Display options
Cite
Essandoh K, Yang L, Wang X, et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015;1852(11):2362-71doi: 10.1016/j.bbadis.2015.08.010.
Essandoh, K., Yang, L., Wang, X., Huang, W., Qin, D., Hao, J., Wang, Y., Zingarelli, B., Peng, T., & Fan, G. C. (2015). Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochimica et biophysica acta, 1852(11), 2362-71. https://doi.org/10.1016/j.bbadis.2015.08.010
Essandoh, Kobina, et al. "Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction." Biochimica et biophysica acta vol. 1852,11 (2015): 2362-71. doi: https://doi.org/10.1016/j.bbadis.2015.08.010
Essandoh K, Yang L, Wang X, Huang W, Qin D, Hao J, Wang Y, Zingarelli B, Peng T, Fan GC. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015 Nov;1852(11):2362-71. doi: 10.1016/j.bbadis.2015.08.010. Epub 2015 Aug 20. PMID: 26300484; PMCID: PMC4581992.
Copy Download .nbib Format: NLM
Share it on

Biochim Biophys Acta. 2015 Nov;1852(11):2362-71. doi: 10.1016/j.bbadis.2015.08.010. Epub 2015 Aug 20.

Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.

Biochimica et biophysica acta

Kobina Essandoh, Liwang Yang, Xiaohong Wang, Wei Huang, Dongze Qin, Jiukuan Hao, Yigang Wang, Basilia Zingarelli, Tianqing Peng, Guo-Chang Fan

Affiliations

  1. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
  2. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi Province, China.
  3. Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
  4. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; The First Hospital, Shanxi Medical University, Taiyuan, Shanxi Province, China.
  5. Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45267, USA.
  6. Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  7. Critical Illness Research, Lawson Health Research Institute, ON N6A 4G5, Canada.
  8. Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. Electronic address: [email protected].

PMID: 26300484 PMCID: PMC4581992 DOI: 10.1016/j.bbadis.2015.08.010

Abstract

Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.

Copyright © 2015 Elsevier B.V. All rights reserved.

Keywords: Cardiac dysfunction; Exosomes; Inflammatory response; Macrophages; Sepsis

References

  1. Crit Care Med. 2004 Mar;32(3):818-25 - PubMed
  2. Biochim Biophys Acta. 2014 May;1842(5):701-11 - PubMed
  3. Crit Care. 2002 Dec;6(6):500-8 - PubMed
  4. Crit Care. 2007;11(5):R107 - PubMed
  5. J Biol Chem. 2001 Dec 21;276(51):47950-7 - PubMed
  6. Chest. 2000 Aug;118(2):503-8 - PubMed
  7. Am J Respir Crit Care Med. 2013 Jun 15;187(12):1303-7 - PubMed
  8. Circ Res. 2004 Dec 10;95(12):1140-53 - PubMed
  9. Shock. 2006 Jan;25(1):43-9 - PubMed
  10. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):431-6 - PubMed
  11. Crit Care Med. 2012 Aug;40(8):2390-9 - PubMed
  12. J Immunol. 2013 May 15;190(10):5152-60 - PubMed
  13. Biochim Biophys Acta. 2015 Jan;1852(1):1-11 - PubMed
  14. Nat Rev Rheumatol. 2014 Jun;10(6):356-64 - PubMed
  15. Scand J Immunol. 2006 Mar;63(3):151-4 - PubMed
  16. Free Radic Biol Med. 2007 Jul 1;43(1):90-9 - PubMed
  17. BMJ. 2007 Oct 27;335(7625):879-83 - PubMed
  18. J Clin Invest. 1993 May;91(5):2314-9 - PubMed
  19. Circ Res. 2004 Oct 1;95(7):700-7 - PubMed
  20. J Cell Sci. 2002 Jun 15;115(Pt 12):2505-15 - PubMed
  21. Crit Care Med. 2001 Jul;29(7):1303-10 - PubMed
  22. Crit Care. 2007;11(6):R120 - PubMed
  23. J Biol Chem. 2010 Jun 4;285(23):17442-52 - PubMed
  24. Nat Med. 2003 May;9(5):517-24 - PubMed
  25. N Engl J Med. 2003 Jan 9;348(2):138-50 - PubMed
  26. Crit Care Res Pract. 2012;2012:896430 - PubMed
  27. Nat Immunol. 2013 Aug;14(8):793-803 - PubMed
  28. Ann Intern Med. 1990 Aug 1;113(3):227-42 - PubMed
  29. Mol Cancer. 2014;13:88 - PubMed
  30. Am J Physiol Heart Circ Physiol. 2002 Jun;282(6):H2316-23 - PubMed
  31. Crit Care. 2008;12(6):R158 - PubMed
  32. J Immunol. 2014 Jun 1;192(11):5324-31 - PubMed
  33. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H800-6 - PubMed
  34. J Mol Cell Cardiol. 2014 Sep;74:139-50 - PubMed
  35. Crit Care Med. 2007 Feb;35(2):358-64 - PubMed
  36. J Immunol. 2005 Jun 1;174(11):7268-77 - PubMed
  37. Blood. 2007 Nov 1;110(9):3234-44 - PubMed
  38. Blood. 2014 Dec 11;124(25):3669-70 - PubMed
  39. J Allergy Clin Immunol. 2013 Apr;131(4):1194-203, 1203.e1-14 - PubMed
  40. J Cell Physiol. 2013 Jul;228(7):1584-93 - PubMed
  41. J Clin Invest. 1985 Oct;76(4):1539-53 - PubMed
  42. Crit Care Med. 2011 Jul;39(7):1739-48 - PubMed
  43. Curr Angiogenes. 2013;2(1):54-59 - PubMed
  44. J Biol Chem. 2007 Aug 31;282(35):25779-89 - PubMed

Publication Types

Grant support