Distribution of constitutive (COX-1) and inducible (COX-2) cyclooxygenase in postviral human liver cirrhosis: a possible role for COX-2 in the pathogenesis of liver cirrhosis

Abstract

Aims: Prostaglandins produced by the action of cyclooxygenases (COX) are important mediators of systemic vasodilatation and inflammation in liver cirrhosis. The aim of this study was to investigate the distribution of COX-1 and COX-2 in postviral cirrhosis.

Methods: The immunohistochemical expression of the constitutive (COX-1) and the inducible (COX-2) isoenzymes was investigated in 15 patients with cirrhosis after hepatitis B and C infection; three normal control livers were also analysed.

Results: COX-2 was absent from normal liver but was highly expressed in cirrhosis, mainly in the inflammatory, sinusoidal, vascular endothelial, and biliary epithelial cells. Low amounts of COX-1 were expressed in both normal and cirrhotic livers, exclusively in sinusoidal and vascular endothelial cells, with no differences seen between normal and cirrhotic livers.

Conclusions: COX-2 is overexpressed in liver cirrhosis, and possibly contributes to prostaglandin overproduction, which may be a major component of the inflammation and hyperdynamic circulation associated with cirrhosis. Because COX-2 is thought to contribute to tumour development, high COX-2 production could be a contributor to hepatocellular carcinoma development in cirrhosis. The finding of COX-2 and not COX-1 upregulation in cirrhosis could provide a possible new role for selective COX-2 inhibitors in reducing inflammation and minimising the occurrence of hepatocellular carcinoma in patients with cirrhosis.

Figure 1

Immunoperoxidase showing COX-2 expression in (A) normal and (B–F) cirrhotic liver samples. (A) Normal human liver showing complete absence of COX-2 immunoreactivity. CV, central (terminal hepatic) vein region; original magnification, ×10. (B) A cirrhotic liver showing infiltration with inflammatory cells, which show dense COX-2 immunoreactivity (arrow); original magnification, ×25. (C) Large number of blood vessels seen in a cirrhotic liver showing COX-2 expression (arrows); original magnification, ×50. (D) Macrophage-like cells (arrows) infiltrating between hepatocytes show high COX-2 immunoreactivity; original magnification, ×100. (E) COX-2 immunoreactivity is seen in sinusoidal cells (arrows) in cirrhotic liver. The COX-2 positive sinusoidal cells are seen surrounding negatively stained hepatocytes; original magnification, ×50. (F) A liver cirrhosis sample showing COX-2 expression in the epithelial lining of bile ducts; original magnification, ×100.

Figure 2

Immunoperoxidase staining showing COX-1 distribution in (A) normal liver and (B,C) human cirrhotic liver. (A) COX-1 is seen in normal liver, localised in the sinusoidal cells (arrows); original magnification, ×50. (B) In cirrhotic liver, COX-1 immunoreactivity is seen in the perivenular region (arrow) and in sinusoidal cells extending from the terminal hepatic vein; original magnification, ×25. (C) COX-1 is localised to the endothelial lining of two blood vessels seen in cirrhotic liver (arrows), with no expression in hepatocytes; original magnification, ×100. (D) A negative control in which the primary antibodies (COX-1 and COX-2) were omitted from the staining procedure, showing complete absence of staining and indicating the high specificity of the antibody used in our study; original magnification, ×50.