Metabolic Brain Disease

, Volume 17, Issue 4, pp 325–334 | Cite as

Nitric Oxide in Liver Inflammation and Regeneration

  • Paloma Martin-Sanz
  • Sonsoles Hortelano
  • Nuria A. Callejas
  • Nora Goren
  • Marta Casado
  • Miriam Zeini
  • Lisardo Boscá


Hepatocytes express and release inflammatory mediators after challenge with bacterial cell wall molecules and proinflammatory cytokines. Nitric oxide synthase-2 (NOS-2) is expressed under these conditions and the high-output NO synthesis that follows contributes to the inflammatory response in this tissue and participates in the onset of several hepatopathies. However, in the course of liver regeneration, for example, after partial hepatectomy, NOS-2 is expressed at moderate levels and contributes to inhibit apoptosis and to favor progression in the cell cycle until the organ size and function are restored. The mechanisms involved in the regulation of NOS-2 expression under these conditions are revised.

Nitric oxide transcription factors liver inflammation liver regeneration apoptosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baeuerle, P.A. (1998). IB-NF?B structures: At the interface of inflammation control. Cell 95:729-731.Google Scholar
  2. Baeuerle, P.A., and Baichwal, V.R. (1997). NF-?B as a frequent target for immunosuppressive and antiinflammatory molecules. Adv. Immunol. 65:111-137.Google Scholar
  3. Bellas, R.E., FitzGerald, M.J., Fausto, N., and Sonenshein, G.E. (1997). Inhibition of NF-?B activity induces apoptosis in murine hepatocytes. Am. J. Pathol. 151:891-896.Google Scholar
  4. Camargo, C.A.J., Madden, J.F., Gao, W., Selvan, R.S., and Clavien, P.A. (1997). Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology 26:1513-1520.Google Scholar
  5. Campbell, J.S., Prichard, L., Schaper, F., Schmitz, J., Stephenson-Famy, A., Rosenfeld, M.E., et al. (2001). Expression of suppressors of cytokine signaling during liver regeneration. J. Clin. Invest. 107:1285-1292.Google Scholar
  6. Casado, M., Callejas, N.A., Rodrigo, J., Zhao, X., Dey, S.K., Bosca, L., et al. (2001). Contribution of cyclooxygenase 2 to liver regeneration after partial hepatectomy. FASEB J. 15:2016-2018.Google Scholar
  7. Clavien, P.A. (1997). IL-6, a key cytokine in liver regeneration. Hepatology 25:1294-1296.Google Scholar
  8. Clemens, M.G. (1999). Nitric oxide in liver injury. Hepatology 30:1-5.Google Scholar
  9. Cressman, D.E., Greenbaum, L.E., DeAngelis, R.A., Ciliberto, G., Furth, E.E., Poli, V., et al. (1996). Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274:1379-1383.Google Scholar
  10. Curran, R.D., Billiar, T.R., Stuehr, D.J., Hofmann, K., and Simmons, R.L. (1989). Hepatocytes produce nitrogen oxides from L-arginine in response to inflammatory products of Kupffer cells. J. Exp. Med. 170:1769-1774.Google Scholar
  11. DeAngelis, R.A., Kovalovich, K., Cressman, D.E., and Taub, R. (2001). Normal liver regeneration in p50/nuclear factor ·B1 knockout mice. Hepatology 33:915-924.Google Scholar
  12. Debonera, F., Aldeguer, X., Shen, X., Gelman, A.E., Gao, F., Que, X., et al. (2001). Activation of interleukin-6/STAT3 and liver regeneration following transplantation. J. Surg. Res. 96:289-295.Google Scholar
  13. DeWitt, D.L. (1991). Prostaglandin endoperoxide synthase: Regulation of enzyme expression. Biochim. Biophys. Acta 1083:121-134.Google Scholar
  14. Diaz-Guerra, M.J., Velasco, M., Martin-Sanz, P., and Bosca, L. (1996). Evidence for common mechanisms in the transcriptional control of type II nitric oxide synthase in isolated hepatocytes. Requirement of NF-?B activation after stimulation with bacterial cell wall products and phorbol esters. J. Biol. Chem. 271:30114-30120.Google Scholar
  15. Diaz-Guerra, M.J., Velasco, M., Martin-Sanz, P., and Bosca, L. (1997). Nuclear factor ·B is required for the transcriptional control of type II NO synthase in regenerating liver. Biochem. J. 326:791-797.Google Scholar
  16. Diehl, A.M., and Rai, R.M. (1996). Liver regeneration 3: Regulation of signal transduction during liver regeneration. FASEB J. 10:215-227.Google Scholar
  17. Diez-Fernandez, C., Sanz, N., Bosca, L., Hortelano, S., and Cascales, M. (1997). Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide. Br. J. Pharmacol. 121:820-826.Google Scholar
  18. Fausto, N. (1999). Lessons from genetically engineered animal models. V. Knocking out genes to study liver regeneration: Present and future. Am. J. Physiol. 277:G917-G921.Google Scholar
  19. Fausto, N. (2000). Liver regeneration. J. Hepatol. 32:19-31.Google Scholar
  20. Fausto, N., Laird, A.D., and Webber, E.M. (1995). Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration. FASEB J. 9:1527-1536.Google Scholar
  21. Fry, D.E. (2000). Sepsis syndrome. Am. Surg. 66:126-132.Google Scholar
  22. Galea, E., and Feinstein, D.L. (1999). Regulation of the expression of the inflammatory nitric oxide synthase (NOS2) by cyclic AMP. FASEB J. 13:2125-2137.Google Scholar
  23. Gallucci, R.M., Simeonova, P.P., Toriumi,W., and Luster, M.I. (2000). TNF-? regulates transforming growth factor-alpha expression in regenerating murine liver and isolated hepatocytes. J. Immunol. 164:872-878.Google Scholar
  24. Glockzin, S., von Knethen, A., Scheffner, M., and Brune, B. (1999). Activation of the cell death program by nitric oxide involves inhibition of the proteasome. J. Biol. Chem. 274:19581-19586.Google Scholar
  25. Goss, J.A., Mangino, M.J., Callery, M.P., and Flye, M.W. (1993). Prostaglandin E2 downregulates Kupffer cell production of IL-1 and IL-6 during hepatic regeneration. Am. J. Physiol. 264:G601-G608.Google Scholar
  26. Greenbaum, L.E., Li,W., Cressman, D.E., Peng, Y., Ciliberto, G., Poli, V., et al. (1998). CCAAT enhancer-binding protein b is required for normal hepatocyte proliferation in mice after partial hepatectomy. J. Clin. Invest. 102:996-1007.Google Scholar
  27. Guidotti, L.G., McClary, H., Loudis, J.M., and Chisari, F.V. (2000). Nitric oxide inhibits hepatitisBvirus replication in the livers of transgenic mice. J. Exp. Med. 191:1247-1252.Google Scholar
  28. Hickey, M.J., Sharkey, K.A., Sihota, E.G., Reinhardt, P.H., Macmicking, J.D., Nathan, C., et al. (1997). Inducible nitric oxide synthase-deficient mice have enhanced leukocyte-endothelium interactions in endotoxemia. FASEB J. 11:955-964.Google Scholar
  29. Hierholzer, C., Harbrecht, B., Menezes, J.M., Kane, J., MacMicking, J., Nathan, C.F., et al. (1998). Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J. Exp. Med. 187:917-928.Google Scholar
  30. Hollenberg, S.M., Easington, C.R., Osman, J., Broussard, M., and Parrillo, J.E. (1999). Effects of nitric oxide synthase inhibition on microvascular reactivity in septic mice. Shock 12:262-267.Google Scholar
  31. Hollenberg, S.M., Broussard, M., Osman, J., and Parrillo, J.E. (2000). Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ. Res. 86:774-778.Google Scholar
  32. Hortelano, S., Dewez, B., Genaro, A.M., Diaz-Guerra, M.J., and Bosca, L. (1995). Nitric oxide is released in regenerating liver after partial hepatectomy. Hepatology 21:776-786.Google Scholar
  33. Huang, P.L., and Fishman, M.C. (1996). Genetic analysis of nitric oxide synthase isoforms: Targeted mutation in mice. J. Mol. Med. 74:415-421.Google Scholar
  34. Kaplowitz, N. (2000). Mechanisms of liver cell injury. J. Hepatol. 32(Suppl. 1):39-47.Google Scholar
  35. Kim, Y.M., Talanian, R.V., and Billiar, T.R. (1997). Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms. J. Biol. Chem. 272:31138-31148.Google Scholar
  36. Knight, B., Yeoh, G.C., Husk, K.L., Ly, T., Abraham, L.J., Yu, C., et al. (2000). Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J. Exp. Med. 192:1809-1818.Google Scholar
  37. Kumins, N.H., Hunt, J., Gamelli, R.L., and Filkins, J.P. (1997). Molsidomine increases endotoxic survival and decreases cytokine production. Shock 7:200-205.Google Scholar
  38. Lavon, I., Goldberg, I., Amit, S., Landsman, L., Jung, S., Tsuberi, B.Z., et al. (2000). High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-·B activation. Nat. Med. 6:573-577.Google Scholar
  39. Lee, L.A. (2001). Advances in hepatocyte transplantation: A myth becomes reality. J. Clin. Invest. 108:367-369.Google Scholar
  40. Li, J., and Billiar, T.R. (1999a). Nitric oxide. IV. Determinants of nitric oxide protection and toxicity in liver. Am. J. Physiol. 276:G1069-G1073.Google Scholar
  41. Li, J., and Billiar, T.R. (1999b). The anti-apoptotic actions of nitric oxide in hepatocytes. Cell Death Differ. 6:952-955.Google Scholar
  42. MacMicking, J., Xie, Q.W., and Nathan, C. (1997). Nitric oxide and macrophage function. Annu. Rev. Immunol. 15:323-350.Google Scholar
  43. Martin-Sanz, P., Callejas, N.A., Casado, M., Diaz-Guerra, M.J., and Bosca, L. (1998). Expression of cyclooxygenase-2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro-inflammatory cytokines. Br. J. Pharmacol. 125:1313-1319.Google Scholar
  44. Michalopoulos, G.K., and DeFrances, M.C. (1997). Liver regeneration. Science 276:60-66.Google Scholar
  45. Mojena, M., Hortelano, S., Castrillo, A., Diaz-Guerra, M.J., Garcia-Barchino, M.J., Saez, G.T., et al. (2001). Protection by nitric oxide against liver inflammatory injury in animals carrying a nitric oxide synthase-2 transgene. FASEB J. 15:583-585.Google Scholar
  46. Morikawa, A., Kato,Y., Sugiyama, T., Koide, N., Chakravortty, D., Yoshida, T., et al. (1999). Role of nitric oxide in lipopolysaccharide-induced hepatic injury in D-galactosamine-sensitized mice as an experimental endotoxic shock model. Infect. Immun. 67:1018-1024.Google Scholar
  47. Nussler, A.K., Beger, H.G., Liu, Z.Z., and Billiar, T.R. (1995). Nitric oxide, hepatocytes and inflammation. Res. Immunol. 146:671-677.Google Scholar
  48. Obolenskaya, M., Schulze-Specking, A., Plaumann, B., Frenzer, K., Freudenberg, N., and Decker, K. (1994a). Nitric oxide production by cells isolated from regenerating rat liver. Biochem. Biophys. Res. Commun. 204:1305-1311.Google Scholar
  49. Obolenskaya, M.Y., Vanin, A.F., Mordvintcev, P.I., Mulsch, A., and Decker, K. (1994b). Epr evidence of nitric oxide production by the regenerating rat liver. Biochem. Biophys. Res. Commun. 202:571-576.Google Scholar
  50. Pastor, C.M., Losser, M.R., and Payen, D. (1995). Nitric oxide donor prevents hepatic and systemic perfusion decrease induced by endotoxin in anesthetized rabbits. Hepatology 22:1547-1553.Google Scholar
  51. Rai, R.M., Lee, F.Y., Rosen, A., Yang, S.Q., Lin, H.Z., Koteish, A., et al. (1998). Impaired liver regeneration in inducible nitric oxide synthase deficient mice. Proc. Natl. Acad. Sci. U.S.A. 95:13829-13834.Google Scholar
  52. Rosenfeld, M.E., Prichard, L., Shiojiri, N., and Fausto, N. (2000). Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice. Am. J. Pathol. 156:997-1007.Google Scholar
  53. Sakamoto, T., Liu, Z., Murase, N., Ezure, T., Yokomuro, S., Poli, V., et al. (1999). Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy. Hepatology 29:403-411.Google Scholar
  54. Schoen, J.M., Wang, H.H., Minuk, G.Y., and Lautt,W.W. (2001). Shear stress-induced nitric oxide release triggers the liver regeneration cascade. Nitric Oxide 5:453-464.Google Scholar
  55. Scotte, M., Masson, S., Lyoumi, S., Hiron, M., Teniere, P., Lebreton, J. P., et al. (1997). Cytokine gene expression in liver following minor or major hepatectomy in rat. Cytokine 9:859-867.Google Scholar
  56. Streetz, K.L., Wustefeld, T., Klein, C., Manns, M.P., and Trautwein, C. (2001). Mediators of inflammation and acute phase response in the liver. Cell. Mol. Biol. 47:661-673.Google Scholar
  57. Szabo, C., and Billiar, T.R. (1999). Novel roles of nitric oxide in hemorrhagic shock. Shock 12:1-9.Google Scholar
  58. Taub, R. (1998). Blocking NF-?B in the liver: The good and bad news. Hepatology 27:1445-1446.Google Scholar
  59. Taylor, B.S., and Geller, D.A. (2000). Molecular regulation of the human inducible nitric oxide synthase (iNOS) gene. Shock 13:413-424.Google Scholar
  60. Taylor, B.S., Shao, L., Gambotto, A., Ganster, R.W., and Geller, D.A. (1999). Inhibition of cytokine-induced nitric oxide synthase expression by gene transfer of adenoviral I·B®. Surgery 126:142-147.Google Scholar
  61. Titheradge, M.A. (1999). Nitric oxide in septic shock. Biochim. Biophys. Acta 1411:437-455.Google Scholar
  62. Velasco, M., Diaz-Guerra, M.J., Martin-Sanz, P., Alvarez, A., and Bosca, L. (1997). Rapid Up-regulation of I·Bb and abrogation of NF-?B activity in peritoneal macrophages stimulated with lipopolysaccharide. J. Biol. Chem. 272:23025-23030.Google Scholar
  63. Vos, T.A., Gouw, A.S., Klok, P.A., Havinga, R., van Goor, H., Huitema, S., et al. (1997). Differential effects of nitric oxide synthase inhibitors on endotoxin-induced liver damage in rats. Gastroenterology 113:1323-1333.Google Scholar
  64. Webber, E.M., Bruix, J., Pierce, R.H., and Fausto, N. (1998). Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 28:1226-1234.Google Scholar
  65. Xie, Q.W., Whisnant, R., and Nathan, C. (1993). Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by IFN? and bacterial lipopolysaccharide. J. Exp. Med. 177:1779-1784.Google Scholar
  66. Yamada, Y., Webber, E.M., Kirillova, I., Peschon, J.J., and Fausto, N. (1998). Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: Requirement for type 1 but not type 2 receptor. Hepatology 28:959-970.Google Scholar
  67. Yamashita, T., Kawashima, S., Ohashi, Y., Ozaki, M., Ueyama, T., Ishida, T., et al. (2000). Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation 101:931-937.Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Paloma Martin-Sanz
  • Sonsoles Hortelano
  • Nuria A. Callejas
  • Nora Goren
  • Marta Casado
  • Miriam Zeini
  • Lisardo Boscá

There are no affiliations available

Personalised recommendations