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Superoxide, NO and CO in liver microcirculation: Physiology and pathophysiology

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Journal of Hepato-Biliary-Pancreatic Surgery

Abstract

Superoxide anion (O2 ), nitric oxide (NO), and carbon monoxide (CO) are metabolites of molecular oxygen endogenously generated through oxygen activation by a variety of oxidases and oxygenases such as xanthine oxidase and NADPH oxidase, NO synthase, and heme oxygenase, respectively. There is an increasing body of evidence showing that these active oxygen metabolites not only exert their cytotoxic properties but also play a modulatory role in regulation of cell function in and around hepatic sinusoidal vessels. Among them, CO generated by heme oxygenase is a novel vasodilatory mediator which can upregulate cGMP in fatstoring Ito cells, liver-specific microvascular pericytes which encircle sinusoidal walls, and thereby control the microvascular tone under control conditions. When exposed to endotoxemia, Kupffer cells and hepatocytes can express inducible NO synthase activity which serves as a NO-dependent cytotoxic mechanisms involving peroxynitrite formation. Disclosure of the whole picture of NO- and CO-dependent mechanisms for regulation of hepatic microcirculation gives a clue to understanding the physiology and pathophysiology of liver function.

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References

  1. Bautista AP, Spitzer JJ (1994) Inhibition of nitric oxide formation in vivo enhances superoxide release by the perfused liver. Am J Physiol 266:G783-G788

    CAS  PubMed  Google Scholar 

  2. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    CAS  PubMed  Google Scholar 

  3. Ma TT, Ischiropoulos H, Brass CA (1995) Endotoxin-stimulated nitric oxide production increases injury and reduces rat liver chemiluminescence during reperfusion. Gastroenterology 108(2):463–469

    Article  CAS  PubMed  Google Scholar 

  4. Pastor CM, Billiar TR (1995) Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats. Am J Physiol 268:G177-G182

    CAS  PubMed  Google Scholar 

  5. Obolenskaya MY, Vanin AF, Mordvintcev PI, Mülsch A, Decker K (1994) EPR evidence of nitric oxide production by the regenerating rat liver. Biochem Biophys Res Commun 202:571–576

    Article  CAS  PubMed  Google Scholar 

  6. Buttery LDK, Evans TJ, Springall DR, Carpenter A, Cohen J, Polak JM (1994) Immunohistochemical localization of inducible nitric oxide synthase in endotoxin-treated rats. Lab Invest 71:755–764

    CAS  PubMed  Google Scholar 

  7. Rockey DC, Chung JJ (1995) Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 95(3):199–206

    Google Scholar 

  8. Kurose I, Kato S, Ishii H, Fukumura D, Miura S, Suematsu M, Tsuchiya M (1993) Nitric oxide mediates lipopolysaccharideinduced alteration of mitochondrial function in cultured hepatocytes and isolated perfused liver. Hepatology 18(2):380–388

    Article  CAS  PubMed  Google Scholar 

  9. Kurose I, Miura S, Fukumura D, Yonei Y, Saito H, Tada S, Suematsu M, Tsuchiya M (1993) Nitric oxide mediates Kupffer cell-induced reduction ofmitochondrial energization in hepatoma cells: A comparison with oxidative burst. Cancer Res 53(11): 2676–2682

    CAS  PubMed  Google Scholar 

  10. Pastor CM, Payen DM (1994) Effect ofmodifying nitric oxide pathway on liver circulation in a rabbit endotoxin shock model. Shock 2:196–202

    CAS  PubMed  Google Scholar 

  11. Nishida J, McCuskey RS, McDonnell D, Fox ES (1994) Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia. Am J Physiol 267 (6 Pt 1):G1135–41 Issn: 0002-9513

    CAS  PubMed  Google Scholar 

  12. Suematsu M, Tamatani T, Delano FA, Miyasaka M, Forrest M, Suzuki H, Schmid-Schonbein GW (1994) Microvascular oxidative stress preceding leukocyte activation elicted by in vivo nitric oxide suppression. Am J Physiol 266:H2410-H2415

    CAS  PubMed  Google Scholar 

  13. Jaeschke H, Schini VB, Farhood A (1992) Role of nitric oxide in oxidant stress during ischemia/reperfusion injury of the liver. Life Sci. 50:1797–1804

    Article  CAS  PubMed  Google Scholar 

  14. Suematsu M, Suzuki H, Ishii Kato S, Yanagisawa T, Asako H, Suzuki M, Tsuchiya M (1992) Early midzonal oxidative stress preceding cell death in hypoperfused rat liver. Gastroenterology 103:994–1001

    CAS  PubMed  Google Scholar 

  15. Kooij A, Frederiks WM, Gossrau R, van Noorden CJF (1991) Localization of xanthine oxidoreductase activity using the tissue pnotectant polyvinyl alcohol and final electron acceptor tetranitro BT. J Histochem Cytochem 39:87–93

    CAS  PubMed  Google Scholar 

  16. Suzuki H, Suematsu M, Ishii H, Kato S, Miki H, Mori M, Ishimura Y, Nishino T, Tsuchiya M (1994) Prostaglandin E1 abrogates zone-specific oxidative injury in hypoperfused rat liver. J Clin Invest 93:155–164

    CAS  PubMed  Google Scholar 

  17. Suematsu M, Kato S, Ishii H, Yanagisawa T, Asako H, Oshio C, Tsuchiya M (1991) Intralobular heterogeneity of carbon tetrachloride-induced oxidative stress demonstrated by digital imaging fluorescence microscopy. Lab Invest 64:167–173.

    CAS  PubMed  Google Scholar 

  18. Nishino T, Tamura I (1991) The mechanism of conversion of xanthine dehydrogenase and the role of the enzyme in reperfusion injury. Adv Exp Med Biol 309A:327–333

    CAS  PubMed  Google Scholar 

  19. Jaeschke H, Kleinwaechter C, Wendel A (1992) NADH-dependent reductive stress and ferritin-bound iron in allyl alcohol-induced lipid peroxidation in vivo. Chem Biol Interact 81:57–68

    CAS  PubMed  Google Scholar 

  20. Maines MD (1988) Heme oxygenase: Function multiplicity, regulatory mechanisms, and clinical applications. ASEB J 2:2557–2568

    CAS  Google Scholar 

  21. Brüne B, Ullrich V (1987) Inhibition of platelet aggregation by carbon monoxide mediated by activation of guanylate cyclase. Mol Pharmacol 32:497–504

    PubMed  Google Scholar 

  22. Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH (1993) Carbon monoxide: A putative neural messenger. Science 259:381–384

    CAS  PubMed  Google Scholar 

  23. Maines MD, Trakshel GM, Kutty RK (1986) Characterization of two constitutive forms of rat liver microsomal heme oxygenase: Only one molecular species of the enzyme is inducible. J Biol Chem 261:11131–11137

    PubMed  Google Scholar 

  24. Suematsu M, Goda N, Sano T, Kashiwagi S, Shinoda Y, Ishimura Y (1995) Carbon monoxide: An endogenous modulator of sinusoidal tone in the perfused rat liver. J Clin Invest 96:2431–2437

    CAS  PubMed  Google Scholar 

  25. Mittal MK, Gupta TK, Lee F-Y, Sieber CC, Groszmann RJ (1994) Nitric oxide modulates hepatic vascular tone in normal rat liver. Am J Physiol 267:G416-G422

    CAS  PubMed  Google Scholar 

  26. Oda M, Tsukada N, Honda K, Komatsu H, Kaneko K, Azuma T, Nishizaki Y, Watanabe N, Tsuchiya M (1987) Hepatic sinusoidal endothelium: Its functional implications in the regulation of sinusoidal blood flow. In: Tsuchiya M, Asano M, Mishima Y, Oda M (eds) Microcirculation—an update, vol 2. Elsevier Amsterdam, pp 317–320

    Google Scholar 

  27. McCuskey RS, Urbaschek R, McCuskey PA, Urbascheck B (1982) In vivo microscopic response of the liver to endotoxins. Klin Wochenschr 60:749–751

    Article  CAS  PubMed  Google Scholar 

  28. Blomhoff R, Rasmussen M, Nilsson A, Norum KR, Berg T, Blaner WS, Kato M, Mertz JR, Goodman DS (1985) Hepatic retinol metabolism. J Biol Chem 260:13560–13565

    CAS  PubMed  Google Scholar 

  29. Suematsu M, Oda M, Suzuki H, Kaneko H, Watanabe N, Furusho T, Masushige S, Tsuchiya M (1993) Intravital and electron microscopic observation of Ito cells in rat hepatic microcirculation. Microvasc Res 46:28–42

    Article  CAS  PubMed  Google Scholar 

  30. Kelley C, D'Amore P, Hechtman HB, Shepro D (1987) Microvascular pericyte contractility in vitro: Comparison with other cells of the vascular wall. J Cell Biol 104:483–490

    Article  CAS  PubMed  Google Scholar 

  31. Joyce NC, Haire MF, Palade GE (1985) Contractile proteins in pericytes. I. Immunoperoxidase localization of tropomyosin. J Cell Biol 100:1379–1386

    CAS  PubMed  Google Scholar 

  32. Zhang JX, Pegoli W Jr, Clemens MG (1994) Endothelin-1 induces direct constriction of hepatic sinusoids. Am J Physiol 264 (4 Pt 1):G624-G632

    Google Scholar 

  33. Suematsu M, Shimmura S, Kashiwagi S, Wakabayashi Y, Shinoda Y, Ishimura Y (1996) Fat-storing Ito cells: A modulatory machinery for regulation of hepatic microcirculation? In: Tsuchiya et al. (eds) Gastrointestinal function: Regulation and disturbances, vol 14 Excerpta Medica, Tokyo (in press)

    Google Scholar 

  34. Kawada N, Tran-Thi T-A, Klein H, Decker K (1993) The contraction of hepaticstellate (Ito) cells stimulated with vasoactive substances: Possible involement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem 213:815–823

    Article  CAS  PubMed  Google Scholar 

  35. Rockey DC, Housset CN, Friedman SL (1993) Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 92(4):1795–1804

    CAS  PubMed  Google Scholar 

  36. Tanaka A, Katagiri K, Hoshino M, Hayakawa T, Tsukada K, Takeuchi T (1994) Endothelin-1 stimulates bile acid secretion and vesicular transport in the isolated perfused rat liver. Am J Physiol 266 (2 Pt 1) G324-G329

    CAS  PubMed  Google Scholar 

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Suematsu, M., Kumamoto, Y., Sano, T. et al. Superoxide, NO and CO in liver microcirculation: Physiology and pathophysiology. J Hep Bil Pancr Surg 3, 154–160 (1996). https://doi.org/10.1007/BF02350925

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  • DOI: https://doi.org/10.1007/BF02350925

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