Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Oct;82(4):1321–1325. doi: 10.1172/JCI113733

Tumor necrosis factor and the acute metabolic response to tissue injury in man.

H F Starnes Jr 1, R S Warren 1, M Jeevanandam 1, J L Gabrilove 1, W Larchian 1, H F Oettgen 1, M F Brennan 1
PMCID: PMC442686  PMID: 3139712

Abstract

Tumor necrosis factor (cachectin), a protein produced by monocytes and macrophages, has been implicated as an important mediator of the lethal effects of endotoxic shock and the cachexia of chronic infection. Recombinant human tumor necrosis factor alpha (rTNF) was given intravenously to patients as part of an antineoplastic trial. Fever, tachycardia, and at higher doses, hypotension occurred after a single injection of rTNF. Metabolic effects after rTNF administration were dose related and included enhanced energy expenditure with elevated CO2 production, increased whole body protein metabolism and peripheral amino acid efflux from the forearm, and decreased total arterial amino acid levels associated with a significant increase in plasma cortisol. Elevated serum triglycerides, as well as increased glycerol and free fatty acid turnover were seen, suggesting increased whole body lipolysis and fat utilization after rTNF. These findings indicate that administration of TNF in man reproduces many of the acute physiologic and metabolic responses to tissue injury, including energy substrate mobilization.

Full text

PDF
1321

Selected References

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

  1. Aoki T. T., Brennan M. F., Fitzpatrick G. F., Knight D. C. Leucine meal increases glutamine and total nitrogen release from forearm muscle. J Clin Invest. 1981 Dec;68(6):1522–1528. doi: 10.1172/JCI110406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bessey P. Q., Watters J. M., Aoki T. T., Wilmore D. W. Combined hormonal infusion simulates the metabolic response to injury. Ann Surg. 1984 Sep;200(3):264–281. doi: 10.1097/00000658-198409000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  4. Beutler B., Greenwald D., Hulmes J. D., Chang M., Pan Y. C., Mathison J., Ulevitch R., Cerami A. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature. 1985 Aug 8;316(6028):552–554. doi: 10.1038/316552a0. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Birkhahn R. H., Long C. L., Fitkin D., Jeevanandam M., Blakemore W. S. Whole-body protein metabolism due to trauma in man as estimated by L-[15N]alanine. Am J Physiol. 1981 Jul;241(1):E64–E71. doi: 10.1152/ajpendo.1981.241.1.E64. [DOI] [PubMed] [Google Scholar]
  7. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. DOLE V. P., MEINERTZ H. Microdetermination of long-chain fatty acids in plasma and tissues. J Biol Chem. 1960 Sep;235:2595–2599. [PubMed] [Google Scholar]
  9. Dresler C. M., Jeevanandam M., Brennan M. F. Extremity blood flow in man: comparison between strain-gauge and capacitance plethysmography. Surgery. 1987 Jan;101(1):35–39. [PubMed] [Google Scholar]
  10. Feingold K. R., Grunfeld C. Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo. J Clin Invest. 1987 Jul;80(1):184–190. doi: 10.1172/JCI113046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jeevanandam M., Brennan M. F., Horowitz G. D., Rose D., Mihranian M. H., Daly J., Lowry S. F. Tracer priming in human protein turnover studies with [15N]glycine. Biochem Med. 1985 Oct;34(2):214–225. doi: 10.1016/0006-2944(85)90114-0. [DOI] [PubMed] [Google Scholar]
  12. Jeevanandam M., Lowry S. F., Horowitz G. D., Legaspi A., Brennan M. F. Influence of increasing dietary intake on whole body protein kinetics in normal man. Clin Nutr. 1986 Feb;5(1):41–48. doi: 10.1016/0261-5614(86)90041-5. [DOI] [PubMed] [Google Scholar]
  13. Kawakami M., Pekala P. H., Lane M. D., Cerami A. Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1982 Feb;79(3):912–916. doi: 10.1073/pnas.79.3.912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kurzrock R., Rohde M. F., Quesada J. R., Gianturco S. H., Bradley W. A., Sherwin S. A., Gutterman J. U. Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients. J Exp Med. 1986 Oct 1;164(4):1093–1101. doi: 10.1084/jem.164.4.1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kushner I. The phenomenon of the acute phase response. Ann N Y Acad Sci. 1982;389:39–48. doi: 10.1111/j.1749-6632.1982.tb22124.x. [DOI] [PubMed] [Google Scholar]
  16. Legaspi A., Jeevanandam M., Starnes H. F., Jr, Brennan M. F. Whole body lipid and energy metabolism in the cancer patient. Metabolism. 1987 Oct;36(10):958–963. doi: 10.1016/0026-0495(87)90132-6. [DOI] [PubMed] [Google Scholar]
  17. Nordenström J., Carpentier Y. A., Askanazi J., Robin A. P., Elwyn D. H., Hensle T. W., Kinney J. M. Free fatty acid mobilization and oxidation during total parenteral nutrition in trauma and infection. Ann Surg. 1983 Dec;198(6):725–735. doi: 10.1097/00000658-198312000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pekala P. H., Kawakami M., Angus C. W., Lane M. D., Cerami A. Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1983 May;80(9):2743–2747. doi: 10.1073/pnas.80.9.2743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Picou D., Taylor-Roberts T. The measurement of total protein synthesis and catabolism and nitrogen turnover in infants in different nutritional states and receiving different amounts of dietary protein. Clin Sci. 1969 Apr;36(2):283–296. [PubMed] [Google Scholar]
  20. Rosenblatt S., Clowes G. H., Jr, George B. C., Hirsch E., Lindberg B. Exchange of amino acids by muscle and liver in sepsis. Arch Surg. 1983 Feb;118(2):167–175. doi: 10.1001/archsurg.1983.01390020023004. [DOI] [PubMed] [Google Scholar]
  21. Rouzer C. A., Cerami A. Hypertriglyceridemia associated with Trypanosoma brucei brucei infection in rabbits: role of defective triglyceride removal. Mol Biochem Parasitol. 1980 Oct;2(1):31–38. doi: 10.1016/0166-6851(80)90046-8. [DOI] [PubMed] [Google Scholar]
  22. Simmons P. S., Miles J. M., Gerich J. E., Haymond M. W. Increased proteolysis. An effect of increases in plasma cortisol within the physiologic range. J Clin Invest. 1984 Feb;73(2):412–420. doi: 10.1172/JCI111227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. 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]
  26. Wannemacher R. W., Jr Key role of various individual amino acids in host response to infection. Am J Clin Nutr. 1977 Aug;30(8):1269–1280. doi: 10.1093/ajcn/30.8.1269. [DOI] [PubMed] [Google Scholar]
  27. Warren R. S., Donner D. B., Starnes H. F., Jr, Brennan M. F. Modulation of endogenous hormone action by recombinant human tumor necrosis factor. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8619–8622. doi: 10.1073/pnas.84.23.8619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Warren R. S., Starnes H. F., Jr, Gabrilove J. L., Oettgen H. F., Brennan M. F. The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg. 1987 Dec;122(12):1396–1400. doi: 10.1001/archsurg.1987.01400240042007. [DOI] [PubMed] [Google Scholar]
  29. Wilmore D. W., Long J. M., Mason A. D., Jr, Skreen R. W., Pruitt B. A., Jr Catecholamines: mediator of the hypermetabolic response to thermal injury. Ann Surg. 1974 Oct;180(4):653–669. doi: 10.1097/00000658-197410000-00031. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES