Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
December-2017 Volume 14 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
December-2017 Volume 14 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

  • Authors:
    • Dongmei Zhao
    • Renyu Ding
    • Yina Liu
    • Xiaohan Yin
    • Zhidan Zhang
    • Xiaochun Ma
  • View Affiliations / Copyright

    Affiliations: Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
  • Pages: 5515-5522
    |
    Published online on: September 29, 2017
       https://doi.org/10.3892/etm.2017.5236
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis‑associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)‑induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR in vitro using human umbilical vein endothelial cells (HUVECs). The in vivo data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS‑induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose‑dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS‑induced activation of mitogen‑activated protein kinase 14, proto‑oncogene tyrosine‑protein kinase Src and nuclear factor κB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

View References

1 

Cohen J: The immunopathogenesis of sepsis. Nature. 420:885–891. 2002. View Article : Google Scholar : PubMed/NCBI

2 

Annane D, Bellissant E and Cavaillon JM: Septic shock. Lancet. 365:63–78. 2005. View Article : Google Scholar : PubMed/NCBI

3 

Levi M, van der Poll T and Büller HR: Bidirectional relation between inflammation and coagulation. Circulation. 109:2698–2704. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Opal SM and Esmon CT: Bench-to-bedside review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit Care. 7:23–38. 2003. View Article : Google Scholar : PubMed/NCBI

5 

Schouten M, Wiersinga WJ, Levi M and van der Poll T: Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 83:536–545. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Esmon CT: The protein C pathway. Chest. 124 3 Suppl:26S–32S. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Van de Wouwer M, Collen D and Conway EM: Thrombomodulin-protein C-EPCR system: Integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol. 24:1374–1383. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Miyazaki Y, Inoue T, Kyi M, Sawada M, Miyake S and Yoshizawa Y: Effects of a neutrophil elastase inhibitor (ONO-5046) on acute pulmonary injury induced by tumor necrosis factor alpha (TNFalpha) and activated neutrophils in isolated perfused rabbit lungs. Am J Respir Crit Care Med. 157:89–94. 1998. View Article : Google Scholar : PubMed/NCBI

9 

Qu D, Wang Y, Esmon NL and Esmon CT: Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. J Thromb Haemost. 5:395–402. 2007. View Article : Google Scholar : PubMed/NCBI

10 

Xu J, Qu D, Esmon NL and Esmon CT: Metalloproteolytic release of endothelial cell protein C receptor. J Biol Chem. 275:6038–6044. 2000. View Article : Google Scholar : PubMed/NCBI

11 

Bemard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB and Helterbrand JD: Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med. 29:2051–2059. 2001. View Article : Google Scholar : PubMed/NCBI

12 

Bemard GR: Drotrecogin alfa (activated) (recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med. 31 1 Suppl:S85–S93. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Fowler RA, Hill-Popper M, Stasinos J, Petrou C, Sanders GD and Garber AM: Cost-effective of recombinant human activated protein C and the influence of severity of illness in the treatment of patients with severe sepsis. J Crit Care. 18:181–194. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D and Cardona AF: Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev. 12:CD0043882012.PubMed/NCBI

15 

Cornet AD, Smit EG, Beishuizen A and Groeneveld AB: The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost. 98:579–586. 2007.PubMed/NCBI

16 

Li Y, Sun JF, Cui X, Mani H, Danner RL, Li X, Su JW, Fitz Y and Eichacker PQ: The effect of heparin administration in animal models of sepsis: A prospective study in Escherichia coli-challenged mice and a systematic review and metaregression analysis of published studies. Crit Care Med. 39:1104–1112. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Zhao D, Ding R, Mao Y, Wang L, Zhang Z and Ma X: Heparin rescues sepsis-associated acute lung injury and lethality through the suppression of inflammatory responses. Inflammation. 35:1825–1832. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Wildhagen KC, de Frutos García P, Reutelingsperger CP, Schrijver R, Aresté C, Ortega-Gómez A, Deckers NM, Hemker HC, Soehnlein O and Nicolaes GA: Nonanticoagulant heparin prevents histone-mediated cytotoxicity in vitro and improves survival in sepsis. Blood. 123:1098–1101. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Ding R, Zhao D, Guo R, Zhang Z and Ma X: Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice. Thromb Res. 128:e160–e165. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Li X, Zheng Z, Li X and Ma X: Unfractionated heparin inhibits lipopolysaccharide-induced inflammatory response through blocking P38 MAPK and NF-κB activation on endothelial cell. Cytokine. 60:114–121. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Li X, Zheng Z, Mao Y and Ma X: Unfractionated heparin promotes LPS-induced endothelial barrier dysfunction: A preliminary study on the roles of angiopoietin/Tie2 axis. Thromb Res. 129:e223–e228. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Li X, Li X, Zheng Z, Liu Y and Ma X: Unfractionated heparin suppresses lipopolysaccharide-induced monocyte chemoattractant protein-1 expression in human microvascular endothelial cells by blocking Krüppel-like factor 5 and nuclear factor-κB pathway. Immunobiology. 219:778–785. 2014. View Article : Google Scholar : PubMed/NCBI

23 

National Research Council, . Guide for the care and use of laboratory animals (8th edition). The National Academies Press; Washington DC: 2011

24 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Mu E, Ding R, An X, Li X, Chen S and Ma X: Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and TGF-β/Smad signaling pathway. Thromb Res. 129:479–485. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Hayashi T and Suzuki K: Changes of expression of the protein C pathway components in LPS-induced endotoxemia-implication for sepsis. Cardiovasc Hematol Disord Drug Targets. 15:2–9. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Redini F, Tixier JM, Petitou M, Choay J, Robert L and Hornebeck W: Inhibition of leucocyte elastase by heparin and its derivatives. Biochem J. 252:515–519. 1988. View Article : Google Scholar : PubMed/NCBI

28 

Kenagy RD, Nikkari ST, Welgus HG and Clowes AW: Heparin inhibits the induction of three matrix metalloproteinases (stromelysin, 92-kD gelatinase and collagenase) in primate arterial smooth muscle cells. J Clin Invest. 93:1987–1993. 1994. View Article : Google Scholar : PubMed/NCBI

29 

Terada Y, Eguchi Y, Nosaka S, Toba T, Nakamura T and Shimizu Y: Capillary endothelial thrombomodulin expression and fibrin deposition in rats with continuous and bolus lipopolysaccharide administration. Lab Invest. 83:1165–1173. 2003. View Article : Google Scholar : PubMed/NCBI

30 

Gao XH, Xu XX, Pan R, Li Y, Luo YB, Xia YF, Murata K, Matsuda H and Dai Y: Saponin fraction from Astragalus membranaceus roots protects mice against polymicrobial sepsis induced by cecal ligation and puncture by inhibiting inflammation and upregulating protein C pathway. J Nat Med. 63:421–429. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Vignoli A, Marchetti M, Balducci D, Barbui T and Falanga A: Differential effect of the low-molecular-weight heparin, dalteparin, and unfractionated heparin on microvascular endothelial cell hemostatic properties. Haematologica. 91:207–214. 2006.PubMed/NCBI

32 

Faioni EM, Fontana G, Razzari C, Avagliano L, Bulfamante G, Calvi E, Doi P and Marconi AM: Activation of protein C in human trophoblasts in culture and downregulation of trophoblast endothelial protein C receptor by TNF-α. Reprod Sci. 22:1042–1048. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Ishii H, Uchiyama H and Kazama M: Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost. 65:618–623. 1991.PubMed/NCBI

34 

Song D, Ye X, Xu H and Liu SF: Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice. Blood. 114:2521–2529. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Menschikowski M, Hagelgans A, Eisenhofer G and Siegert G: Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Exp Cell Res. 315:2673–2682. 2009. View Article : Google Scholar : PubMed/NCBI

36 

Lo IC, Lin TM, Chou LH, Liu SL, Wu LW, Shi GY, Wu HL and Jiang MJ: Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells. Cardiovasc Res. 81:771–779. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Wang C, Chi C, Guo L, Wang X, Guo L, Sun J, Sun B, Liu S, Chang X and Li E: Heparin therapy reduces 28-day mortality in adult severe sepsis patients: A systematic review and meta-analysis. Crit Care. 18:5632014. View Article : Google Scholar : PubMed/NCBI

38 

Zarychanski R, About-Setta AM, Kanji S, Turgeon AF, Kumar A, Houston DS, Rimmer E, Houston BL, McIntyre L, Fox-Robichaud AE, et al: The efficacy and safety of heparin in patients with sepsis: A systemati review and metaanalysis. Crit Care Med. 43:511–518. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zhao D, Ding R, Liu Y, Yin X, Zhang Z and Ma X: Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro. Exp Ther Med 14: 5515-5522, 2017.
APA
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., & Ma, X. (2017). Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro. Experimental and Therapeutic Medicine, 14, 5515-5522. https://doi.org/10.3892/etm.2017.5236
MLA
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., Ma, X."Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro". Experimental and Therapeutic Medicine 14.6 (2017): 5515-5522.
Chicago
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., Ma, X."Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro". Experimental and Therapeutic Medicine 14, no. 6 (2017): 5515-5522. https://doi.org/10.3892/etm.2017.5236
Copy and paste a formatted citation
x
Spandidos Publications style
Zhao D, Ding R, Liu Y, Yin X, Zhang Z and Ma X: Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro. Exp Ther Med 14: 5515-5522, 2017.
APA
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., & Ma, X. (2017). Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro. Experimental and Therapeutic Medicine, 14, 5515-5522. https://doi.org/10.3892/etm.2017.5236
MLA
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., Ma, X."Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro". Experimental and Therapeutic Medicine 14.6 (2017): 5515-5522.
Chicago
Zhao, D., Ding, R., Liu, Y., Yin, X., Zhang, Z., Ma, X."Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro". Experimental and Therapeutic Medicine 14, no. 6 (2017): 5515-5522. https://doi.org/10.3892/etm.2017.5236
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team