Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1987 Jan;79(1):124–130. doi: 10.1172/JCI112772

Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro.

K L Moore, S P Andreoli, N L Esmon, C T Esmon, N U Bang
PMCID: PMC424004  PMID: 3025256

Abstract

Endotoxemia is frequently associated clinically with disseminated intravascular coagulation (DIC); however, the mechanism of endotoxin action in vivo is unclear. Modulation of tissue factor (TF) and thrombomodulin (TM) expression on the endothelial surface may be relevant pathophysiologic mechanisms. Stimulation of human umbilical vein endothelial cells with endotoxin (1 microgram/ml) increased surface TF activity from 1.52 +/- 0.84 to 11.89 +/- 8.12 mU/ml-10(6) cells at 6 h (n = 11) which returned to baseline by 24 h. Repeated stimulation at 24 h resulted in renewed TF expression. Endotoxin (1 microgram/ml) also caused a decrease in TM expression to 55.0 +/- 6.4% of control levels at 24 h (n = 10) that remained depressed at 48 h. Both effects were dose and serum dependent. A temporary rise in TF expression accompanied by a sustained fall in TM expression comprise a shift in the hemostatic properties of the endothelium that would favor intravascular coagulation and may contribute to the pathogenesis of DIC in gram-negative septicemia.

Full text

PDF
124

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andreoli S. P., Baehner R. L., Bergstein J. M. In vitro detection of endothelial cell damage using 2-deoxy-D-3H-glucose: comparison with chromium 51, 3H-leucine, 3H-adenine, and lactate dehydrogenase. J Lab Clin Med. 1985 Sep;106(3):253–261. [PubMed] [Google Scholar]
  2. Bevilacqua M. P., Pober J. S., Majeau G. R., Cotran R. S., Gimbrone M. A., Jr Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med. 1984 Aug 1;160(2):618–623. doi: 10.1084/jem.160.2.618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brigham K. L., Woolverton W. C., Blake L. H., Staub N. C. Increased sheep lung vascular permeability caused by pseudomonas bacteremia. J Clin Invest. 1974 Oct;54(4):792–804. doi: 10.1172/JCI107819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brox J. H., Osterud B., Bjørklid E., Fenton J. W., 2nd Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets. Br J Haematol. 1984 Jun;57(2):239–246. doi: 10.1111/j.1365-2141.1984.tb02892.x. [DOI] [PubMed] [Google Scholar]
  5. Broze G. J., Jr, Majerus P. W. Purification and properties of human coagulation factor VII. J Biol Chem. 1980 Feb 25;255(4):1242–1247. [PubMed] [Google Scholar]
  6. Colucci M., Balconi G., Lorenzet R., Pietra A., Locati D., Donati M. B., Semeraro N. Cultured human endothelial cells generate tissue factor in response to endotoxin. J Clin Invest. 1983 Jun;71(6):1893–1896. doi: 10.1172/JCI110945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colucci M., Paramo J. A., Collen D. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest. 1985 Mar;75(3):818–824. doi: 10.1172/JCI111777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Comp P. C., Esmon C. T. Generation of fibrinolytic activity by infusion of activated protein C into dogs. J Clin Invest. 1981 Nov;68(5):1221–1228. doi: 10.1172/JCI110368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Comp P. C., Nixon R. R., Cooper M. R., Esmon C. T. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest. 1984 Dec;74(6):2082–2088. doi: 10.1172/JCI111632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Edwards R. L., Perla D. The effect of serum on monocyte tissue factor generation. Blood. 1984 Sep;64(3):707–714. [PubMed] [Google Scholar]
  11. Esmon C. T., Esmon N. L., Harris K. W. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem. 1982 Jul 25;257(14):7944–7947. [PubMed] [Google Scholar]
  12. Esmon C. T., Owen W. G. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2249–2252. doi: 10.1073/pnas.78.4.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Esmon N. L., DeBault L. E., Esmon C. T. Proteolytic formation and properties of gamma-carboxyglutamic acid-domainless protein C. J Biol Chem. 1983 May 10;258(9):5548–5553. [PubMed] [Google Scholar]
  14. Fulcher C. A., Gardiner J. E., Griffin J. H., Zimmerman T. S. Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V. Blood. 1984 Feb;63(2):486–489. [PubMed] [Google Scholar]
  15. Griffin J. H. Clinical studies of protein C. Semin Thromb Hemost. 1984 Apr;10(2):162–166. doi: 10.1055/s-2007-1004419. [DOI] [PubMed] [Google Scholar]
  16. Harlan J. M., Harker L. A., Striker G. E., Weaver L. J. Effects of lipopolysaccharide on human endothelial cells in culture. Thromb Res. 1983 Jan 1;29(1):15–26. doi: 10.1016/0049-3848(83)90121-4. [DOI] [PubMed] [Google Scholar]
  17. Harlan J. M., Killen P. D., Harker L. A., Striker G. E., Wright D. G. Neutrophil-mediated endothelial injury in vitro mechanisms of cell detachment. J Clin Invest. 1981 Dec;68(6):1394–1403. doi: 10.1172/JCI110390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heflin A. C., Jr, Brigham K. L. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest. 1981 Nov;68(5):1253–1260. doi: 10.1172/JCI110371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jaffe E. A., Hoyer L. W., Nachman R. L. Synthesis of antihemophilic factor antigen by cultured human endothelial cells. J Clin Invest. 1973 Nov;52(11):2757–2764. doi: 10.1172/JCI107471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jakubowski H. V., Kline M. D., Owen W. G. The effect of bovine thrombomodulin on the specificity of bovine thrombin. J Biol Chem. 1986 Mar 15;261(8):3876–3882. [PubMed] [Google Scholar]
  22. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  23. Levin E. G., Loskutoff D. J. Cultured bovine endothelial cells produce both urokinase and tissue-type plasminogen activators. J Cell Biol. 1982 Sep;94(3):631–636. doi: 10.1083/jcb.94.3.631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Loskutoff D. J., van Mourik J. A., Erickson L. A., Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci U S A. 1983 May;80(10):2956–2960. doi: 10.1073/pnas.80.10.2956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lyberg T., Galdal K. S., Evensen S. A., Prydz H. Cellular cooperation in endothelial cell thromboplastin synthesis. Br J Haematol. 1983 Jan;53(1):85–95. doi: 10.1111/j.1365-2141.1983.tb01989.x. [DOI] [PubMed] [Google Scholar]
  26. Marcum J. A., McKenney J. B., Rosenberg R. D. Acceleration of thrombin-antithrombin complex formation in rat hindquarters via heparinlike molecules bound to the endothelium. J Clin Invest. 1984 Aug;74(2):341–350. doi: 10.1172/JCI111429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Maruyama I., Salem H. H., Ishii H., Majerus P. W. Human thrombomodulin is not an efficient inhibitor of the procoagulant activity of thrombin. J Clin Invest. 1985 Mar;75(3):987–991. doi: 10.1172/JCI111800. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meyer D., Baumgartner H. R. Role of von Willebrand factor in platelet adhesion to the subendothelium. Br J Haematol. 1983 May;54(1):1–9. doi: 10.1111/j.1365-2141.1983.tb02061.x. [DOI] [PubMed] [Google Scholar]
  29. Miletich J. P., Jackson C. M., Majerus P. W. Properties of the factor Xa binding site on human platelets. J Biol Chem. 1978 Oct 10;253(19):6908–6916. [PubMed] [Google Scholar]
  30. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  31. Nawroth P. P., Handley D. A., Esmon C. T., Stern D. M. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci U S A. 1986 May;83(10):3460–3464. doi: 10.1073/pnas.83.10.3460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nawroth P. P., Stern D. M., Kisiel W., Bach R. Cellular requirements for tissue factor generation by bovine aortic endothelial cells in culture. Thromb Res. 1985 Dec 1;40(5):677–691. doi: 10.1016/0049-3848(85)90305-6. [DOI] [PubMed] [Google Scholar]
  33. Nawroth P. P., Stern D. M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1;163(3):740–745. doi: 10.1084/jem.163.3.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Owen W. G., Esmon C. T. Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. J Biol Chem. 1981 Jun 10;256(11):5532–5535. [PubMed] [Google Scholar]
  35. Sacks T., Moldow C. F., Craddock P. R., Bowers T. K., Jacob H. S. Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage. J Clin Invest. 1978 May;61(5):1161–1167. doi: 10.1172/JCI109031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Smedly L. A., Tonnesen M. G., Sandhaus R. A., Haslett C., Guthrie L. A., Johnston R. B., Jr, Henson P. M., Worthen G. S. Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase. J Clin Invest. 1986 Apr;77(4):1233–1243. doi: 10.1172/JCI112426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stern D. M., Drillings M., Nossel H. L., Hurlet-Jensen A., LaGamma K. S., Owen J. Binding of factors IX and IXa to cultured vascular endothelial cells. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4119–4123. doi: 10.1073/pnas.80.13.4119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Stern D. M., Nawroth P. P., Kisiel W., Vehar G., Esmon C. T. The binding of factor IXa to cultured bovine aortic endothelial cells. Induction of a specific site in the presence of factors VIII and X. J Biol Chem. 1985 Jun 10;260(11):6717–6722. [PubMed] [Google Scholar]
  39. Stern D., Brett J., Harris K., Nawroth P. Participation of endothelial cells in the protein C-protein S anticoagulant pathway: the synthesis and release of protein S. J Cell Biol. 1986 May;102(5):1971–1978. doi: 10.1083/jcb.102.5.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Suzuki K., Stenflo J., Dahlbäck B., Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem. 1983 Feb 10;258(3):1914–1920. [PubMed] [Google Scholar]
  41. Vigano D'Angelo S., Comp P. C., Esmon C. T., D'Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest. 1986 Feb;77(2):416–425. doi: 10.1172/JCI112319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Walker F. J., Sexton P. W., Esmon C. T. The inhibition of blood coagulation by activated Protein C through the selective inactivation of activated Factor V. Biochim Biophys Acta. 1979 Dec 7;571(2):333–342. doi: 10.1016/0005-2744(79)90103-7. [DOI] [PubMed] [Google Scholar]
  43. Weiss S. J., Young J., LoBuglio A. F., Slivka A., Nimeh N. F. Role of hydrogen peroxide in neutrophil-mediated destruction of cultured endothelial cells. J Clin Invest. 1981 Sep;68(3):714–721. doi: 10.1172/JCI110307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yamada O., Moldow C. F., Sacks T., Craddock P. R., Boogaerts M. A., Jacob H. S. Deleterious effects of endotoxin on cultured endothelial cells: an in vitro model of vascular injury. Inflammation. 1981 Jun;5(2):115–126. doi: 10.1007/BF00914201. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES