Notch signaling and progenitor/ductular reaction in steatohepatitis.

Background And Objective: Persistent hepatic progenitor cells (HPC) activation resulting in ductular reaction (DR) is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries.

SerpinB3 Promotes Pro-fibrogenic Responses in Activated Hepatic Stellate Cells.

SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis.

Antibodies against oxidized phospholipids in laboratory tests exploring lupus anti-coagulant activity.

Lupus anti-coagulants (LA) are a variety of anti-phospholipid antibodies characterized by their capacity to interfere with phospholipid-dependent coagulation assays. LA are increasingly recognized as important predictors of thrombosis. However, the antigen specificity of LA is still poorly characterized.

Purinergic P2Y2 receptors promote hepatocyte resistance to hypoxia.

Background/aims: ATP stimulation of purinergic P2 receptors (P2YR and P2XR) regulates several hepatic functions. Here we report the involvement of ATP-mediated signals in enhancing hepatocyte tolerance to lethal stress.

Methods: The protection given by purinergic agonists was investigated in rat hepatocytes exposed to hypoxia.

Anti-phospholipid antibodies associated with alcoholic liver disease target oxidized phosphatidylserine on apoptotic cell plasma membranes.

Background/aims: Circulating anti-phospholipid antibodies (aPL) are often present in patients with alcoholic liver disease (ALD). The observations that defects in the disposal of apoptotic corpses leads to the development of aPL prompted us to investigate whether ALD-associated aPL might recognize antigens in apoptotic cells.

Methods: Apoptosis was induced in HuT-78 human T-lymphoma and HepG2 hepatoma cells by, respectively, FAS ligation with CH11 monoclonal antibodies or the incubation with ethanol (400 mmol/L).

Signal pathway responsible for hepatocyte preconditioning by nitric oxide.

Nitric oxide (NO) improves liver resistance to hypoxia/reperfusion injury acting as a mediator of hepatic preconditioning. However, the mechanisms involved are still poorly understood. In this study, we have investigated the mechanisms by which short-term exposure to the NO donor (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino])-diazen-1-ium-1,2-diolate (NOC-9) increases hepatocyte tolerance to hypoxic injury.

Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes.

Ischemic preconditioning improves liver resistance to hypoxia and reduces reperfusion injury following transplantation. However, the intracellular signals that mediate the development of liver hypoxic preconditioning are largely unknown. We have investigated the signal pathway leading to preconditioning in freshly isolated rat hepatocytes.

Ethanol potentiates hypoxic liver injury: role of hepatocyte Na(+) overload.

Centrilobular hypoxia has been suggested to contribute to hepatic damage caused by alcohol intoxication. However, the mechanisms involved are still poorly understood. We have investigated whether alterations of Na(+) homeostasis might account for ethanol-mediated increase in hepatocyte sensitivity to hypoxia.

Alterations of Na(+) homeostasis in hepatocyte reoxygenation injury.

Reperfusion injury represents an important cause of primary graft non-function during liver transplantation. However, the mechanism responsible for cellular damage during reoxygenation has not yet been completely understood. We have investigated whether changes in intracellular Na(+) distribution might contribute to cause hepatocyte damage during reoxygenation buffer after 24 h of cold storage.

Hydroxyethyl radicals in ethanol hepatotoxicity.

Alcoholic patients and experimental animals exposed to ethanol display biochemical signs of oxidative damage, suggesting a possible role of free radicals in causing some of the toxic effects of alcohol. The use of electron spin resonance (ESR) spectroscopy associated with spin trapping technique has demonstrated that hydroxyethyl radicals are generated during ethanol metabolism by the microsomal monoxygenase system, involving the alcohol-inducible cytochrome P450 2E1 (CYP2E1). Recent observations in rats fed intragastrically with a high fat diet containing ethanol indicate that the formation of hydroxyethyl radicals is associated with stimulation of lipid peroxidation and development of liver damage.