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Bone Marrow Mesenchymal Stem Cells Combat Lipopolysaccharide-Induced Sepsis in Rats via Amendment of P38-MAPK Signaling Cascade

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Abstract

Sepsis is a systemic inflammatory disorder which often occurs during extremely stressful conditions such as trauma, burn, shock, and infection. This study investigated the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) against hepatic, renal, and pulmonary responses caused by a single administration of lipopolysaccharide (LPS) (10 mg/kg, i.p) in rats. Treatment with BM-MSCs (5 × 105 in 0.1 ml PBS, i.p.) 3 h after LPS antagonized the LPS-induced increment of the liver enzymes (ALT, AST) and kidney functions (BUN, sCr). BM-MSCs decreased tissue levels of P38-MAPK, NF-κB, STAT-3, TNF-α, IL-1β, iNOS, Bax together with elevation of the anti-inflammatory cytokine IL-10 and the anti-apoptotic biomarker Bcl-2. Meanwhile, rats exhibited marked reduction of the broncho-alveolar lavage fluid levels of TNF-α, IL-1β, and IFN-γ. Interestingly, BM-MSCs normalized both broncho-alveolar lavage fluid (BALF) neutrophils count and lung wet/dry ratios. Briefly, these findings may provide a preclinical platform for the management of LPS-induced sepsis using BM-MSCs via their ameliorative anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.

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References

  1. van der Poll, T., and S.M. Opal. 2008. Host-pathogen interactions in sepsis. The Lancet Infectious Diseases 8: 32–43.

    Article  PubMed  Google Scholar 

  2. Russell, J.A. 2006. Management of sepsis. The New England Journal of Medicine 355: 1699–1713.

    Article  CAS  PubMed  Google Scholar 

  3. Angus, D.C., and T. van der Poll. 2013. Severe sepsis and septic shock. The New England Journal of Medicine 369: 840–851.

    Article  CAS  PubMed  Google Scholar 

  4. Hotchkiss, R.S., G. Monneret, and D. Payen. 2013. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews. Immunology 13: 862–874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Remick, D.G., D.E. Newcomb, G.L. Bolgos, and D.R. Call. 2000. Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13: 110–116.

    Article  CAS  PubMed  Google Scholar 

  6. Gallay, P., S. Carrel, M.P. Glauser, C. Barras, R.J. Ulevitch, P.S. Tobias, J.D. Baumgartner, and D. Heumann. 1993. Purification and characterization of murine lipopolysaccharide-binding protein. Infection and Immunity 61: 378–383.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Craig, R., A. Larkin, A.M. Mingo, D.J. Thuerauf, C. Andrews, P.M. McDonough, and C.C. Glembotski. 2000. p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. Journal of Biology and Chemistry 275: 23814–23824.

    Article  CAS  Google Scholar 

  8. Peng, T., T. Zhang, X. Lu, and Q. Feng. 2009. JNK1/c-fos inhibits cardiomyocyte TNF-alpha expression via a negative crosstalk with ERK and p38 MAPK in endotoxaemia. Cardiovascular Research 81: 733–741.

    Article  CAS  PubMed  Google Scholar 

  9. Di Nicola, M., C. Carlo-Stella, M. Magni, M. Milanesi, P.D. Longoni, P. Matteucci, S. Grisanti, and A.M. Gianni. 2002. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838–3843.

    Article  PubMed  Google Scholar 

  10. Bernardo, M.E., and W.E. Fibbe. 2013. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13: 392–402.

    Article  CAS  PubMed  Google Scholar 

  11. Friedenstein, A.J., K.V. Petrakova, A.I. Kurolesova, and G.P. Frolova. 1968. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6: 230–247.

    Article  CAS  PubMed  Google Scholar 

  12. Fukuchi, Y., H. Nakajima, D. Sugiyama, I. Hirose, T. Kitamura, and K. Tsuji. 2004. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 22: 649–658.

    Article  CAS  PubMed  Google Scholar 

  13. Glennie, S., I. Soeiro, P.J. Dyson, E.W. Lam, and F. Dazzi. 2005. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105: 2821–2827.

    Article  CAS  PubMed  Google Scholar 

  14. Caplan, A.I., and J.E. Dennis. 2006. Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry 98: 1076–1084.

    Article  CAS  PubMed  Google Scholar 

  15. Boregowda, S.V., and D.G. Phinney. 2012. Therapeutic applications of mesenchymal stem cells: current outlook. BioDrugs 26: 201–208.

    Article  CAS  PubMed  Google Scholar 

  16. DelaRosa, O., B. Sanchez-Correa, S. Morgado, C. Ramirez, B. del Rio, R. Menta, E. Lombardo, R. Tarazona, and J.G. Casado. 2012. Human adipose-derived stem cells impair natural killer cell function and exhibit low susceptibility to natural killer-mediated lysis. Stem Cells and Development 21: 1333–1343.

    Article  CAS  PubMed  Google Scholar 

  17. Aggarwal, B.B., and K. Natarajan. 1996. Tumor necrosis factors: developments during the last decade. European Cytokine Network 7: 93–124.

    CAS  PubMed  Google Scholar 

  18. Krampera, M., L. Cosmi, R. Angeli, A. Pasini, F. Liotta, A. Andreini, V. Santarlasci, B. Mazzinghi, G. Pizzolo, F. Vinante, P. Romagnani, E. Maggi, S. Romagnani, and F. Annunziato. 2006. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24: 386–398.

    Article  CAS  PubMed  Google Scholar 

  19. Prasanna, S.J., D. Gopalakrishnan, S.R. Shankar, and A.B. Vasandan. 2010. Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One 5: e9016.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yagi, H., A. Soto-Gutierrez, N. Navarro-Alvarez, Y. Nahmias, Y. Goldwasser, Y. Kitagawa, A.W. Tilles, R.G. Tompkins, B. Parekkadan, and M.L. Yarmush. 2010. Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1. Molecular Therapy 18: 1857–1864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. El-Attar, S., L.A. Elsayed, and L. Rashed. 2012. Role of stem cells and antioxidant on modulation of body defense mechanism in lipopolysaccharide-induced acute lung injury in rats. Cairo Univ Journal of Medicine 80: 559–573.

    Google Scholar 

  22. Iyer, S.S., E. Torres-Gonzalez, D.C. Neujahr, M. Kwon, K.L. Brigham, D.P. Jones, A.L. Mora, and M. Rojas. 2010. Effect of bone marrow-derived mesenchymal stem cells on endotoxin-induced oxidation of plasma cysteine and glutathione in mice. Stem Cells International 2010: 868076.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cocchetto, D.M., and T.D. Bjornsson. 1983. Methods for vascular access and collection of body fluids from the laboratory rat. Journal of Pharmaceutical Sciences 72: 465–492.

    Article  CAS  PubMed  Google Scholar 

  24. Alhadlaq, A., and J.J. Mao. 2004. Mesenchymal stem cells: isolation and therapeutics. Stem Cells and Development 13: 436–448.

    Article  CAS  PubMed  Google Scholar 

  25. Mei, S.H., S.D. McCarter, Y. Deng, C.H. Parker, W.C. Liles, and D.J. Stewart. 2007. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Medicine 4: e269.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lam, C.F., Y.C. Liu, J.K. Hsu, P.A. Yeh, T.Y. Su, C.C. Huang, M.W. Lin, P.C. Wu, P.J. Chang, and Y.C. Tsai. 2008. Autologous transplantation of endothelial progenitor cells attenuates acute lung injury in rabbits. Anesthesiology 108: 392–401.

    Article  PubMed  Google Scholar 

  27. Sims, J.E., and D.E. Smith. 2010. Nature Reviews Immunology 102: 10–89.

    Google Scholar 

  28. Vilcek, J., and T.H. Lee. 1991. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. Journal of Biology and Chemistry 266: 7313–7316.

    CAS  Google Scholar 

  29. Eskdale, J., D. Kube, H. Tesch, and G. Gallagher. 1997. Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence. Immunogenetics 46: 120–128.

    Article  CAS  PubMed  Google Scholar 

  30. Thiel, D.J., M.H. le Du, R.L. Walter, A. D'Arcy, C. Chene, M. Fountoulakis, G. Garotta, F.K. Winkler, and S.E. Ealick. 2000. Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex. Structure 8: 927–936.

    Article  CAS  PubMed  Google Scholar 

  31. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  32. J. D. Bancroft, A. Stevens, D. R. Turner. 2002. Theory and practice of histological techniques. In: New York, Churchill, Livingstone. Vol.5th Ed. pp: 172-175.

  33. Oz, H.S., T.S. Chen, and M. Neuman. 2009. Nutrition intervention: a strategy against systemic inflammatory syndrome. JPEN Journal of Parenteral and Enteral Nutrition 33: 380–389.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Oz, H.S., C.J. McClain, and H.T. Nagasawa. 2004. Diverse antioxidants protect against acetaminophen hepatotoxicity. Journal of Biochemical and Molecular Toxicology 18: 361–368.

    Article  CAS  PubMed  Google Scholar 

  35. Shin, S., Y. Kim, S. Jeong, S. Hong, I. Kim, W. Lee, and S. Choi. 2013. The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. International Journal of Medical Sciences 10: 8–18.

    Article  CAS  PubMed  Google Scholar 

  36. Cai, Y., Z. Zou, L. Liu, S. Chen, Y. Chen, Z. Lin, K. Shi, L. Xu, and Y. Chen. 2015. Bone marrow-derived mesenchymal stem cells inhibits hepatocyte apoptosis after acute liver injury. International Journal of Clinical and Experimental Pathology 8: 107–116.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sener, G., H. Toklu, C. Kapucu, F. Ercan, G. Erkanli, A. Kacmaz, M. Tilki, and B.C. Yegen. 2005. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surgery Today 35: 52–59.

    Article  CAS  PubMed  Google Scholar 

  38. Takahashi, K., H. Mizukami, K. Kamata, W. Inaba, N. Kato, C. Hibi, and S. Yagihashi. 2012. Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat. PLoS One 7: e30134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guttridge, D.C., C. Albanese, J.Y. Reuther, R.G. Pestell, and A.S. Baldwin Jr. 1999. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Molecular and Cellular Biology 19: 5785–5799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu, S.H., K. Ma, X.R. Xu, and B. Xu. 2010. A single dose of carbon monoxide intraperitoneal administration protects rat intestine from injury induced by lipopolysaccharide. Cell Stress & Chaperones 15: 717–727.

    Article  CAS  Google Scholar 

  41. Rousseau, S., M. Papoutsopoulou, A. Symons, D. Cook, J.M. Lucocq, A.R. Prescott, A. O'Garra, S.C. Ley, and P. Cohen. 2008. TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages. Journal of Cell Science 121: 149–154.

    Article  CAS  PubMed  Google Scholar 

  42. Ramana, K.V., A.B. Reddy, R. Tammali, and S.K. Srivastava. 2007. Aldose reductase mediates endotoxin-induced production of nitric oxide and cytotoxicity in murine macrophages. Free Radical Biology & Medicine 42: 1290–1302.

    Article  CAS  Google Scholar 

  43. Kim, H.J., H.S. Lee, Y.H. Chong, and J.L. Kang. 2006. p38 Mitogen-activated protein kinase up-regulates LPS-induced NF-kappaB activation in the development of lung injury and RAW 264.7 macrophages. Toxicology 225: 36–47.

    Article  CAS  PubMed  Google Scholar 

  44. de Jong, P.R., A.W. Schadenberg, T. van den Broek, J.M. Beekman, F. van Wijk, P.J. Coffer, B.J. Prakken, and N.J. Jansen. 2012. STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass. PLoS One 7: e35070.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Severgnini, M., S. Takahashi, L.M. Rozo, R.J. Homer, C. Kuhn, J.W. Jhung, G. Perides, M. Steer, P.M. Hassoun, B.L. Fanburg, B.H. Cochran, and A.R. Simon. 2004. Activation of the STAT pathway in acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 286: L1282–L1292.

    Article  CAS  PubMed  Google Scholar 

  46. Leventhal, J.S., J. Ni, M. Osmond, K. Lee, G.L. Gusella, F. Salem, and M.J. Ross. 2016. Autophagy limits endotoxemic acute kidney injury and alters renal tubular epithelial cell cytokine expression. PLoS One 11: e0150001.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Eltablawy, N.A., and L.A. Rashed. 2015. The key role of Kefir probiotic in enhancement the therapeutic action of mesenchymal stem cells in LPS-induced liver injury. Journal Biomedical and Pharmaceutical Research 4: 90–100.

    CAS  Google Scholar 

  48. Heremans, H., R. Dijkmans, H. Sobis, F. Vandekerckhove, and A. Billiau. 1987. Regulation by interferons of the local inflammatory response to bacterial lipopolysaccharide. Journal of Immunology 138: 4175–4179.

    CAS  Google Scholar 

  49. Billiau, A. 1996. Interferon-gamma: biology and role in pathogenesis. Advances in Immunology 62: 61–130.

    Article  CAS  PubMed  Google Scholar 

  50. Badger, A.M., P.C. Meunier, R.A. Weiss, and P.J. Bugelski. 1988. Modulation of rat bronchoalveolar lavage cell function by the intratracheal delivery of interferon-gamma. Journal of Interferon Research 8: 251–260.

    Article  CAS  PubMed  Google Scholar 

  51. Seifert, P.S., N. Haeffner-Cavaillon, M.D. Appay, and M.D. Kazatchkine. 1991. Bacterial lipopolysaccharides alter human endothelial cell morphology in vitro independent of cytokine secretion. The Journal of Laboratory and Clinical Medicine 118: 563–569.

    CAS  PubMed  Google Scholar 

  52. Oppenheimer-Marks, N., and M. Ziff. 1988. Migration of lymphocytes through endothelial cell monolayers: augmentation by interferon-gamma. Cellular Immunology 114: 307–323.

    Article  CAS  PubMed  Google Scholar 

  53. Dustin, M.L., R. Rothlein, A.K. Bhan, C.A. Dinarello, and T.A. Springer. 1993. Tissue distribution, biochemistry and function of a natural adherence molecule (ICAM-1): induction by IL-a and interferon-g. Journal of Immunology 137: 245–254.

    Google Scholar 

  54. Lee, J.W., X. Fang, N. Gupta, V. Serikov, and M.A. Matthay. 2009. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proceedings of the National Academy of Sciences of the United States of America 106: 16357–16362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Danchuk, S., J.H. Ylostalo, F. Hossain, R. Sorge, A. Ramsey, R.W. Bonvillain, J.A. Lasky, B.A. Bunnell, D.A. Welsh, D.J. Prockop, and D.E. Sullivan. 2011. Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-alpha-induced protein 6. Stem Cell Research & Therapy 2: 27.

    Article  CAS  Google Scholar 

  56. Nemeth, K., A. Leelahavanichkul, P.S. Yuen, B. Mayer, A. Parmelee, K. Doi, P.G. Robey, K. Leelahavanichkul, B.H. Koller, J.M. Brown, X. Hu, I. Jelinek, R.A. Star, and E. Mezey. 2009. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine 15: 42–49.

    Article  CAS  PubMed  Google Scholar 

  57. Ornellas, D.S., T. Maron-Gutierrez, F.M. Ornellas, F.F. Cruz, G.P. Oliveira, I.H. Lucas, L. Fujisaki, M.G. Oliveira, W.R. Teodoro, V.L. Capelozzi, P. Pelosi, M.M. Morales, and P.R. Rocco. 2011. Early and late effects of bone marrow-derived mononuclear cell therapy on lung and distal organs in experimental sepsis. Respiratory Physiology & Neurobiology 178: 304–314.

    Article  CAS  Google Scholar 

  58. Mei, S.H., J.J. Haitsma, C.C. Dos Santos, Y. Deng, P.F. Lai, A.S. Slutsky, W.C. Liles, and D.J. Stewart. 2010. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. American Journal of Respiratory and Critical Care Medicine 182: 1047–1057.

    Article  CAS  PubMed  Google Scholar 

  59. Krasnodembskaya, A., G. Samarani, Y. Song, H. Zhuo, X. Su, J.W. Lee, N. Gupta, M. Petrini, and M.A. Matthay. 2012. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. American Journal of Physiology. Lung Cellular and Molecular Physiology 302: L1003–L1013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Demiralay, R., N. Gursan, and H. Erdem. 2013. The effects of erdosteine and N-acetylcysteine on apoptotic and antiapoptotic markers in pulmonary epithelial cells in sepsis. Eurasian Journal of Medicine 45: 167–175.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Kanazawa, H., Y. Fujimoto, T. Teratani, J. Iwasaki, N. Kasahara, K. Negishi, T. Tsuruyama, S. Uemoto, and E. Kobayashi. 2011. Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a rat model. PLoS One 6: e19195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cui, W.Y., A.Y. Tian, and T. Bai. 2011. Protective effects of propofol on endotoxaemia-induced acute kidney injury in rats. Clinical and Experimental Pharmacology & Physiology 38: 747–754.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors are greatly indebted and grateful to Dr. Adel Bakeer Kholoussy, Professor of Pathology, Faculty of Medicine, Cairo University, for examining and interpreting histopathological results. The authors thank Dr. Heba Mohammed Diaa, Veterinary Doctor, Animal House, Surgical Department, Faculty of Medicine, Cairo University, for her kind help in isolation of broncho-alveolar lavage fluids.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, MTI University, Cairo, Egypt

    Omnia S. Zaki

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Marwa M. Safar & Afaf A. Ain-Shoka

  3. Department of Pharmacology and Biochemistry, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt

    Marwa M. Safar

  4. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt

    Laila A. Rashed

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  1. Omnia S. Zaki
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Correspondence to Omnia S. Zaki.

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The investigation was approved by the Ethics Committee for Animal Experimentation of Pharmacy, Cairo University (Permit number: PT 599), and complies with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

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Zaki, O.S., Safar, M.M., Ain-Shoka, A.A. et al. Bone Marrow Mesenchymal Stem Cells Combat Lipopolysaccharide-Induced Sepsis in Rats via Amendment of P38-MAPK Signaling Cascade. Inflammation 41, 541–554 (2018). https://doi.org/10.1007/s10753-017-0710-6

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