Expression of nitric oxide synthase isoforms in human liver cirrhosis

J Pathol. 2003 Aug;200(5):647-55. doi: 10.1002/path.1377.

Abstract

Several mediators of systemic vasodilatation in liver cirrhosis have been reported. Among these is nitric oxide (NO), which has been proposed as one of the main mediators. In this study, sera and liver biopsies were analysed from 15 patients with clinically and pathologically diagnosed liver cirrhosis. In addition, sera from seven and liver biopsies from three healthy controls were used. Serum levels of nitrite (the end product of NO) were measured using the Griess reaction and the expression of the inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (ecNOS) proteins was investigated using immunohistochemistry. This study shows that serum nitrite levels (94 +/- 9.8 micro mol/l) in cirrhotic patients were significantly (p < 0.05) increased in comparison with the controls (36.6 +/- 11.03 micro mol/l). iNOS was completely absent from the control group but was highly expressed in the livers from the cirrhotic group. iNOS was seen mainly in the inflammatory cells infiltrating the portal tracts, blood monocyte-like cells, hepatocytes, sinusoidal cells, and endothelial cells. However, expression of ecNOS was only seen in the vascular endothelial cells of both the control and the cirrhotic groups, but was much higher in the latter. It is therefore clear that NO is augmented in cirrhotic patients and it is mainly produced by induction of iNOS. Moreover, NO up-regulation is dependent on the inflammatory stage of liver cirrhosis. ecNOS production could be a normal chronic adaptation mechanism of the endothelium to the chronically increased splanchnic blood flow secondary to portal hypertension. In the near future, the appropriate inhibition of NO activity by using NOS-active agents may provide a novel strategy for the treatment of patients with liver cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Endothelium, Vascular / enzymology
  • Female
  • Humans
  • Immunoenzyme Techniques
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / enzymology*
  • Liver Cirrhosis / pathology
  • Male
  • Middle Aged
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nitrites / blood
  • Protein Isoforms / metabolism

Substances

  • Nitrites
  • Protein Isoforms
  • NOS2 protein, human
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III