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. 1993 Jun;217(6):668–675. doi: 10.1097/00000658-199306000-00008

Tumor necrosis factor-induced mortality is reversed with cyclooxygenase inhibition.

J R Fletcher 1, J N Collins 1, E D Graves 3rd 1, A Luterman 1, M D Williams 1, S D Izenberg 1, C B Rodning 1
PMCID: PMC1242873  PMID: 8507112

Abstract

OBJECTIVE: The authors hypothesized that TNF would induce eicosanoid synthesis, and a cyclooxygenase inhibitor would attenuate both eicosanoid synthesis and improve survival in an LD90 TNF-induced (150 ng/kg/i.v./5 min) mortality model. SUMMARY BACKGROUND DATA: Tumor necrosis factor is a cardinal mediator in sepsis; however, little is known about its effects on arachidonate metabolism. METHODS: Conscious male rats with carotid arterial and jugular venous catheters were randomized for mortality: group I, TNF alone (150 kg/i.v./15 min, n = 30); group II, ibuprofen (30 mg/kg/i.v. at t = -20 and +240 min), plus TNF, (n = 28); and for hemodynamics, eicosanoid synthesis, blood gases: group III, TNF alone, (n = 8); group IV, ibuprofen + TNF (n = 8); group V, monoclonal antibody to TNF plus TNF (n = 8). Mortality was determined at 4-72 hr. Other parameters determined over 4 hours (0, 5, 60, 120, 240 min). RESULTS: TNF stimulated synthesis of (a) TXB2 (71 +/- 30 pg/ml, mean +/- SE at base vs. 117 +/- 18 at 4 hr, p < 0.02); (b) PGE2 (70 +/- 6 pg/ml at base vs. 231 +/- 68 at 4 hr, p < 0.02); (c) 6PGF (52 +/- 6 pg/ml at base vs. 250 +/- 80 at 4 hr, p < 0.02). Ibuprofen significantly (p < 0.05) inhibited eicosanoid synthesis from TNF. TNF-induced mortality (87%, 26/30) was dramatically decreased with ibuprofen (11%, 3/28), at 4, 24, and 72 hr (p < 0.01). Monoclonal antibody to TNF prevented all abnormalities and had 100% survival. Hemodynamic events were similar in both groups, but metabolic acidosis was attenuated with ibuprofen. CONCLUSIONS: TNF stimulates arachidonic acid metabolism in vivo. A cyclooxygenase inhibitor attenuates eicosanoid synthesis and dramatically improves survival. TNF appears to have different effect on tissues that synthesize certain eicosanoids. Hypotension from TNF is not mediated via the eicosanoids. TNF-induced mortality, like endotoxemia/sepsis may be mediated, in part, via arachidonic acid metabolites. These new findings support the notion that cyclooxygenase inhibitors may be used as adjunctive therapy in clinical sepsis.

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Selected References

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  1. Bachwich P. R., Chensue S. W., Larrick J. W., Kunkel S. L. Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun. 1986 Apr 14;136(1):94–101. doi: 10.1016/0006-291x(86)90881-8. [DOI] [PubMed] [Google Scholar]
  2. Baud L., Perez J., Friedlander G., Ardaillou R. Tumor necrosis factor stimulates prostaglandin production and cyclic AMP levels in rat cultured mesangial cells. FEBS Lett. 1988 Oct 24;239(1):50–54. doi: 10.1016/0014-5793(88)80543-x. [DOI] [PubMed] [Google Scholar]
  3. Bauss F., Dröge W., Männel D. N. Tumor necrosis factor mediates endotoxic effects in mice. Infect Immun. 1987 Jul;55(7):1622–1625. doi: 10.1128/iai.55.7.1622-1625.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  5. Bevilacqua M. P., Pober J. S., Wheeler M. E., Cotran R. S., Gimbrone M. A., Jr Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion. Am J Pathol. 1985 Dec;121(3):394–403. [PMC free article] [PubMed] [Google Scholar]
  6. Burch R. M., Tiffany C. W. Tumor necrosis factor causes amplification of arachidonic acid metabolism in response to interleukin 1, bradykinin, and other agonists. J Cell Physiol. 1989 Oct;141(1):85–89. doi: 10.1002/jcp.1041410113. [DOI] [PubMed] [Google Scholar]
  7. Camussi G., Bussolino F., Salvidio G., Baglioni C. Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor. J Exp Med. 1987 Nov 1;166(5):1390–1404. doi: 10.1084/jem.166.5.1390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ciancio M. J., Hunt J., Jones S. B., Filkins J. P. Comparative and interactive in vivo effects of tumor necrosis factor alpha and endotoxin. Circ Shock. 1991 Feb;33(2):108–120. [PubMed] [Google Scholar]
  9. Damas P., Reuter A., Gysen P., Demonty J., Lamy M., Franchimont P. Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med. 1989 Oct;17(10):975–978. doi: 10.1097/00003246-198910000-00001. [DOI] [PubMed] [Google Scholar]
  10. Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ertel W., Morrison M. H., Wang P., Ba Z. F., Ayala A., Chaudry I. H. The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin, and interleukins. Ann Surg. 1991 Aug;214(2):141–148. doi: 10.1097/00000658-199108000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Evans D. A., Jacobs D. O., Revhaug A., Wilmore D. W. The effects of tumor necrosis factor and their selective inhibition by ibuprofen. Ann Surg. 1989 Mar;209(3):312–321. doi: 10.1097/00000658-198903000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Feingold K. R., Doerrler W., Dinarello C. A., Fiers W., Grunfeld C. Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin-1, and the interferons is blocked by inhibition of prostaglandin synthesis. Endocrinology. 1992 Jan;130(1):10–16. doi: 10.1210/endo.130.1.1370149. [DOI] [PubMed] [Google Scholar]
  14. Feuerstein G., Hallenbeck J. M., Vanatta B., Rabinovici R., Perera P. Y., Vogel S. N. Effect of gram-negative endotoxin on levels of serum corticosterone, TNF alpha, circulating blood cells, and the survival of rats. Circ Shock. 1990 Mar;30(3):265–278. [PubMed] [Google Scholar]
  15. Fletcher J. R., Ramwell P. W. Lidocaine or indomethacin improves survival in baboon endotoxin shock. J Surg Res. 1978 Mar;24(3):154–160. doi: 10.1016/0022-4804(78)90168-3. [DOI] [PubMed] [Google Scholar]
  16. Fletcher J. R. The role of prostaglandins in sepsis. Scand J Infect Dis Suppl. 1982;31:55–60. [PubMed] [Google Scholar]
  17. Haliday E. M., Ramesha C. S., Ringold G. TNF induces c-fos via a novel pathway requiring conversion of arachidonic acid to a lipoxygenase metabolite. EMBO J. 1991 Jan;10(1):109–115. doi: 10.1002/j.1460-2075.1991.tb07926.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hesse D. G., Tracey K. J., Fong Y., Manogue K. R., Palladino M. A., Jr, Cerami A., Shires G. T., Lowry S. F. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet. 1988 Feb;166(2):147–153. [PubMed] [Google Scholar]
  19. Hinshaw L. B., Solomon L. A., Erdös E. G., Reins D. A., Gunter B. J. Effects of acetylsalicylic acid on the canine response to endotoxin. J Pharmacol Exp Ther. 1967 Sep;157(3):665–671. [PubMed] [Google Scholar]
  20. Hinshaw L. B., Tekamp-Olson P., Chang A. C., Lee P. A., Taylor F. B., Jr, Murray C. K., Peer G. T., Emerson T. E., Jr, Passey R. B., Kuo G. C. Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circ Shock. 1990 Mar;30(3):279–292. [PubMed] [Google Scholar]
  21. Jacobs E. R., Soulsby M. E., Bone R. C., Wilson F. J., Jr, Hiller F. C. Ibuprofen in canine endotoxin shock. J Clin Invest. 1982 Sep;70(3):536–541. doi: 10.1172/JCI110645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kettelhut I. C., Fiers W., Goldberg A. L. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4273–4277. doi: 10.1073/pnas.84.12.4273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Koike K., Hirota K., Ohmichi M., Kadowaki K., Ikegami H., Yamaguchi M., Miyake A., Tanizawa O. Tumor necrosis factor-alpha increases release of arachidonate and prolactin from rat anterior pituitary cells. Endocrinology. 1991 Jun;128(6):2791–2798. doi: 10.1210/endo-128-6-2791. [DOI] [PubMed] [Google Scholar]
  24. Kunkel S. L., Spengler M., May M. A., Spengler R., Larrick J., Remick D. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem. 1988 Apr 15;263(11):5380–5384. [PubMed] [Google Scholar]
  25. Larrick J. W., Graham D., Toy K., Lin L. S., Senyk G., Fendly B. M. Recombinant tumor necrosis factor causes activation of human granulocytes. Blood. 1987 Feb;69(2):640–644. [PubMed] [Google Scholar]
  26. Mathison J. C., Wolfson E., Ulevitch R. J. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest. 1988 Jun;81(6):1925–1937. doi: 10.1172/JCI113540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Matthews N., Neale M. L., Jackson S. K., Stark J. M. Tumour cell killing by tumour necrosis factor: inhibition by anaerobic conditions, free-radical scavengers and inhibitors of arachidonate metabolism. Immunology. 1987 Sep;62(1):153–155. [PMC free article] [PubMed] [Google Scholar]
  28. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  29. Myers A. K., Robey J. W., Price R. M. Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice. Br J Pharmacol. 1990 Mar;99(3):499–502. doi: 10.1111/j.1476-5381.1990.tb12957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Natanson C., Eichenholz P. W., Danner R. L., Eichacker P. Q., Hoffman W. D., Kuo G. C., Banks S. M., MacVittie T. J., Parrillo J. E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989 Mar 1;169(3):823–832. doi: 10.1084/jem.169.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pober J. S., Bevilacqua M. P., Mendrick D. L., Lapierre L. A., Fiers W., Gimbrone M. A., Jr Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol. 1986 Mar 1;136(5):1680–1687. [PubMed] [Google Scholar]
  32. Remick D. G., Kunkel R. G., Larrick J. W., Kunkel S. L. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest. 1987 Jun;56(6):583–590. [PubMed] [Google Scholar]
  33. Remick D. G., Strieter R. M., Eskandari M. K., Nguyen D. T., Genord M. A., Raiford C. L., Kunkel S. L. Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations. Am J Pathol. 1990 Jan;136(1):49–60. [PMC free article] [PubMed] [Google Scholar]
  34. Short B. L., Miller M. K., Fletcher J. R. Improved survival in the suckling rat model of group B streptococcal sepsis after treatment with nonsteroidal anti-inflammatory drugs. Pediatrics. 1982 Sep;70(3):343–347. [PubMed] [Google Scholar]
  35. Simpson S. Q., Casey L. C. Role of tumor necrosis factor in sepsis and acute lung injury. Crit Care Clin. 1989 Jan;5(1):27–47. [PubMed] [Google Scholar]
  36. Suffys P., Beyaert R., De Valck D., Vanhaesebroeck B., Van Roy F., Fiers W. Tumour-necrosis-factor-mediated cytotoxicity is correlated with phospholipase-A2 activity, but not with arachidonic acid release per se. Eur J Biochem. 1991 Jan 30;195(2):465–475. doi: 10.1111/j.1432-1033.1991.tb15727.x. [DOI] [PubMed] [Google Scholar]
  37. Talmadge J. E., Bowersox O., Tribble H., Lee S. H., Shepard H. M., Liggitt D. Toxicity of tumor necrosis factor is synergistic with gamma-interferon and can be reduced with cyclooxygenase inhibitors. Am J Pathol. 1987 Sep;128(3):410–425. [PMC free article] [PubMed] [Google Scholar]
  38. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  39. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  40. Tracey K. J., Lowry S. F., Fahey T. J., 3rd, Albert J. D., Fong Y., Hesse D., Beutler B., Manogue K. R., Calvano S., Wei H. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet. 1987 May;164(5):415–422. [PubMed] [Google Scholar]
  41. Turner C. R., Esser K. M., Wheeldon E. B., Slivjak M., Smith E. F., 3rd Cardiovascular and pulmonary effects of human recombinant tumor necrosis factor in the conscious rat. Circ Shock. 1989 Aug;28(4):369–384. [PubMed] [Google Scholar]
  42. Waage A. Production and clearance of tumor necrosis factor in rats exposed to endotoxin and dexamethasone. Clin Immunol Immunopathol. 1987 Dec;45(3):348–355. doi: 10.1016/0090-1229(87)90087-0. [DOI] [PubMed] [Google Scholar]
  43. Warren R. S., Starnes H. F., Jr, Alcock N., Calvano S., Brennan M. F. Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo. Am J Physiol. 1988 Aug;255(2 Pt 1):E206–E212. doi: 10.1152/ajpendo.1988.255.2.E206. [DOI] [PubMed] [Google Scholar]
  44. Wise W. C., Cook J. A., Eller T., Halushka P. V. Ibuprofen improves survival from endotoxic shock in the rat. J Pharmacol Exp Ther. 1980 Oct;215(1):160–164. [PubMed] [Google Scholar]

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