The calcium channel blocker nisoldipine minimizes the release of tumor necrosis factor and interleukin-6 following rat liver transplantation

  • E. Savier
  • R. G. Thurman
  • J. J. Lemasters
  • S. I. Shedlofsky
  • A. T. Swim
Conference paper

Abstract

Kupffer cells, when activated, release toxic cytokines such as tumor necrosis factor (TNF), which can cause tissue injury. Takei et al. have reported that nisoldipine, a calcium channel blocker which decreases phagocytotic activity by Kupffer cells, also diminishes liver and lung injury and dramatically improves survival following liver transplantation [27]. Therefore, we studied the effect of nisoldipine on the time course of TNF and interleukin-6 (IL-6) release following cold storage and liver transplantation in the rat. Livers were stored under survival and non-survival conditions in cold Euro-Collins solution in the presence or absence of nisoldipine (1.4 µM). After storage, the effluent was collected for determination of cytokines. The liver was then transplanted orthotopically and serum was collected at various time intervals for up to 5 h. In the effluent, TNF levels were very low in both the control and nisoldipine-treated groups and IL-6 was not measurable. Furthermore, when livers were stored under survival conditions and transplanted (liver stored in the cold for 4 h), serum TNF (2 U/ml) and IL-6 (350 U/ml) values were minimal in both the control and nisoldipine-treated groups. In contrast, when livers were stored under non-survival conditions and transplanted (liver stored in the cold for 10 h), TNF levels increased to 15 ±2 U/ml, 150 min after graft reperfusion, an increase which was prevented by nisoldipine (6.5 U/ml). Serum IL-6 levels were also elevated 300 min after transplantation in livers stored for 10 h. Nisoldipine also reduced the release of this cytokine. Serum transaminases (SGOT) were elevated to values around 2000 U/l 5 h following transplantation. In the nisoldipine-treated group, values were lower between 60 and 300 min. In the lung, interstitial and alveolar edema and cellular infiltration were detectable 5 h postoperatively and were diminished by nisoldipine. These data confirmed that TNF and IL-6 release were minimal following cold storage and transplantation of livers stored under survival conditions, but were elevated transiently after transplantation under non-survival conditions. Nisoldipine prevented cytokine release, most likely by blocking the activation of Kupffer cells, which may explain how it decreases liver and lung injury very early following liver transplantation.

Key words

Nisoldipine Tumor necrosis factor Interleukin-6 Liver transplantation 

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References

  1. 1.
    Aarden LA, de Groot ER, Schaap OL, Landsdorp PM (1987) Production of hybridoma growth factor by human monocytes. Eur J Immunol 17:1411–1416PubMedCrossRefGoogle Scholar
  2. 2.
    Akira S, Hirano T, Taga T, Kishimoto T (1990) Biology of multifunctional cytokines: IL 6 and related molecules (IL1 andTNF). FASEB J 4:2860–2867PubMedGoogle Scholar
  3. 3.
    Bergmeyer HU (1988) Methods of Enyzmatic Analysis. Academic Press, New YorkGoogle Scholar
  4. 4.
    Beutler B, Cerami A (1988) The history, properties, and biological effects of cachectin. Biochemistry 27:7575–7582PubMedCrossRefGoogle Scholar
  5. 5.
    Bouma JMW, Smit MJ (1989) Gadolinium chloride selectively blocks endocytosis by Kupffer cells. In: Wisse E, Knook DL, Decker K (eds) Cells of the hepatic sinusoid II. The Kupffer Cell Foundation, Rijswijk, The Netherlands, pp 132–133Google Scholar
  6. 6.
    Caldwell-Kenkel JC, Currin RT, Tanaka Y, Thurman RG, Lemasters JJ (1989) Reperfusion injury to endothelial cells following cold ischemic storage of rat liver. Hepatology 10:292–299PubMedCrossRefGoogle Scholar
  7. 7.
    Colletti LM, Burtch GD, Remick DG, Kunkel SL, Strieter RM, Guice KS, Oldham KT, Campbell DA (1990) The production of tumor necrosis factor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion. Transplantation 49:268–272PubMedCrossRefGoogle Scholar
  8. 8.
    Connor HD, Gao W, Nukina S, Lemasters JJ, Mason RP, Thurman RG (1991) Free radicals are involved in graft failure following orthotopic liver transplantation: An EPR spin trapping study. Transplantation (submitted)Google Scholar
  9. 9.
    Currin RT, Lichtman SN, Thurman RG, Lemasters JJ (1991) Pentoxifylline, adenosine, prostaglandin E1 and nisoldipine inhibit tumor necrosis factor release from LPS-stimulated rat Kupffer cells. Hepatology (in press)Google Scholar
  10. 10.
    Decker K (1990) Biologically active products of stimulated liver macrophages (Kupffer cells). Eur J Biochem 192:245–261PubMedCrossRefGoogle Scholar
  11. 11.
    Ford HR, Hoffman RA, Tweardy DJ, Kispert P, Wang S, Simmons RL (1991) Evidence that production of interleukin-6 within the rejecting allograft coincides with cytotoxic lymphocyte-T development. Transplantation 51:656–661PubMedCrossRefGoogle Scholar
  12. 12.
    Greig PD, Woolf GM, Sinclair SB, Abecassis M, Strasberg SM, Taylor BR, Blendis LM, Superina RA, Glynn MFX, Langer B, Levy GA (1989) Treatment of primary liver graft nonfunction with prostaglandin E1. Transplantation 48:447–453PubMedCrossRefGoogle Scholar
  13. 13.
    Heinrich PC, Castell JV, Andus T (1990) Interleukin-6 and the acute phase response. Biochem J 265:621–636PubMedGoogle Scholar
  14. 14.
    Hess P, Lansman JB, Tsien RW (1984) Different modes of Ca channel gating behavior favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–544PubMedCrossRefGoogle Scholar
  15. 15.
    Hijioka T, Rosenberg RL, Lemasters JJ, Thurman RG (1991) Rat Kupffer cells contain voltage-dependent calcium channels: Studies with Bay K-8644. FASEB J 5: A1390Google Scholar
  16. 16.
    Hocking DC, Phillips PG, Ferro TJ, Johnson A (1990) Mechanisms of pulmonary edema induced by tumor necrosis factor-α. Circ Res 67:68–77PubMedCrossRefGoogle Scholar
  17. 17.
    Kamada N, Calne RY (1979) Orthotopic liver transplantation in the rat. Technique using cuff for portal vein anastomosis and biliary drainage. Transplantation 28:47–50PubMedCrossRefGoogle Scholar
  18. 18.
    Karck U, Peters T, Decker K (1988) The release of tumor necrosis factor from endotoxin-stimulated rat Kupffer cells is regulated by prostaglandin E2 and dexamethasone. J Hepatology 7: 352–361CrossRefGoogle Scholar
  19. 19.
    Kramer SM, Carver ME (1986) Serum-free in vitro bioassay for the detection of tumor necrosis factor. J Immunol Methods 93: 201–206PubMedCrossRefGoogle Scholar
  20. 20.
    Kuiper J, Zijlstra FJ, Kamps JAAM, Berkel TJC van (1988) Identification of prostaglandin D2 as the major eicosanoid from liver endothelial and Kupffer cells. Biochim Biophys Acta 959: 143–152PubMedCrossRefGoogle Scholar
  21. 21.
    Kuiper J, Zijlstra FJ, Kamps JAAM, Berkel TJC van (1989) Cellular communication inside the liver. Biochem J 262:195–201PubMedGoogle Scholar
  22. 22.
    Mathison JC, Wolfson E, Ulevitch RJ (1988) Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 81: 1925–1937PubMedCrossRefGoogle Scholar
  23. 23.
    Miyata T, Todo S, Imventarza O, Furukawa H, Starzl TE (1989) Endogenous endotoxemia during orthotopic liver transplantation in dogs. Transplant Proc 21:3861–3862PubMedGoogle Scholar
  24. 24.
    Post S, Goerig M, Otto G, Manner M, Senninger N, Kommerell B, Herfarth C (1990) Prostanoid release in experimental liver transplantation. Transplantation 49:490–494PubMedCrossRefGoogle Scholar
  25. 25.
    Schindler R, Mancilla J, Endres S, Ghorbani R, Clark S, Dinarello CA (1990) Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75:40–47PubMedGoogle Scholar
  26. 26.
    Steel RGD, Torrie JH (1980) Principles and procedures in statistics: A biometric approach. McGraw-Hill, New YorkGoogle Scholar
  27. 27.
    Takei Y, Marzi I, Kauffman FC, Currin RT, Lemasters JJ, Thurman RG (1990) Increase in survival time of liver transplants by protease inhibitors and a calcium channel blocker, nisoldipine. Transplantation 50:14–20PubMedCrossRefGoogle Scholar
  28. 28.
    Thurman RG, Cowper KB, Marzi I, Currin RT, Lemasters JJ (1988) Activation of Kupffer cells by storage of the liver in Euro-Collins solution. Hepatology 8:261Google Scholar
  29. 29.
    Thurman RG, Marzi I, Seitz G, Thies J, Lemasters JJ, Zimmermann FA (1988) Hepatic reperfusion injury following orthotopic liver transplantation in the rat. Transplantation 46:502–506PubMedCrossRefGoogle Scholar
  30. 30.
    Tiegs G, Wolter M, Wendel A (1989) Tumor necrosis factor is a terminal mediator in galactosamine/endotoxin-induced hepatitis in mice. Biochem Pharmacol 38:627–631PubMedCrossRefGoogle Scholar
  31. 31.
    Tilg H, Vogel W, Aulitzky WE, Herold M, Konigsrainer A, Margreiter R, Huber C (1990) Evaluation of cytokines and cytokine-induced secondary messages in sera of patients after liver transplantation. Transplantation 49:1074–1080PubMedCrossRefGoogle Scholar
  32. 32.
    Wang JF, Wendel A (1990) Studies on the hepatotoxicity of galactosamine/endotoxin or galactosamine/TNF in the perfused mouse liver. Biochem Pharmacol 39:267–270PubMedCrossRefGoogle Scholar
  33. 33.
    Zimmermann FA, Butcher GW, Davies HS, Brons G, Kamada N, Turel O (1979) Techniques of orthotopic liver transplantation in the rat and some studies of the immunologic response to fully allogeneic liver grafts. Transplant Proc 1:571–577Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • E. Savier
    • 1
  • R. G. Thurman
    • 1
  • J. J. Lemasters
    • 2
  • S. I. Shedlofsky
    • 3
  • A. T. Swim
    • 3
  1. 1.Toxicology Department of PharmacologyLaboratory of HepatobiologyUSA
  2. 2.Laboratory for Cell Biology, Department of Cell Biology and AnatomyThe University of North Carolina at Chapel HillChapel HillUSA
  3. 3.Veterans Affairs HospitalUniversity of KentuckyLexingtonUSA

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