Serine protease inhibitors prevent alcoholic liver injury]

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially characterized. It now appears that Kupffer cell derived TNF-alpha participates in several aspects of alcoholic liver injury. On the other hand, protease inhibitors have been used successfully for treatment of intractable diseases in which TNF-alpha is involved in the pathogenesis, including ulcerative colitis and Crohn's disease. Here, we will review new evidence for the proposal that serine protease inhibitors prevents alcoholic liver injury via mechanisms dependent on Kupffer cell derived TNF-alpha.     

Gender difference in alcoholic liver injury]

Gender differences of alcoholic liver injury have been described previously, but mechanisms have only partially characterized. For example, it is known that females develop alcoholic liver injury more rapidly and to a greater extent than males. It now appears that estrogen participates in several aspects of this phenomenon. On the other hand, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut-derived endotoxins via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cell and alcohol-induced liver injury.     

Effect of low-molecular-weight heparin on the commitment of bone marrow cells to liver sinusoidal endothelial cells in CCl(4)-induced liver injury.

BACKGROUND/AIMS: Recently liver regeneration by bone marrow transplantation has been proposed as an alternative source of functional liver cells. We investigate commitment of bone marrow cells (BMCs) to liver regeneration and the effect of dalteparin sodium (DS) on regeneration of the damaged liver caused by carbon tetrachloride (CCl(4)) administration in the mice. METHODS: Liver injury was produced in 8-week-old mice by treating with CCl(4) for 4 weeks. Thereafter, mice received a lethal dose of irradiation (10Gy) to whole body, followed by injection of 1x10(7) green fluorescent protein (GFP)-positive BMCs via the tail vein. DS (50IU/kg, intraperitoneally) was administered daily for 28 consecutive days starting at 1 day post-BMC transplantation. Lineage marker analysis of GFP-positive liver cells was performed immunostaining with a CD31 antibody. RESULT: Four weeks after BMC transplantation, GFP-positive cells in the CCl(4)-damaged liver could be detected in the lobule displaying a meshwork architecture extending from the periportal to pericentral regions, a pattern simulating sinusoidal lining. This localization of GFP-positive cells suggested that these cells were closely associated with sinusoidal endothelial cells. By staining the GFP-positive cells for CD31, it was confirmed that the majority of the GFP-positive cells are also positive for CD31. The GFP(+)CD31(+) cells were barely detected in the control group (1.0+/-1.2 per field). In marked contrast, a numerous number of GFP(+)CD31(+) cells were detected in the liver section obtained from the CCl(4)-induced liver damage group (3.8+/-1.3 per field, P<0.05 versus control). The number of GFP(+)CD31(+) cells in CCl(4) plus DS-treated group was further increased to 8.3+/-1.3 per field (P<0.05 versus CCl(4)-induced liver damage group). CONCLUSION: The majority of GFP-positive BMCs was committed to sinusoidal endothelial cells. DS promoted BMC differentiation into sinusoidal endothelial cells in the CCl(4)-damaged liver.     

Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease

Chronic cholestasis often results in premature death from liver failure with fibrosis; however, the molecular mechanisms contributing to biliary cirrhosis are not demonstrated. In this article, we show that the death signal mediated by TNF-related apoptosis-inducing ligand (TRAIL) receptor 2/death receptor 5 (DR5) may be a key regulator of cholestatic liver injury. Agonistic anti-DR5 monoclonal antibody treatment triggered cholangiocyte apoptosis, and subsequently induced cholangitis and cholestatic liver injury in a mouse strain-specific manner. TRAIL- or DR5-deficient mice were relatively resistant to common bile duct ligation-induced cholestasis, and common bile duct ligation augmented DR5 expression on cholangiocytes, sensitizing mice to DR5-mediated cholangitis. Notably, anti-DR5 monoclonal antibody-induced cholangitis exhibited the typical histological appearance, reminiscent of human primary sclerosing cholangitis. Human cholangiocytes constitutively expressed DR5, and TRAIL expression and apoptosis were significantly elevated in cholangiocytes of human primary sclerosing cholangitis and primary biliary cirrhosis patients. Thus, TRAIL/DR5-mediated apoptosis may substantially contribute to chronic cholestatic disease, particularly primary sclerosing cholangitis.