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Cell Therapy with Bone Marrow Mononuclear Cells in Elastase-Induced Pulmonary Emphysema

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Abstract

Emphysema is characterized by destruction of alveolar walls with loss of gas exchange surface and consequent progressive dyspnea. This study aimed to evaluate the efficiency of cell therapy with bone marrow mononuclear cells (BMMC) in an animal model of elastase-induced pulmonary emphysema. Emphysema was induced in C57Bl/J6 female mice by intranasal instillation of elastase. After 21 days, the mice received bone marrow mononuclear cells from EGFP male mice with C57Bl/J6 background. The groups were assessed by comparison and statistically significant differences (p < 0.05) were observed among the groups treated with BMMC and evaluated after 7, 14 and 21 days. Analysis of the mean linear intercept (Lm) values for the different groups allowed to observe that the group treated with BMMC and evaluated after 21 days showed the most significant result. The group that received no treatment showed a statistically significant difference when compared to other groups, except the group treated and evaluated after 21 days, evidencing the efficacy of cell therapy with BMMC in pulmonary emphysema.

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References

  1. Jardim, J. R., & Nascimento, A. O. (2007). Epidemiologia, impacto e tratamento da doença pulmonar obstrutiva crônica (DPOC) no Brasil. Revista Racine, 101, 32–47.

    Google Scholar 

  2. Wong, A. P., Dultly, A. E., Sacher, A., Lee, H., Hwang, D. M., Liu, M., et al. (2007). Targeted cell replacement with bone marrow cells for airway epithelial regeneration. American Journal of Physiology. Lung Cellular and Molecular Physiology, 293, 740–752.

    Article  Google Scholar 

  3. WHO Global Alliance against Chronic Respiratory Diseases (GARD) General meeting report, Istambul, 2008, Turkey, 30–31 May.

  4. Global Initiative for Chronic Lung Disease (2010). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Available:http://www.goldcopd.org/S.

  5. Mannino, D. M. (2011). The natural history of chronic obstructive pulmonary disease. Pneumonologia i Alergologia Polska, 79(2), 139–143.

    PubMed  Google Scholar 

  6. Leuenberger, P., Brandt, R., Keller, R., Knoblauch, A., Kuhn, M., Perruchoud, A.P. et al. (1997). Conduta na Doença Obstrutiva Crônica.

  7. Barnes, P. J. (2003). New concepts in chronic obstructive pulmonary disease. Annual Review of Medicine, 54, 113–129.

    Article  PubMed  CAS  Google Scholar 

  8. Jardim, J.R., Oliveira, J.A., Nascimento, O. (2004). II Consenso Brasileiro sobre Doença Pulmonar Obstrutiva Crônica (DPOC). Jornal de Pneumologia, 30(Supl 5).

  9. March, T. H., Green, F. H., Hahn, F. F., & Nikula, K. J. (2000). Animal models of emphysema and their relevance to studies of particle-induced disease. Inhalation Toxicology, 4, 155–187.

    Google Scholar 

  10. Shapiro, S. (2000). Animal models for COPD. Chest, 117, 223–227.

    Article  Google Scholar 

  11. Fujita, M., & Nakanishi, Y. (2007). The pathogenesis of COPD: lessons learned from in vivo animal models. Medical Science Monitor, 13, 19–24.

    Google Scholar 

  12. Antunes, M. A., & Rocco, P. R. M. (2011). Elastase-induced pulmonary emphysema: insights from experimental models. Anais da Academia Brasileira de Ciências, 83(4), 1385–1395.

    Article  PubMed  CAS  Google Scholar 

  13. Weiss, D. J., Kolls, J. K., Ortiz, L. A., Panoskaltsis-Mortari, A., & Prockop, D. J. (2008). Stem cells and cell therapies in lung biology and lung diseases. Proceedings of the American Thoracic Society, 5, 637–667.

    Article  PubMed  Google Scholar 

  14. Sueblinvong, V., & Weiss, D. J. (2009). Cell therapy approaches for lung diseases: a current status. Current Opinion in Pharmacology, 9, 268–273.

    Article  PubMed  CAS  Google Scholar 

  15. Ribeiro-Paes, J. T., Bilaqui, A., Greco, O. T., Ruiz, M. A., Alves-de-Moraes, L. B. C., Faria, C. A., et al. (2009). Terapia celular em doenças pulmonares: existem perspectivas? Revista Brasileira de Hematologia e Hemoterapia, 31(1), 140–148.

    Article  Google Scholar 

  16. Ribeiro Paes, J. T., Bilaqui, A., Greco, O. T., Ruiz, M. A., Marcelino, M. Y., Stessuk, T., et al. (2011). Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. International Journal of COPD, 6, 63–71.

    PubMed  Google Scholar 

  17. Ribeiro-Paes, J.T., Stessuk, T., Kozma, R.H. (2012). Cell therapy in chronic obstructive pulmonary disease: State of the art and perspectives, chronic obstructive pulmonary disease—current concepts and practice, Dr. Kian-Chung Ong (Ed.), ISBN: 978-953-51-0163-5, InTech. Available from: http://www.intechopen.com/books/chronic-obstructive-pulmonary-disease-current-concepts-and-practice/cell-therapy-in-chronic-obstructive-pulmonary-disease-state-of-the-art-and-perspectives.

  18. Ishizawa, K., Ishizawa, K., Kubo, H., Yamada, M., Kobayashi, S., Suzuki, T., et al. (2003). Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells. Biochemical and Biophysical Research Communications, 324(1), 276–280.

    Article  Google Scholar 

  19. Ishizawa, K., Kubo, H., Yamada, M., Kobayashi, S., Numasaki, M., Ueda, S., et al. (2004). Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Letters, 556(1–3), 249–252.

    Article  PubMed  CAS  Google Scholar 

  20. Yamada, M., Kubo, H., Kobayashi, S., Ishizawa, K., Numasaki, M., Ueda, S., et al. (2004). Bone marrow-derived progenitors cells are important for lung repair after lipopolisaccharide-induced lung injury. The Journal of Immunology, 172, 1266–1272.

    PubMed  CAS  Google Scholar 

  21. Kuang, P. P., Lucey, E., Rishikof, D. C., Humphries, D. E., Bronsnick, D., & Goldstein, R. H. (2005). Engraftment of neonatal lung fibroblasts into the normal and elastase-injured lung. American Journal of Respiratory Cell and Molecular Biology, 33(4), 249–252.

    Article  Google Scholar 

  22. Murakami, S., Nagaya, N., Itoh, T., Iwase, T., Fujisato, T., Nishioka, K., et al. (2005). Adrenomedullin regenerates alveoli and vasculature in elastase-induced pulmonary emphysema in mice. American Journal of Respiratory and Critical Care Medicine, 172, 581–589.

    Article  PubMed  Google Scholar 

  23. Adachi, Y., Oyazu, H., Taketani, S., Minamino, K., Yamaguchi, K., Shultz, L. D., et al. (2006). Treatment and transfer of emphysema by a new bone marrow transplantation method from normal mice to Tsk mice and vice versa. Stem Cells, 24, 2071–2077.

    Article  PubMed  Google Scholar 

  24. Mao, J. T., Goldin, J. G., Dermad, J., Ibrahin, G., Brown, M. S., Emerick, A., et al. (2002). A pilot study of all-trans-retinoic acid for the treatment of human emphysema. American Journal of Respiratory and Critical Care Medicine, 165, 718–723.

    PubMed  Google Scholar 

  25. Suratt, B. T., Cool, C. D., Serls, A. E., Chen, L., Varella-Garcia, M., Shpall, E. J., et al. (2003). Human pulmonary chimerism after hematopoietic stem cell transplantation. American Journal of Respiratory and Critical Care Medicine, 168, 318–322.

    Article  PubMed  Google Scholar 

  26. Lama, V. N., Smith, L., Badri, L., Flint, A., Andrei, A. C., Murray, S., et al. (2007). Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. The Journal of Clinical Investigation, 117, 989–996.

    Article  PubMed  CAS  Google Scholar 

  27. Schrepfer, S., Deuse, T., Reichenspurner, H., Fishbein, M. P., Robbins, R. C., & Pelletier, M. P. (2007). Stem cell transplantation: the lung barrier. Transplantation Proceedings, 39, 573–576.

    Article  PubMed  CAS  Google Scholar 

  28. Barbosa de Oliveira, V. A., Ribeiro-Paes, J. T., Kozma, R. H., Longhini dos Santos, N., Faria, C. A., & Ribeiro-Paes, M. J. O. (2011). Estudo comparativo de dois procedimentos de fixação histológica para análise de enfisema pulmonar induzido experimentalmente. Ciência Pesquisa e Consciência, 3, 7–11.

    Google Scholar 

  29. Weibel, E. R. (1963). Principles and methods for the morphometric study of the lung and other organs. Laboratory Investigation, 12, 130–155.

    Google Scholar 

  30. Kawakami, M., Matsuo, Y., Yoshiura, K., Nagase, T., & Yamashita, N. (2008). Sequential and quantitative analysis of a murine model of elastase-induced emphysema. Biological and Pharmaceutical Bulletin, 31, 1434–1438.

    Article  PubMed  CAS  Google Scholar 

  31. Kuhn, C., Yu, S. Y., Chraplyvy, M., Linder, H. E., & Senior, R. M. (1976). The induction of emphysema with elastase. II. Changes in connective tissue. Laboratory Investigation, 34(4), 372–380.

    PubMed  CAS  Google Scholar 

  32. Snider, G. L., Lucey, E. C., & Stone, P. J. (1986). Animal models of emphysema. American Review of Respiratory Disease, 133, 149–169.

    PubMed  CAS  Google Scholar 

  33. Kuhn, C., 3rd, & Tavassoli, F. (1976). The scanning electron microscopy of elastase-induced emphysema. A comparison with emphysema in man. Laboratory Investigation, 34(1), 2–9.

    PubMed  Google Scholar 

  34. Massaro, G. C., & Massaro, D. (1997). Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nature Medicine, 3(6), 675–677.

    Article  PubMed  CAS  Google Scholar 

  35. Hele, D. (2001). First Siena international conference on animal models of chronic obstructive pulmonary disease, Certosa di Pontignano. Universidade of Siena, Italy, September 30-October 2, 2001. Respiratory Research, 2002, 3–12.

    Article  Google Scholar 

  36. Kononov, S., Brewer, K., Sakai, H., Cavalcante, F. S. A., Sabayanagam, C. R., Ingenito, E. P. E., et al. (2001). Roles of mechanical forces and collagen failure in the development of elastase-induced emphysema. American Journal of Respiratory and Critical Care Medicine, 164, 1920–1926.

    PubMed  CAS  Google Scholar 

  37. Mahadeva, R., & Shapiro, S. D. (2002). Chronic obstrutive pulmonary disease: experimental animal models of pulmonary emphysema. Thorax, 57, 908–914.

    Article  PubMed  CAS  Google Scholar 

  38. Cheng, S. L., Wang, H. C., Yu, C. J., Tsao, P. N., Carmeliet, P., Cheng, S. J., et al. (2009). Prevention of elastase-induced emphysema in placenta growth factor knock-out mice. Respiratory Research, 10, 115–124.

    Article  PubMed  Google Scholar 

  39. Lüthje, L., Raupach, T., Michels, H., Unsöld, B., Hasenfuss, G., Kögler, et al. (2009). Exercise intolerance and systemic manifestations of pulmonary emphysema in a mouse model. Respiratory Research, 10, 7–16.

    Article  PubMed  Google Scholar 

  40. MacPherson, H., Keir, P., Webb, S., Samuel, K., Boyle, S., Bickmore, W., et al. (2005). Bone marrow derived SP cells can contribute to respiratory tract of mice in vivo. Journal of Cell Science, 118, 2441–2450.

    Article  PubMed  CAS  Google Scholar 

  41. Rojas, M., Xu, J., Woods, C. R., Mora, A. L., Spears, W., Roman, J., et al. (2005). Bone marrow-derived mesenchymal stem cells in repair of the injured lung. American Journal of Respiratory Cell and Molecular Biology, 33(2), 145–152.

    Article  PubMed  CAS  Google Scholar 

  42. Kahler, C. M., Wechselberg, J., Hilbe, W., Gschwendtner, A., Colleselli, D., Niederegger, H., et al. (2007). Peripheral infusion of rat bone marrow derived endothelial progenitors cells leads to homming in acute lung injury. Respiratory Research, 8, 50.

    Article  PubMed  Google Scholar 

  43. Sueblinvong, V., & Weiss, D. J. (2009). Stem cells and cell therapy approaches in lung biology and diseases. Translational Research, 156(3), 188–205.

    Article  Google Scholar 

  44. Giangreco, A., Arwert, E. N., Rosewell, I. R., Snyder, J., Watt, F. M., & Stripp, B. R. (2009). Stem cells are dispensable for lung homeostasis but restaure airways after injury. PNAS, 106(23), 9286–9291.

    Article  PubMed  CAS  Google Scholar 

  45. Kotton, D. N., Ma, B. Y., Cardoso, W. V., Sanderson, E. A., Summer, R. S., Willians, M. C., et al. (2001). Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development, 28(24), 5181–5188.

    Google Scholar 

  46. Katsha, A. M., Ohkouchi, S., Xin, H., Kanehira, M., Sun, R., Nukiwa, T., et al. (2010). Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Molecular Therapy, 19(1), 196–203.

    Article  PubMed  Google Scholar 

  47. Schweitzer, K. S., Johnstone, B. H., Garrison, J., Rush, N. I., Cooper, S., Traktuev, D. O., et al. (2011). Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. American Journal of Respiratory and Critical Care Medicine, 183, 215–225.

    Article  PubMed  Google Scholar 

  48. Krause, D. S. (2008). Bone marrow-derived cells and stem cells in lung repair. Proceedings of the American Thoracic Society, 5(3), 323–327.

    Article  PubMed  Google Scholar 

  49. Krause, D. S., Theise, N. D., Collector, M. I., Henegariu, O., Hwang, S., Gardner, R., et al. (2001). Multi-organ, multi-linage enfragment by a single bone marrow-derived stem cell. Cell, 105, 369–377.

    Article  PubMed  CAS  Google Scholar 

  50. Wagers, A. J., & Weissman, I. (2004). Plasticity of adult stem cells. Cell, 116, 639–648.

    Article  PubMed  CAS  Google Scholar 

  51. Faria, C.A., Kozma, R.L.H, Stessuk,T. and Ribeiro-Paes, J.T. (2012). Experimental basis and new insights for cell therapy in chronic obstructive pulmonary disease. Stem Cell Rev 8(4):1236-44

    Google Scholar 

  52. Shigemura, N., Okumura, M., Mizuno, S., Imanishi, Y., Matsuyama, A., Shiono, H., et al. (2006). Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema. American Journal of Respiratory and Critical Care Medicine, 174, 1199–1205.

    Article  PubMed  Google Scholar 

  53. Loebinger, M. R., & Janes, S. M. (2007). Stem cells for lung disease. Chest, 132(1), 279–285.

    Article  PubMed  Google Scholar 

  54. Selman, M., Cisneros-Lira, J., Gaxiola, M., Ramírez, R., Kudlacz, E. M., Mitchell, P. G., et al. (2003). Matrix mielloproteinases inhibition attenuates tobacco smoke-induced emphysema in guinea pigs. Chest, 123, 1633–1641.

    Article  PubMed  CAS  Google Scholar 

  55. Chung, K. F., & Adcock, I. M. (2008). Multifaceted mechanisms in COPD: inflammation, immunity, and tissue repair and destruction. European Respiratory Journal, 31, 1334–1356.

    Article  PubMed  CAS  Google Scholar 

  56. Sampsonas, F., Kaparianos, A., Lykouras, D., Karkoulias, K., & Spiropoulos, K. (2007). DNA sequence variations of metalloproteinases: their role in asthma and COPD. Postgraduate Medical Journal, 83, 244–250.

    Article  PubMed  CAS  Google Scholar 

  57. Le Quément, C., Guénon, I., Gillon, J. Y., Valença, S., Cayron-Elizondo, V., Lagente, V., et al. (2008). The selective MMP-12 inhibitor, AS111793 reduces airway inflammation in mice exposed to cigarette smoke. British Journal of Pharmacology, 154, 1206–1215.

    Article  PubMed  Google Scholar 

  58. Churg, A., Cosio, M., & Wright, J. L. (2008). Mechanisms of cigarette smoke-induced COPD: insights from animal models. American Journal of Physiology. Lung Cellular and Molecular Physiology, 294, L612–L631.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to João Tadeu Ribeiro-Paes.

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Longhini-dos-Santos, N., Barbosa-de-Oliveira, V.A., Kozma, R.H. et al. Cell Therapy with Bone Marrow Mononuclear Cells in Elastase-Induced Pulmonary Emphysema. Stem Cell Rev and Rep 9, 210–218 (2013). https://doi.org/10.1007/s12015-012-9419-y

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