Clinical implication of vascular cell adhesion molecule-1 and very late activation antigen-4 interaction, and matrix metalloproteinase-2 production in patients with liver disease

OBJECTIVES: To clarify the role of adhesion molecule in liver cell injury. PATIENTS AND METHODS: The serum levels of soluble: vascular cell adhesion molecule-1 (sVCAM-1), and the expression of VCAM-1 and its ligand, very late activation antigen-4 (VLA-4), were examined in patients with various liver diseases. In addition, the presence of matrix metalloproteinase-2 (MMP-2) was investigated because the release of MMP-2 is thought to be mediated by VLA-4-positive cells. sVCAM-1 and MMP-2 were measured by ELISA assay, and VCAM-1 and VLA-4 were studied by immunohistological methods. RESULTS: In acute hepatitis (AH) patients, the serum level of sVCAM-1 was significantly elevated compared with that in other cohorts. VCAM-1 was expressed on sinusoidal lining cells but not on hepatocytes. In patients with chronic liver disease, sVCAM-1 levels rose in concert with the progression of chronic hepatitis (CH), and VCAM-1 was also expressed. VLA-4 was detected in both mononuclear cells and Kupffer cells in AH livers, but mainly in Kupffer cells in patients with CH. In AH patients, MMP-2, levels were similar to those in control subjects, but in CH and liver cirrhosis patients, MMP-2 level was elevated in association with CH progression. CONCLUSIONS: The immune response through the VCAM-1 and VLA-4 pathways is important in hepatocyte injury, especially in AH patients, to attach VLA-di-positive mononuclear cells to VCAM-1-positive sinusoidal Pining cells. The distribution of VLA-4-positive cells differs between AH and CH patients. VLA-4-positive Kupffer cells in chronic liver diseases might be involved in the progression of CH, perhaps through the mechanism of upregulation of MMP-2 production.