Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin


Phospholipase A2 (PLA2) activity was measured in the serum of 23 individuals infused intravenously with endotoxin (EN) at a dose of 4 ng/kg body weight. A marked increase in PLA2 was noted 3 h after EN challenge (mean 828 ± 513 units/ml), reached its maximum at 24 h after the challenge (mean 2667 ± 2442 units/ ml), and was still evident at 48 h (mean 763 ± 366 units/ml). In contrast, TNF levels were maximal (mean 712 ± 375 pg/ml) 90 min after the EN challenge and subsided to very low values (5 ± 5 pg/ml) 5 h after the challenge. There was a positive correlation between the maximum response of TNF and that of PLA2 (r = 0.82,P < 0.01). Administration of ibuprofen or pentoxifylline did not alter the PLA2 response. EN challenge did not affect serum pancreatic PLA2 concentration or that of the lysosomal cationic enzyme, lysozyme. Neutralizing antibody against human recombinant (synovial type) PLA2 completely abolished PLA2 activity in the sera tested. We conclude that EN infusions cause marked intravascular release of nonpancreatic secretory PLA2 and that the magnitude of this response seems to be related to the prior generation of TNF.

This is a preview of subscription content, log in to check access.


  1. 1.

    Hesse, D. G., K. J. Tracey, Y. Fong, K. R. Manogue, M. A. Palladino, Jr., A. Cerami, G. T. Shires, andS. F. Lowry. 1988. Cytokine appearance in human endotoxemia and primate bacteremia.Surg. Gynecol. Obstet. 166:147–153.

  2. 2.

    Michie, H. R., K. R. Manogue, D. R. Spriggs, A. Revhaug, S. O'Dwyer, C. A. Dinarello, A. Cerami, S. M. Wolff, andD. W. Wilmore. 1988. Detection of circulating tumor necrosis factor after endotoxin administration.N. Engl. J. Med. 318:1481–1486.

  3. 3.

    Suffredini, A. F., R. E. Fromm, M. M. Parker, et al. 1989. The cardiovascular response of normal humans to the: administration of endotoxin.N. Engl. J. Med. 321:280–287.

  4. 4.

    Engelhardt, R., A. Mackensen, C. Galanos, andR. Andreesen. 1990. Biological response to intravenously administered endotoxin in patients with advanced cancer.J. Biol. Resp. Mod. 9:480–491.

  5. 5.

    Cannon, J. G., R. G. Tompkins, J. A. Gelfand, H. R. Michie, G. G. Stanford, J. W. van der Meer, S. Endres, G. Lonnemann, J. Corsetti, B. Chernow, et al. 1990. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever.J. Infect. Dis. 161:79–84.

  6. 6.

    Engelhardt, R., A. Mackensen, andC. Galanos. 1991. Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients.Cancer Res. 51:2524–2530.

  7. 7.

    Shalaby, M. R., A. Waage, L. Aarden, andT. Espevik. 1989. Endotoxin, tumor necrosis factor-α and interleukin 1 induce interleukin 6 production in vivo.Clin. Immun. Immunopathol. 53:488–498.

  8. 8.

    Martich, G. D., R. L. Danner, M. Ceska, andA. F. Suffredini. 1991. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: The effect of antiinflammatory agents.J. Exp. Med. 173:1021–1024.

  9. 9.

    Van Zee, K. J., L. E. DeForge, E. Fischer, M. A. Marano, J. S. Kenney, D. G. Remick, S. F. Lowry, andL. L. Moldawer. 1991. IL-8 in septic shock, endotoxemia, and after IL-1 administration.J. Immunol. 146:3478–3482.

  10. 10.

    Danner, R. L., A. F. Suffredini, A. L. Van Dervort, M. Ceska, P. L. Stuetz, J. A. Zablotny, andE. A. Patterson. 1990. Detection of interleukin 6 (IL-6) and interleukin 8 (IL-8) during septic shock in humans.Clin. Res. 38:352A.

  11. 11.

    Vadas, P., andJ. B. Hay. 1983. Involvement of circulating phospholipase A2 in the pathogenesis of the hemodynamic changes in endotoxin shock.Can. J. Physiol. Pharmacol. 61:561–566.

  12. 12.

    Vadas, P., W. Pruzanski, andE. Stefanski. 1988. Extracellular phospholipase A2: Causative agent in circulatory collapse of septic shock?Agents Actions 24:320–325.

  13. 13.

    Vadas, P., W. Pruzanski, E. Stefanski, L. G. Ellies, J. E. Aubin, A. Sos, andA. Melcher. 1991. Extracellular phospholipase A2 secretion is a common effector pathway of interleukin-1 and tumor necrosis factor action.Immunol. Lett. 28:187–194.

  14. 14.

    Vadas, P., W. Pruzanski, E. Stefanski, B. Sternby, R. Mustard, J. Bohnen, I. Fraser, V. Farewell, andC. Bombardier. 1988. Pathogenesis of hypotension in septic shock: Correlation of circulating phospholipase A2 levels with circulatory collapse.Crit, Care Med. 16:1–7.

  15. 15.

    Stefanski, E., W. Pruzanski, B. Sternby, andP. Vadas. 1986. Purification of a soluble phospholipase A2 from synovial fluid in rheumatoid arthritis.J. Biochem. 100:1297–1303.

  16. 16.

    Sternby, B., andB. Akerstrom. 1984. Immunoreactive pancreatic colipase, lipase and phospholipase A2 in human plasma and urine from healthy individuals.Biochim. Biophys. Acta 789:164–169.

  17. 17.

    Osserman, E. F., andD. P. Lawlor. 1967. Serum and urinary lysozyme (muramidase) in monocytic and monomyelocytic leukemia.J. Exp. Med. 124:921–952.

  18. 18.

    Pruzanski, W., andM. E. Platts. 1970. Serum and urinary proteins, lysozyme (muramidase), and renal dysfunction in mono and myelomonocytic leukemia.J. Clin. Invest. 49:1694–1708.

  19. 19.

    Beutler, B., N. Krochin, I. W. Milsark, C. Luedke, andA. Cerami. 1986. Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance.Science 232:977–980.

  20. 20.

    Tracey, K. J., B. Beutler, S. F. Lowry, J. Merryweather, S. Wolpe, I. W. Milsark, R. J. Hariri, T. I. Fahey III,A. Zentella, andJ. D. Albert. 1986. Shock and tissue injury induced by recombinant human cachectin.Science 234:470–473.

  21. 21.

    Tracey, K. J., S. F. Lowry, T. J. Fahey III,J. D. Albert, Y. Fonc, D. Hesse, B. Beutler, K. R. Manogue, S. Galvano, H. Wei, A. Cerami, andG. T. Shirer. 1987. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog.Surg. Gynecol. Obstet. 164:415–422.

  22. 22.

    Vadas, P., andJ. B. Hay. 1980. The release of phospholipase A2 from aggregated platelets and stimulated macrophages of sheep.Life Sci. 26:1721–1729.

  23. 23.

    Pruzanski, W., P. Vadas, andE. Stefanski. 1985. Activity of phospholipase A2 in sera and synovial fluids in arthritis.J. Rheumatol. 12:211–216.

  24. 24.

    Pruzanski, W., andP. Vadas. 1988. Secretory synovial fluid phospholipase A2 and its role in the pathogenesis of inflammation in arthritis.J. Rheumatol. 15:1601–1603.

  25. 25.

    Seilhamer, J. J., W. Pruzanski, P. Vadas, S. Plant, J. A. Miller, J. Kloss, andL. K. Johnson. 1989. Cloning and recombinant expression of phospholipase A2 present in rheumatoid arthritic synovial fluid.J. Biol. Chem. 264:5335–5338.

  26. 26.

    Kramer, R. M., C. Hession, B. Johansen, G. Hayes, P. McGray, E. P. Chow, R. Tizard, andR. B. Pepinsky. 1989. Structure and properties of a human nonpancreatic phospholipase A2.J. Biol. Chem. 264:5768–5775.

  27. 27.

    Pruzanski, W., P. Vadas, andV. Fornasier. 1986. Inflammatory effect of intradermal administration of soluble phospholipase A2 in rabbits.J. Invest. Dermatol. 86:380–383.

  28. 28.

    Vadas, P., W. Pruzanski, J. Kim, andV. Fornasier. 1989. The proinflammatory effect of intra-articular injection of soluble human and venom phospholipase A2.Am. J. Pathol. 134:807–811.

  29. 29.

    Bomalaski, J. S., P. Lavton, andJ. L. Browning. 1991. Human extracellular recombinant phospholipase A2 induces an inflammatory response in rabbit joints.J. Immunol. 146:3904–3910.

  30. 30.

    Edelson, J. D., P. Vadas, J. Villar, J. B. Mullen, andW. Pruzanski. 1991. Acute lung injury induced by phospholipase A2. Structural and functional changes.Am. Rev. Respir. Dis. 143:11–20.

  31. 31.

    Sedor, J. R., T. W. Sedlak, K. Hornbuckle, W. H. Herman, andM. Konieczkowski. 1991. Inflammatory cytokines induce expression of a non-pancreatic (type II) mesangial cell phospholipase A2 mRNA in a highly regulated manner.J. Am. Soc. Nephrol. 1:481.

  32. 32.

    Oka, S., andH. Arita. 1991. Inflammatory factors stimulate expression of group II phospholipase A2 in rat cultured astrocytes. Two distinct pathways of the gene expression.J. Biol. Chem. 266:9956–9960.

  33. 33.

    Chang, J., S. C. Gilman, andA. J. Lewis. 1986. Interleukin 1 activates phospholipase A2 in rabbit chondrocytes: A possible signal for IL-1 action.J. Immunol. 136:1283–1287.

  34. 34.

    Chin, J. E., andY. Lin. 1988. Effects of recombinant human interleukin-1β on rabbit articular chondrocytes. Stimulation of prostanoid release and inhibition of cell growth.Arthritis Rheum. 31:1290–1296.

  35. 35.

    Suffys, P., F. Van Roy, W. Fiers. 1988. Tumor necrosis factor and interleukin 1 activate phospholipase in rat chondrocytes.FEBS Lett. 232:24–28.

  36. 36.

    Pfeilschifter, J., W. Pignat, F. Marki, andI. Wiesenberg. 1989. Release of phospholipase A2 activity from rat vascular smooth muscle cells mediated by cAMP.Eur. J. Biochem. 181:237–242.

  37. 37.

    Pfeilschifter, J., W. Pignat, K. Vosbeck, andF. Marki. 1989. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells.Biochem. Biophys. Res. Commun. 159:385–394.

  38. 38.

    Spriggs, D. R., M. L. Sierman, K. Imamura, M. Mohri, C. Rodriguez, G. Robbins, andD. W. Kufe. 1990. Phospholipase A2 activation and autoinduction of tumor necrosis factor gene expression by tumor necrosis factor.Cancer Res. 50:7101–7107.

  39. 39.

    Mohri, M., D. R. Spriggs, andD. Kufe. 1990. Effects of lipopolysaccharide on phospholipase A2 activity and tumor necrosis factor expression in HL-60 cells.J. Immunol. 144:2678–2682.

  40. 40.

    Bauldry, S. A., C. E. McCall, S. L. Cousart, andD. A. Bass. 1991. Tumor necrosis factor-α priming of phospholipase A2 activation in human neutrophils. An alternative mechanism of priming.J. Immunol. 146:1277–1285.

  41. 41.

    Revhaug, A., H. R. Michie, J. M. Manson, J. M. Waters, C. A. Dinarello, S. M. Wolff, andD. W. Wilmore. 1988. Inhibition of cyclo-oxygenase attenuates the metabolic response to endotoxin in humans.Arch. Surg. 123:162–170.

  42. 42.

    Kettelhut, I. C., W. Fiers, andA. L. Goldberg. 1987. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors.Proc. Natl. Acad. Sci. U.S.A. 84:4273–4277.

  43. 43.

    Morton, A. R., P.Vadas, E.Stefanski, W.Pruzanski, and A.Pierratos. 1989. Increased levels of phospholipase A2 in renal failure patients. American Society of Nephrology 22nd Annual Meeting.

  44. 44.

    Vadas, P., W.Pruzanski, and V.Farewell. 1991. A predictive model for the clearance of soluble phospholipase A2 during septic shock.J. Lab. Clin. Med(in press).

  45. 45.

    Davidson, F. F., E. A. Dennis, M. Powell, andJ. R. Glenney, Jr. 1987. Inhibition of phospholipase A2 by “lipocortins” and calpactins. An effect of binding to substrate phospholipids.J. Biol. Chem. 262:1698–1705.

  46. 46.

    Conricorde, K. M., andR. S. Ochs. 1989. Mechanism for the inhibitory and stimulatory actions of proteins on the a activity of phospholipase A2.Biochim. Biophys. Acta 1003:36–43.

  47. 47.

    Nakano, T., andH. Arita. 1990. Enhanced expression of group II phospholipase A2 gene in the tissues of endotoxin shock rats and its suppression by glucocorticoids.FEBS Lett. 273:23–26.

  48. 48.

    Nakano, T., O. Ohara, H. Teraoka, andH. Arita. 1990. Group II phospholipase A2 mRNA synthesis is stimulated by two distinct mechanisms in rat vascular smooth muscle cells.FEBS Lett. 261:171–174.

  49. 49.

    Green, J. A., G. M. Smith, R. Buchta, R. Lee, K. Y. Ho, I. A. Rajkovic, andK. F. Scott. 1991. Circulating phospholipase A2 activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritis.Inflammation 15:355–367.

  50. 50.

    Okusawa, S., J. A. Gelfand, T. Ikejima, R. J. Conolly, andC. A. Dinarello. 1988. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition.J. Clin. Invest. 81:1162–1172.

  51. 51.

    Heath, M. F., D. Tighe, R. Moss, andE. D. Bennett. 1990. Relevance of serum phospholipase A2 assays to the assessment of septic shock.Crit. Care Med. 18:766–767.

  52. 52.

    Waxman, K. 1990. Pentoxifylline in septic shock.Crit. Care Med. 18:243–244.

  53. 53.

    Tighe, D., R. Moss, M. F. Heath, J. Hynd, andE. D. Bennett. 1989. Pentoxifylline reduces pulmonary leukostasis and improves capillary patency in a rabbit peritonitis model.Circ. Shock 28:159–164.

  54. 54.

    Rossignol, L., M. Plantavid, H. Chap, andL. Douste-Blazy. 1988. Effects of two methylxanthines, pentoxifylline and propenfylline on arachidonic acid metabolism in platelets stimulated by thrombin.Biochem. Pharmacol. 37:3229–3236.

  55. 55.

    Bessler, H., R. Gilgal, M. Djaldetti, andI. Zahavi. 1986. Effect of pentoxifylline on the phagocytic activity, cAMP levels and Superoxide anion production by monocytes and polymorphonuclear cells.J. Leukocyte Biol. 40:747–754.

  56. 56.

    Scott, K. F. 1991. Phospholipase A2: A new target for monoclonal antibody therapy in sepsis. Abstracts 2nd international congress on the immune consequences of trauma, shock and sepsis mechanisms and therapeutic approaches. Munich. 46.

  57. 57.

    Buchta, R., J. A.Green, G. M.Smith, and K.Scott. 1991.E. coli-induced septic shock in the baboon: An animal model for the evaluation of neutralising monoclonal antibodies to phospholipase A2. Abstracts 2nd international congress on the immune consequences of trauma and sepsis mechanisms and therapeutic approaches. Munich. 86.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pruzanski, W., Wilmore, D.W., Suffredini, A. et al. Hyperphospholipasemia A2 in human volunteers challenged with intravenous endotoxin. Inflammation 16, 561–570 (1992).

Download citation


  • Public Health
  • Body Weight
  • Internal Medicine
  • Ibuprofen
  • Lysozyme