PAF and TNFα Interactions in the Pathophysiology of Septic Shock

  • Reuven Rabinovici
  • Tian Li Yue
  • Jerome Vernick
  • Giora Feuerstein
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 314)


The septic shock syndrome is a medical emergency caused in part by the release into the circulation of bacterial lipopolysaccharide (LPS) endotoxin. The evolving concept in the pathophysiology of septic shock suggests that endotoxin induces its detrimental effects indirectly through the production of multiple mediators among which platelet activating factor (PAF) and tumor necrosis factor-a (TNFa) play a major role. The role of PAF and TNFa in endotoxemia was inferred from the following observations: 1 ) many of the manifestations of septic shock such as hypotension, hemoconcentration, thrombocytopenia and leukopenia can be produced by PAF and TNFa (Table 1 ); 2) elevated levels of PAF and TNFa were found in various septic conditions (Table 2); and 3) PAF antagonists and anti-TNFa neutralizing antibodies were shown to convey significant protection in animal models of septic shock (Table 3).


Septic Shock Disseminate Intravascular Coagulation Lipid Mediator Endotoxic Shock Produce Oxygen Radical 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    G. Camussi, F. Bussolino, G. Salvido, and C. Baglioni, J Exp Med 166: 1390 (1987).PubMedCrossRefGoogle Scholar
  2. 2.
    F. Bussolino, F. Breviario, N. Aglietta, F. Sanavio, A. Bosia, and E. Dejana, Biochim Biophys Acta 927: 43 (1987).PubMedCrossRefGoogle Scholar
  3. 3.
    F. Bussolino, F. Breviario, C. Tetta, M. Aglietta, A. Mantovani, and E. Dejana, J Clin Invest 77: 2027 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    F. Bussolino, G. Camussi, and C. Baglioni, J Biol Chem 263: 11856 (1988).PubMedGoogle Scholar
  5. 5.
    H. Hayashi, I. Kudo, T. Kato, and K. Inoue, iin: “Platelet-activating factor and diseases,” K. Saito, and D. J. Hanahan, eds., Int Med Publishers, Tokyo (1989).Google Scholar
  6. 6.
    B. Bonavida, J. M. Mencia-Huerta, and P. Braquet, J Lipid Mediators (in press).Google Scholar
  7. 7.
    B. Bonavida, J. M. Mencia-Huerta, and P. Braquet, J Allergy Appl Immunol (in press).Google Scholar
  8. 8.
    M. Rola-Pleszczyski, J. Bosse, E. Bissonnette, and C. Dubois, Prostaglandins 35: 802(1988).CrossRefGoogle Scholar
  9. 9.
    M. Paubert-Braquet, P. Koltz, M. O. Longchamp, J. Guilbaud, D. Hosford, and P. Braquet, J Lipid Mediators (in press).Google Scholar
  10. 10.
    A. Floch, A. Bousseau, E. Hetier, F. Floch, P-E. Bost, and I. Cavero, J Lipid Mediators 1: 349 (1989).Google Scholar
  11. 11.
    X-M. Sun, and W. Hsueh, J Clin Invest 81: 1328 (1988).PubMedCrossRefGoogle Scholar
  12. 12.
    M. G. Sirois, G. E. Plante, J. J. Oppenheim, P. Braquet, and P. Sirois, J Lipid Mediators (in press).Google Scholar
  13. 13.
    D. Howat, F. Desa, C. Chander, A. Moore, and D. A. Willoughby, J Lipid Mediators (in press).Google Scholar
  14. 14.
    J. S. Warren, P. A. Barton, D. M. Mandel, and K. Matrosic, Lab Invest 63: 764 (1990).Google Scholar
  15. 15.
    H. Heuer, and K. H. Webber, Prostaglandins 35: 814 (1988).CrossRefGoogle Scholar
  16. 16.
    X-M. Sun, W. Hsueh, and G. Torre-Amione, Am J Pathol 136: 949 (1990).PubMedGoogle Scholar
  17. 17.
    A. K. Myers, J. W. Robey, and R. M. Price, Br J Pharmacol 99: 499 (1990).PubMedGoogle Scholar
  18. 18.
    T-L Yue, R. Rabinovici, M. Farhat, and G. Feuerstein, J Lipid Mediators 3: 13 (1991).Google Scholar
  19. 19.
    T-L. Yue, R. Rabinovici, M. Farhat, and G. Feuerstein, Prostaglandins 39: 469 (1990).PubMedCrossRefGoogle Scholar
  20. 20.
    R. Rabinovici, T-L. Yue, M. Farhat, E. F. Smith III, M. Slivjak, and G. Feuerstein, J Pharmacol Exp Ther 255: 256 (1990).PubMedGoogle Scholar
  21. 21.
    S. W. Chang, C. O. Fedderson, P. M. Henson, and N. F. Voelkel, J Clin Invest 79: 1498(1987).PubMedCrossRefGoogle Scholar
  22. 22.
    T-L Yue, M. Farhat, R. Rabinovici, P. Y. Perera, S. N. Vogel, and G. Feuerstein, J Pharmacol Exp Ther 254: 976 (1990).PubMedGoogle Scholar
  23. 23.
    K. E. Stephens, A. Ishizaka, J. W. Larrick, and T. A. Raffin, Am Rev Respir Dis 137: 1364(1988).PubMedGoogle Scholar
  24. 24.
    D. C. Hocking, P. G. Phillips, T. J. Ferro, and A. Johnson, Circ Res 67: 68 (1990).PubMedGoogle Scholar
  25. 25.
    M. L Dustin, R. Rothlein, A. K. Bhan, C. A. Dinarello, and T. A. Springer, J Immunol 137: 245 (1986).PubMedGoogle Scholar
  26. 26.
    M. P. Bevilacqua, M. E. Wheeler, J. S. Pober, W. Fiers, D. L Mendrick, R. S. Cotran, and M. A. Gimbrone, in: “Leukocyte Emigration and its Sequelae,” H. Z. Movat, ed., Karger, Basel (1987).Google Scholar
  27. 27.
    H. Shennib, R. C. Chiu, D. S. Mulder, G. K. Richards, and J. Prentis, Am Rev Resp Dis 130: 444 (1984).PubMedGoogle Scholar
  28. 28.
    N. B. Vedder, B. W. Fouty, R. K. Winn, J. M. Harlan, and C. L Rice, Surgery 106: 509(1989).PubMedGoogle Scholar
  29. 29.
    D. C. Morrison and R. J. Ulevitch, Am J Pathol 93: 527 (1978).Google Scholar
  30. 30.
    J. A. Cook, W. C. Wise, and P. V. Halushka, J Clin Invest 65: 227 (1980).PubMedCrossRefGoogle Scholar
  31. 31.
    W. W. Spink and J. Vick, J Exp Med 114: 501 (1961).PubMedCrossRefGoogle Scholar
  32. 32.
    W. W. Spink, R. B. Davis, R. Potter, and S. Chartrand, J Clin Invest 43: 696 (1964).PubMedCrossRefGoogle Scholar
  33. 33.
    C. G. Cochrane, in: “Handbook of Endotoxin,” L. B. Hinshaw, ed., Elsevier, Amsterdam, New York, Tokyo (1985).Google Scholar
  34. 34.
    G. F. Evans and S. H. Zuckerman, Agents and Actions 26: 329 (1989).PubMedCrossRefGoogle Scholar
  35. 35.
    G. Feuerstein, J. M. Hallenbeck, B. Vanatta, R. Rabinovici, P. Y. Perara, and S. N. Vogel, Circ Shock 30: 265 (1990).PubMedGoogle Scholar
  36. 36.
    A. Wagga, Clin Immunol Immunopathl 45: 348 (1987).CrossRefGoogle Scholar
  37. 37.
    G. J. Bagby, J. J. Thompson, L A. Wilson, and R. M. Hazel, Circ Shock 28: 385 (1989).PubMedGoogle Scholar
  38. 38.
    J. C. Mathison, E. Wolfson, and R. J. Ulevitch, J Clin Invest 81: 1925 (1988).PubMedCrossRefGoogle Scholar
  39. 39.
    B. Beutler, I. W. Milsark, and A. Cerami, J Immun 135: 3972 (1985).PubMedGoogle Scholar
  40. 40.
    K. J. Tracey, Y. Fong, D. J. Hesse, K. R. Manouge, A. T. Lee, G. C. Kuo, S. F. Lowry, and A. Cerami, Nature 330: 662 (1987).PubMedCrossRefGoogle Scholar
  41. 41.
    D. G. Hesse, K. J. Tracey, Y. Fong, K. R. Manouge, M. A. Palladino, A. Cerami, T. Shires, and S. F. Lowry, Surg Gynecol Obstet 166: 147 (1988).PubMedGoogle Scholar
  42. 42.
    H. R. Michie, K. R. Manouge, D. R. Spriggs, A. Revhaug, S. O’Dwyer, C. A. Dinarello, A. Cerami, S. M. Wolff, and D. W. Wilmore, N Engl J Med 318: 1481 (1988).Google Scholar
  43. 43.
    T. Doebber, M. Wu, J. Robbins, B. Choy, M. Chang, and T. Shen, Biochem Biophys Res Commun 127: 799 (1985).PubMedCrossRefGoogle Scholar
  44. 44.
    F. Bussolino, M. G. Porcellini, L. Varese, and A. Bosia, Throm Res 48: 619 (1987).CrossRefGoogle Scholar
  45. 45.
    Z. Terashita, Y. Imura, K. Nishikawa, and S. Sumida, Eur J Pharmacol 109: 257 (1985).PubMedCrossRefGoogle Scholar
  46. 46.
    A. Etienne, F. Hecquet, C. Soulard, B. Spinnewyn, F. Clostre, and P. Braquet, Agents and Actions 17: 368 (1985).CrossRefGoogle Scholar
  47. 47.
    J. Casals-Stenzel, Eur J Pharmacol 135: 117 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    J. Fletcher, M. Earnest, J. Moore, A. Disimone, and N. Abumard, Circ Shock 27: 359(1989).Google Scholar
  49. 49.
    B. Beutler, I. W. Milsark, and A. Cerami, Science 229: 869 (1985).PubMedCrossRefGoogle Scholar
  50. 50.
    J. C. Mathison, E. Wolfson, and R. J. Ulevitch, J Clin Invest 81: 1925 (1988).PubMedCrossRefGoogle Scholar
  51. 51.
    K. J. Tracey, Y. Fong, D. J. Hesse, K. R. Manouge, A. T. Lee, G. C. Kuo, S. F. Lowry, and A. Cerami, Nature 330: 662 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Reuven Rabinovici
    • 2
  • Tian Li Yue
    • 1
  • Jerome Vernick
    • 2
  • Giora Feuerstein
    • 1
  1. 1.Department of Cardiovascular PharmacologySmithKline Beecham PharmaceuticalsKing of PrussiaUSA
  2. 2.Department of SurgeryJefferson Medical CollegePhiladelphiaUSA

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