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Bone marrow mesenchymal stem cells ameliorate lung injury through anti-inflammatory and antibacterial effect in COPD mice

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Summary

The anti-inflammatory and antibacterial mechanisms of bone marrow mesenchymal stem cells (MSCs) ameliorating lung injury in chronic obstructive pulmonary disease (COPD) mice induced by cigarette smoke and Haemophilus Parainfluenza (HPi) were studied. The experiment was divided into four groups in vivo: control group, COPD group, COPD+HPi group, and COPD+HPi+MSCs group. The indexes of emphysematous changes, inflammatory reaction and lung injury score, and antibacterial effects were evaluated in all groups. As compared with control group, emphysematous changes were significantly aggravated in COPD group, COPD+HPi group and COPD+HPi+MSCs group (P<0.01), the expression of necrosis factor-kappaB (NF-κB) signal pathway and proinflammatory cytokines in bronchoalveolar lavage fluid (BALF) were increased (P<0.01), and the phagocytic activity of alveolar macrophages was downregulated (P<0.01). As compared with COPD group, lung injury score, inflammatory cells and proinflammatory cytokines were significantly increased in the BALF of COPD+HPi group and COPD+HPi+MSCs group (P<0.01). As compared with COPD+HPi group, the expression of tumor necrosis factor-α stimulated protein/gene 6 (TSG-6) was increased, the NF-κB signal pathway was depressed, proinflammatory cytokine was significantly reduced, the anti-inflammatory cytokine IL-10 was increased, and lung injury score was significantly reduced in COPD+HPi+MSCs group. Meanwhile, the phagocytic activity of alveolar macrophages was significantly enhanced and bacterial counts in the lung were decreased. The results indicated cigarette smoke caused emphysematous changes in mice and the phagocytic activity of alveolar macrophages was decreased. The lung injury of acute exacerbation of COPD mice induced by cigarette smoke and HPi was alleviated through MSCs transplantation, which may be attributed to the fact that MSCs could promote macrophages into anti-inflammatory phenotype through secreting TSG-6, inhibit NF-кB signaling pathway, and reduce inflammatory response through reducing proinflammatory cytokines and promoting the expression of the anti-inflammatory cytokine. Simultaneously, MSCs could enhance phagocytic activity of macrophages and bacterial clearance. Meanwhile, we detected anti-inflammatory and antibacterial activity of macrophages regulated by MSCs in vitro. As compared with RAW264.7+HPi+CSE group, the expression of NF-кB p65, IL-1β, IL-6 and TNF-α was significantly reduced, and the phagocytic activity of macrophages was significantly increased in RAW264.7+HPi+CSE+MSCs group (P<0.01). The result indicated the macrophages co-cultured with MSCs may inhibit NF-кB signaling pathway and promote phagocytosis by paracrine mechanism.

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References

  1. Weiss DJ. Stem cells, cell therapies, and bioengineering in lung biology and diseases. Comprehensive review of the recent literature 2010-2012. Ann Am Thorac Soc, 2013,10(5):S45–97

    PubMed  Google Scholar 

  2. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med, 2006,173(10):1114–1121

    Article  PubMed  Google Scholar 

  3. Gaschler GJ, Skrtic M, Zavitz CC, et al. Bacteria challenge in smoke-exposed mice exacerbates inflammation and skews the inflammatory profile. Am J Respir Crit Care Med, 2009,179(8):666–675

    Article  CAS  PubMed  Google Scholar 

  4. Morissette MC, Shen P, Thayaparan D, et al. Impacts of peroxisome proliferator-activated receptor-gamma activation on cigarette smoke-induced exacerbated response to bacteria. Eur Respir J, 2015,45(1):191–200

    Article  CAS  PubMed  Google Scholar 

  5. Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov, 2013,12(7):543–559

    Article  PubMed  Google Scholar 

  6. Compton C, McBryan D, Bucchioni E, et al. The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease. Pulm Pharmacol Ther, 2013,26(5):562–573

    Article  CAS  PubMed  Google Scholar 

  7. Bagaitkar J, Demuth DR, Scott DA. Tobacco use increases susceptibility to bacterial infection. Tob Induc Dis, 2008,4:12

    Article  PubMed  PubMed Central  Google Scholar 

  8. Daniels JM, Snijders D, de Graaff CS, et al. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2010,181(2):150–157

    Article  CAS  PubMed  Google Scholar 

  9. Sandhu SK, Chu J, Yurkovich M, et al. Variations in the management of acute exacerbations of chronic obstructive pulmonary disease. Can Respir J, 2013,20(3):175–179

    Article  PubMed  PubMed Central  Google Scholar 

  10. Baker AH, Sica V, Work LM, et al. Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia. Proc Natl Acad Sci USA, 2007,104(9):3597–3602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rodrigo SF, van Ramshorst J, Hoogslag GE, et al. Intramyocardial injection of autologous bone marrow derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of Follow-up. J Cardiovasc Transl Res, 2013,6(5):816–25

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gupta N, Su X, Popov B, et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol, 2007, 179(3):1855–1863

    Article  CAS  PubMed  Google Scholar 

  13. Weiss DJ, Casaburi R, Flannery R, et al. Aplacebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest, 2013,143(6):1590–1598

    Article  CAS  PubMed  Google Scholar 

  14. Gupta N, Krasnodembskaya A, Kapetanaki M, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax, 2012,67(6):533–539

    Article  PubMed  PubMed Central  Google Scholar 

  15. Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem cellsis mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells, 2010,28:2229–2238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ho MS, Mei SH, Stewart DJ. The immunomodulatory and therapeutic effects of mesenchymal stromal cells for acute lung injury and sepsis. J Cell Physiol, 2015,230(11):2606–2617

    Article  CAS  PubMed  Google Scholar 

  17. Nemeth K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 2009,15:42–49

    Article  CAS  PubMed  Google Scholar 

  18. Liu HM, Ma LJ, Wu JZ, et al. MSCs relieve lung injury of COPD Mice through promoting proliferation of endogenous lung stem cells. J Huazhong Univ Sci Technol Med Sci, 2015,35(6):828–833

    Article  CAS  PubMed  Google Scholar 

  19. Zhen GH, Liu HM, Gu NB, et al. Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci, 2008,13:3415–3422

    Article  CAS  PubMed  Google Scholar 

  20. Liu HM, Ma LJ, Wu JZ, et al. Apoptosis of alveolar wall cells in chronic obstructive pulmonary disease patients with pulmonary emphysema is involved in emphysematous changes. J Huazhong Univ Sci Technol Med Sci, 2009,29(4):466–469

    Article  PubMed  Google Scholar 

  21. Liu HM, Zhen GH, Zhang ZX, et al. Effects of bone marrow mesenchymal stem cells transplantation on the apoptosis of alveolar wall cells in papain and Co60-induced pulmonary emphysema rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi (Chinese), 2008,24(2):210–214

    Google Scholar 

  22. Wilkinson TS, Dhaliwal K, Hamilton TW, et al. Trappin-2 promotes early clearance of Pseudomonas aeruginosa through CD14-dependent macrophage activation and neutrophil recruitment. Am J Pathol, 2009,174(4):1338–1346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Luther K, Torosantucci A, Brakhage AA, et al. Phagocytosis of Aspergillus fumigatus conidia by murine macrophages involves recognition by the dectin-1 beta-glucan receptor and Toll-like receptor 2. Cell Microbiol, 2007,9(2):368–381

    Article  CAS  PubMed  Google Scholar 

  24. Nyunoya T, Monick MM, Klingelhutz A, et al. Cigarette smoke induces cellular senescence. Am J Respir Cell Mol Biol, 2006,35(6):681–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. He Z, Hua J, Song Z. Concise review: Mesenchymal stem cells ameliorate tissue injury via secretion of tumor necrosis factor-alpha stimulated protein/gene 6. Stem Cells Int, 2014,2014:761091

    Article  PubMed  PubMed Central  Google Scholar 

  26. Milner CM, Higman VA, Day AJ. TSG-6: a pluripotent inflammatory mediator? Biochem Soc Trans, 2006,34(Pt 3):446–450

    Article  CAS  PubMed  Google Scholar 

  27. Szanto S, Bardos T, Gal I, et al. Enhanced neutrophil extravasation and rapid progression of proteoglycan-induced arthritis in TSG-6-knockout mice. Arthritis Rheum, 2004,50(9):3012–3022

    Article  CAS  PubMed  Google Scholar 

  28. Hodge S, Hodge G, Ahern J, et al. Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol, 2007,37(6):748–755

    Article  CAS  PubMed  Google Scholar 

  29. Tzouvelekis A, Laurent G, Bouros D. Stem cell therapy in chronic obstructive pulmonary disease. Seeking the prometheus effect. Curr Drug Targets, 2013,14 (2):246–252

    Article  CAS  PubMed  Google Scholar 

  30. Gu W, Song L, Li XM, et al. Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERKMAPK pathways. Sci Rep, 2015,5:8733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Choi H, Lee RH, Bazhanov N, et al. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kB signaling in resident macrophages. Blood, 2011,118(2):330–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Respiratory Medicine, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, 450003, China

    Hong-mei Liu  (刘红梅), Yi-tong Liu  (刘怡彤), Jing Zhang  (张 静) & Li-jun Ma  (马利军)

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  1. Hong-mei Liu  (刘红梅)
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  2. Yi-tong Liu  (刘怡彤)
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  3. Jing Zhang  (张 静)
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  4. Li-jun Ma  (马利军)
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Corresponding author

Correspondence to Hong-mei Liu  (刘红梅).

Additional information

This project was supported by Medical Research of Henan Province (No. 102300410247).

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Liu, Hm., Liu, Yt., Zhang, J. et al. Bone marrow mesenchymal stem cells ameliorate lung injury through anti-inflammatory and antibacterial effect in COPD mice. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 37, 496–504 (2017). https://doi.org/10.1007/s11596-017-1763-3

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  • DOI: https://doi.org/10.1007/s11596-017-1763-3

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