Von Willebrand gene expression in damaged human liver.

BACKGROUND/AIMS: von Willebrand factor (vWf) is an adhesive glycoprotein known to play a role in hemostasis and in tissue injury. It is found in high levels in plasma of patients with acute hepatic failure and chronic liver disease. The aim of this study was to investigate the pattern of tissue vWf in acute liver failure in humans. METHODOLOGY: We studied vWf immunostaining and mRNA expression in the liver of three patients with fulminant liver failure, two patients with chronic liver disease, and two controls. PECAM-1 (CD31) immunostaining and mRNA expression were used as an additional endothelial marker. RESULTS: In chronic liver cirrhosis, vWf deposits were strongly detected at the scar-parenchyma interface. In fulminant hepatic failure, intense deposits were seen in tissue sections in the area of necrosis. A similar pattern of immunostaining was seen with PECAM-1. vWf transcripts were abundant in the liver of patients with chronic disease and minimally expressed in patients with acute hepatic failure and in controls. CONCLUSIONS: vWf is deposited within the liver sinusoids early after liver damage. The factor is only partially produced locally during the acute phase of the disease, but is overproduced in chronic disease states. These changes may suggest a role for vWf in liver injury and repair.

Platelet-endothelial cell adhesion molecule-1 gene expression in liver sinusoidal endothelial cells during liver injury and repair.

BACKGROUND/AIMS: Platelet-endothelial cell adhesion molecule (PECAM)-1 is suggested to be critical for transmigration processes. It is a matter of debate whether PECAM-1 is expressed in liver sinusoids and whether it is involved in liver inflammation. METHODS: Indirect immunostaining and in situ hybridization was used to analyze PECAM-1 gene expression in normal and diseased rat and human livers as well as in isolated rat sinusoidal endothelial cells (SECs), hepatic stellate cells and hepatocytes. At various time points after the administration of CCl4 (6 h, 24 h, 48 h, and 72 h), PECAM-1 gene expression was analyzed in livers and in SECs by immunostaining, and Northern blot analysis. RESULTS: In normal rat or human livers PECAM-1 immunoreactivity was detected along the sinusoids in a pattern similar to ICAM-1 staining. PECAM-1 specific transcripts were detected in freshly isolated and cultured SECs. After a single CCl4-administration, PECAM-1 immunoreactivity did not increase along the sinusoids in contrast to the early increase of ICAM-1. Northern blot analysis indicated that PECAM-1 expression in liver tissue and in isolated SECs does not increase after a single administration of CCl4, whereas ICAM-1 steady-state level increased after 6 h. In diseased human livers PECAM-1 was detectable along the sinusoids, within inflammatory infiltrates and within fibrotic septa. Neither in acutely nor chronically diseased human livers was an obvious increase of PECAM-1 immunoreactivity detectable. CONCLUSIONS: PECAM-1 is expressed by SECs. In contrast to ICAM-1, PECAM-1 transcript level is not enhanced during liver damage.

Sinusoidal intercellular adhesion molecule-1 up-regulation precedes the accumulation of leukocyte function antigen-1-positive cells and tissue necrosis in a model of carbontetrachloride-induced acute rat liver injury.

The mechanisms leading to the infiltration of inflammatory cells into the liver and to liver cell necrosis remain undefined. To elucidate this process, the present work analyzes the kinetics of the expression of intercellular adhesion molecule-1 (ICAM-1) and the accumulation of inflammatory leukocyte function antigen-1 (LFA-1)-positive cells in relation to the appearance of hepatocellular necrosis in the model of acute carbontetrachloride (CCl4)-induced liver injury. ICAM-1- and LFA-1-immunoreactivity was analyzed in normal livers and in livers obtained 3, 6, 9, 12, 18, 24, 48, and 72 hours after CCl4-administration, as well as in liver cells isolated 3, 6, 9, 12, 18, and 24 hours after CCl4-administration. Total RNA extracted from livers and cells was used for Northern blot analysis. ICAM-1-positivity, which was detected along the sinusoids in normal rat livers, increased 3 to 6 hours after CCl4-administration and finally accumulated in the necrotic areas (24 to 48 hours post-administration). ICAM-1 steady-state mRNA levels in liver tissue increased 3 to 6 hours after CCl4-treatment and returned to normal levels at 48 hours after treatment. Increased amounts of ICAM-1-specific transcripts could be observed in isolated sinusoidal endothelial cells and in hepatocytes as early as 3 to 6 hours after CCl4-administration. In normal rat livers, a few LFA-1-immunoreactive cells were present around the vessel walls. Starting 12 hours after CCl4-administration, the number of LFA-1-immunoreactive cells increased around the vessel walls and along the sinusoids, accumulating later in the necrotic areas. In accordance, the number of mononuclear phagocytes isolated from the liver increased 12 hours after CCl4-treatment. These data demonstrate an early up-regulation of ICAM-1 in liver cells and the accumulation of LFA-1-expressing cells prior to the development of necrotic areas. The up-regulation of ICAM-1 and accumulation of inflammatory cells seem to be critical for the induction of CCl4-induced hepatotoxicity.