Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1990 Jun;85(6):1936–1943. doi: 10.1172/JCI114656

Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat.

L M Colletti 1, D G Remick 1, G D Burtch 1, S L Kunkel 1, R M Strieter 1, D A Campbell Jr 1
PMCID: PMC296661  PMID: 2161433

Abstract

Cytokines are recognized as critical early mediators of organ injury. We attempted to determine whether or not severe hepatic ischemia/reperfusion injury results in tumor necrosis factor-alpha (TNF-alpha) release with subsequent local and systemic tissue injury. After 90 min of lobar hepatic ischemia, TNF was measurable during the reperfusion period in the plasma of all 14 experimental animals, with levels peaking between 9 and 352 pg/ml. Endotoxin was undetectable in the plasma of these animals. Pulmonary injury, as evidenced by a neutrophilic infiltrate, edema and intra-alveolar hemorrhage developed after hepatic reperfusion. The neutrophilic infiltrate was quantitated using a myeloperoxidase (MPO) assay; this demonstrated a significant increase in MPO after only 1 h of reperfusion. Anti-TNF antiserum pretreatment significantly reduced the pulmonary MPO after hepatic reperfusion. After a 12-h reperfusion period, there was histologic evidence of intra-alveolar hemorrhage and pulmonary edema. Morphometric assessment showed that pretreatment with anti-TNF antiserum was able to completely inhibit the development of pulmonary edema. Liver injury was quantitated by measuring serum glutamic pyruvic transaminase which showed peaks at 3 and 24 h. Anti-TNF antiserum pretreatment was able to significantly reduce both of these peak elevations. These data show that hepatic ischemia/reperfusion results in TNF production, and that this TNF is intimately associated with pulmonary and hepatic injury.

Full text

PDF
1936

Images in this article

1940Image
on p.1940
1940Image
on p.1940
1940Image
on p.1940
1940Image
on p.1940
1941Image
on p.1941
1941Image
on p.1941

Selected References

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

  1. Bell R. C., Coalson J. J., Smith J. D., Johanson W. G., Jr Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med. 1983 Sep;99(3):293–298. doi: 10.7326/0003-4819-99-3-293. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. The endogenous mediator of endotoxic shock. Clin Res. 1987 Apr;35(3):192–197. [PubMed] [Google Scholar]
  3. Bevilacqua M. P., Pober J. S., Majeau G. R., Fiers W., Cotran R. S., Gimbrone M. A., Jr Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4533–4537. doi: 10.1073/pnas.83.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Colletti L. M., Burtch G. D., Remick D. G., Kunkel S. L., Strieter R. M., Guice K. S., Oldham K. T., Campbell D. A., Jr The production of tumor necrosis factor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion. Transplantation. 1990 Feb;49(2):268–272. doi: 10.1097/00007890-199002000-00008. [DOI] [PubMed] [Google Scholar]
  6. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  7. Fein A. M., Lippmann M., Holtzman H., Eliraz A., Goldberg S. K. The risk factors, incidence, and prognosis of ARDS following septicemia. Chest. 1983 Jan;83(1):40–42. doi: 10.1378/chest.83.1.40. [DOI] [PubMed] [Google Scholar]
  8. Ferrante A., Nandoskar M., Walz A., Goh D. H., Kowanko I. C. Effects of tumour necrosis factor alpha and interleukin-1 alpha and beta on human neutrophil migration, respiratory burst and degranulation. Int Arch Allergy Appl Immunol. 1988;86(1):82–91. doi: 10.1159/000234610. [DOI] [PubMed] [Google Scholar]
  9. Fowler A. A., Hamman R. F., Zerbe G. O., Benson K. N., Hyers T. M. Adult respiratory distress syndrome. Prognosis after onset. Am Rev Respir Dis. 1985 Sep;132(3):472–478. doi: 10.1164/arrd.1985.132.3.472. [DOI] [PubMed] [Google Scholar]
  10. Gamble J. R., Harlan J. M., Klebanoff S. J., Vadas M. A. Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8667–8671. doi: 10.1073/pnas.82.24.8667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
  12. Goldblum S. E., Wu K. M., Jay M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J Appl Physiol (1985) 1985 Dec;59(6):1978–1985. doi: 10.1152/jappl.1985.59.6.1978. [DOI] [PubMed] [Google Scholar]
  13. Grau G. E., Taylor T. E., Molyneux M. E., Wirima J. J., Vassalli P., Hommel M., Lambert P. H. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med. 1989 Jun 15;320(24):1586–1591. doi: 10.1056/NEJM198906153202404. [DOI] [PubMed] [Google Scholar]
  14. Hajjar K. A., Hajjar D. P., Silverstein R. L., Nachman R. L. Tumor necrosis factor-mediated release of platelet-derived growth factor from cultured endothelial cells. J Exp Med. 1987 Jul 1;166(1):235–245. doi: 10.1084/jem.166.1.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hayashi H., Chaudry I. H., Clemens M. G., Baue A. E. Hepatic ischemia models for determining the effects of ATP-MgCl2 treatment. J Surg Res. 1986 Feb;40(2):167–175. doi: 10.1016/0022-4804(86)90119-8. [DOI] [PubMed] [Google Scholar]
  16. Kawakami M., Ishibashi S., Ogawa H., Murase T., Takaku F., Shibata S. Cachectin/TNF as well as interleukin-1 induces prostacyclin synthesis in cultured vascular endothelial cells. Biochem Biophys Res Commun. 1986 Dec 15;141(2):482–487. doi: 10.1016/s0006-291x(86)80198-x. [DOI] [PubMed] [Google Scholar]
  17. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  18. Lähdevirta J., Maury C. P., Teppo A. M., Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):289–291. doi: 10.1016/0002-9343(88)90576-1. [DOI] [PubMed] [Google Scholar]
  19. Magilavy D. B., Rothstein J. L. Spontaneous production of tumor necrosis factor alpha by Kupffer cells of MRL/lpr mice. J Exp Med. 1988 Aug 1;168(2):789–794. doi: 10.1084/jem.168.2.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Matuschak G. M., Rinaldo J. E. Organ interactions in the adult respiratory distress syndrome during sepsis. Role of the liver in host defense. Chest. 1988 Aug;94(2):400–406. doi: 10.1378/chest.94.2.400. [DOI] [PubMed] [Google Scholar]
  22. Maury C. P., Teppo A. M. Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection. J Exp Med. 1987 Oct 1;166(4):1132–1137. doi: 10.1084/jem.166.4.1132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Movat H. Z. Tumor necrosis factor and interleukin-1: role in acute inflammation and microvascular injury. J Lab Clin Med. 1987 Dec;110(6):668–681. [PubMed] [Google Scholar]
  25. Nawroth P. P., Bank I., Handley D., Cassimeris J., Chess L., Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1363–1375. doi: 10.1084/jem.163.6.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Obayashi T. Addition of perchloric acid to blood samples for colorimetric limulus test using chromogenic substrate: comparison with conventional procedures and clinical applications. J Lab Clin Med. 1984 Sep;104(3):321–330. [PubMed] [Google Scholar]
  27. Pohlman T. H., Stanness K. A., Beatty P. G., Ochs H. D., Harlan J. M. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin 1, and tumor necrosis factor-alpha increases neutrophil adherence by a CDw18-dependent mechanism. J Immunol. 1986 Jun 15;136(12):4548–4553. [PubMed] [Google Scholar]
  28. 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]
  29. Remick D. G., Strieter R. M., Lynch J. P., 3rd, Nguyen D., Eskandari M., Kunkel S. L. In vivo dynamics of murine tumor necrosis factor-alpha gene expression. Kinetics of dexamethasone-induced suppression. Lab Invest. 1989 Jun;60(6):766–771. [PubMed] [Google Scholar]
  30. Saxne T., Palladino M. A., Jr, Heinegård D., Talal N., Wollheim F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. doi: 10.1002/art.1780310816. [DOI] [PubMed] [Google Scholar]
  31. Scuderi P., Sterling K. E., Lam K. S., Finley P. R., Ryan K. J., Ray C. G., Petersen E., Slymen D. J., Salmon S. E. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet. 1986 Dec 13;2(8520):1364–1365. doi: 10.1016/s0140-6736(86)92007-6. [DOI] [PubMed] [Google Scholar]
  32. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  33. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. 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]
  37. Varani J., Bendelow M. J., Sealey D. E., Kunkel S. L., Gannon D. E., Ryan U. S., Ward P. A. Tumor necrosis factor enhances susceptibility of vascular endothelial cells to neutrophil-mediated killing. Lab Invest. 1988 Aug;59(2):292–295. [PubMed] [Google Scholar]
  38. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  39. Wankowicz Z., Megyeri P., Issekutz A. Synergy between tumour necrosis factor alpha and interleukin-1 in the induction of polymorphonuclear leukocyte migration during inflammation. J Leukoc Biol. 1988 Apr;43(4):349–356. doi: 10.1002/jlb.43.4.349. [DOI] [PubMed] [Google Scholar]
  40. Warren J. S., Yabroff K. R., Remick D. G., Kunkel S. L., Chensue S. W., Kunkel R. G., Johnson K. J., Ward P. A. Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. J Clin Invest. 1989 Dec;84(6):1873–1882. doi: 10.1172/JCI114374. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES