bronchitis and emphysema: an overview. European Journal of Respiratory Diseases. Supplement 146: 77–85.
Parks, W.C., C.L. Wilson, and Y.S. Lopez-Boado. 2004. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nature Reviews. Immunology 4 (8): 617–629. doi:10.1038/nri1418.
Phan, S.H., and S.L. Kunkel. 1992. Lung cytokine production in bleomycin-induced pulmonary fibrosis. Experimental lung research 18 (1): 29–43. doi:10.3109/01902149209020649.
Raghu, G., H.R. Collard, J.J. Egan, F.J. Martinez, J. Behr, K.K. Brown, T.V. Colby, et al. 2011. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. American journal of respiratory and critical care medicine 183 (6): 788–824. doi:10.1164/rccm.2009-040GL.
Santos-Silva, M.A., K.M. Pires, E.T. Trajano, V. Martins, R.T. Nesi, C.F. Benjamin, M.S. Caetano, et al. 2012. Redox imbalance and pulmonary function in bleomycin-induced fibrosis in C57BL/6, DBA/2, and BALB/c mice. Toxicologic pathology 40 (5): 731–741. doi:10.1177/0192623312441404.
Szabari, M.V., J. Tolnai, B.A. Maar, H. Parameswaran, E. Bartolak-Suki, B. Suki, and Z. Hantos. 2015. Lung structure and function in elastase-treated rats: a follow-up study. Respiratory physiology & neurobiology 215: 13–19. doi:10.1016/j.resp.2015.04.005.
Teixeira, K.C., F.S. Soares, L.G. Rocha, P.C. Silveira, L.A. Silva, S.S. Valenca, F. Dal Pizzol, E.L. Streck, and R.A. Pinho. 2008. Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulmonary pharmacology & therapeutics 21 (2): 309–316. doi:10.1016/j.pupt.2007.07.006.
Verma, R., M. Brahmankar, L. Kushwah, and B. Suresh. 2013. Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats. Environmental toxicology and pharmacology 36 (3): 769–778. doi:10.1016/j.etap.2013.07.011.
Walkin, L., S.E. Herrick, A. Summers, P.E. Brenchley, C.M. Hoff, R. Korstanje, and P.J. Margetts. 2013. The role of mouse strain differences in the susceptibility to fibrosis: a systematic review. Fibrogenesis & Tissue Repair 6 (1): 18. doi:10.1186/1755-1536-6-18.
Yildirim, Z., Y. Turkoz, M. Kotuk, F. Armutcu, A. Gurel, M. Iraz, S. Ozen, I. Aydogdu, and O. Akyol. 2004. Effects of aminoguanidine and antioxidant erdosteine on bleomycin-induced lung fibrosis in rats. Nitric Oxide 11 (2): 156–165. doi:10.1016/j.niox.2004.07.011.
Zhou, Q., T. Chen, M. Bozkanat, J.C. Ibe, J.W. Christman, J.U. Raj, and G. Zhou. 2014. Intratracheal instillation of high dose adenoviral vectors is sufficient to induce lung injury and fibrosis in mice. PloS One 9 (12): e116142. doi:10.1371/journal.pone.0116142.
Acknowledgments
Isabella Cattani-Cavalieri received a fellowship grant for undergraduate students from CNPq (472417/2012-6). Adriane Graça Reis received a fellowship grant for undergraduate students from FAPERJ (E-26/103.081/2012). Vanessa Pinho Ribeiro received a post-doctoral fellowship grant from CNPq (502917/2012-1). This work was supported by a research grant from FAPERJ E-26/102.254/2013 and from CNPq 400096/2014-5 and 472417/2012-6.
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Cattani-Cavalieri, I., Reis, A.G., Kennedy-Feitosa, E. et al. Pulmonary Emphysema Cross-Linking with Pulmonary Fibrosis and Vice Versa: a Non-usual Experimental Intervention with Elastase and Bleomycin. Inflammation 40, 1487–1496 (2017). https://doi.org/10.1007/s10753-017-0590-9
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DOI: https://doi.org/10.1007/s10753-017-0590-9