No abstract

Ischemia/reperfusion (I/R) is an important problem in liver resection and transplantation that is associated with hepatocellular dysfunction and injury. This study was designed to investigate whether a difference in hepatocyte susceptibility occurs in the periportal (PP) and/or perivenous (PV) zones in response to hypoxia/reoxygenation (H/R), and to delineate the mechanisms underlying this susceptibility. H/R was induced in an in situ perfused mouse liver model with deoxygenated Krebs-Henseleit buffer followed by oxygenated buffer. Selective destruction of PP or PV sites was achieved by digitonin perfusion into the portal or inferior vena cava , and was confirmed by histological evaluations and zone-specific enzymes. Hepatocellular injury was assessed by alanine aminotransferase (ALT) release. In whole liver, H/R significantly increased perfusate ALT. H/R of PP-enriched zones caused ALT release that was similar to that of whole liver ( P revious studies in animal models show that ischemia/reperfusion (I/R) injury to the liver occurs in 2 distinct phases. The early reperfusion injury response occurs between 1 and 6 hours, and reactive oxygen species (ROS), such as superoxide (O 2 Ϫ ), hydrogen peroxide, and/or hydroxyl radical produced during reperfusion, [1][2][3][4][5] have been implicated in this acute hepatic injury process that is independent of leukocyte involvement. Because hepatic proliferation, which is an important determinant of a patient's survival after major hepatic resection, occurs from the periportal (PP) to perivenous (PV) zones, 6 an understanding of the differential vulnerability of hepatic zones to postischemic injury would provide an important basis for preventing liver failure caused by alcoholic addiction or after major hepatectomy and liver transplantation. Given that metabolic heterogeneity of hepatic parenchymal cells occurs along the sinusoids in the acinus wherein zonal differences have been described for gradients of oxygen, hormones, and xenobiotic detox-

Gemcitabine monotherapy is a sufficiently active and well-tolerated therapy for patients who have previously undergone chemotherapy with a platinum-based regimen.

Although carbon monoxide (CO) has been reported to protect against hepatobiliary dysfunction, mechanisms for its actions remain unknown. This study aimed to examine actions of physiologically relevant concentrations of CO on biliary excretion. The effects of transportal administration of CO on bile output and constituents were examined in perfused rat livers. In livers of fed rats, CO regulated bile output biphasically in a dose-dependent manner; transportal administration of CO at 4 micro mol/L stimulated bile output by 10%. Under these circumstances, CO increased paracellular junctional permeability and consequently decreased biliary excretion of bile salts. Choleresis elicited by 4 micro mol/L CO coincided with significant increases in biliary excretion of bilirubin-IXalpha and glutathione. The CO-induced choleresis occurred independently of cyclic GMP, coincided with elevated excretion of K(+) and HCO(3)(-), and was abolished by tetraethylammonium, suggesting stimulatory effects of the gas on potassium channels. CO-mediated choleresis and increased excretion of organic anions appeared to be mediated by mrp2, because Eisai hyperbilirubinemia rats, which genetically lack the transporter, did not exhibit choleresis upon the CO administration. These results suggest that CO stimulates mrp2-dependent excretion of bilirubin-IXalpha through mechanisms involving potassium channels, serving as a cooperator standing behind the heme oxygenase reaction to facilitate hepatic heme detoxification.

Liver has been considered to be a major organ that greatly alters its functions through mechanisms involving endothelin (ET)-1, one of the most potent vasoconstrictors produced by vascular endothelial cells. 1-3 Two classes of ET receptors have been identified: ET A receptor is predominantly expressed on vascular smooth muscle cells and executes vasoconstriction 4,5 ; on the other hand, ET B receptor occurs in endothelial cells, Kupffer cells, and vascular smooth muscle cells, and its stimulation in endothelial cells induces nitric oxide (NO)-mediated vasorelaxation through activation of constitutive NO synthase. 4,[6][7][8] Recent investigation has also shown contribution of eicosanoids to ET-induced biological effects, suggesting that its signaling pathways involve both NO-dependent and -independent mechanisms. 9,10 The ET-1 administration has been shown to aggravate hepatic microvascular changes under varied disease models involving endotoxemia, D-galactosamine-induced liver damage, or anoxia-reoxygenation injury. 11-15 During anoxia-reoxygenation, serum ET-1 levels were elevated, and blockade of its effects by ET antagonists attenuated reperfusion injury, suggesting deteriorating effects of this peptide vasoconstrictor on hepatoportal hemodynamics and bile formation. 2,3 Mechanisms by which ET-1 aggravates the hepatic reperfusion injury have been thought to involve impairment of sinusoidal patency through its vasoconstrictive actions. 14,16 This notion was supported by previous studies showing that transportal administration of ET-1 induces a marked vasoconstriction at portal venules and a reduction of bile flow. [17][18][19] However, biological actions of ET-1 endogenously generated upon the oxygen paradox on biliary function and cell viability have not fully been investigated. Further receptor phenotypes of the ET-1 effects responsible for alterations in reoxygenation-induced hepatobiliary dysfunction are largely unknown.The purpose of this study was to examine effects of anoxia and reoxygenation on endogenous ET-1 release and its pathophysiologic links to maintenance of bile formation and cell viability in isolated perfused rat livers. The current results suggest that ET-1 is released during the early period of reoxygenation and stimulates ET B receptor-mediated signaling to trigger NO-dependent and -independent protective mechanisms against anoxia-reoxygenation injury.Abbreviations: ET, endothelin; L-NAME, N -nitro-L-arginine methyl ester; SNAP, S-nitroso-N-acetyl penicillamine; LDH, lactate dehydrogenase; cGMP, cyclic guanosine monophosphate; A/R, anoxia/reoxygenation; B/P, bile salt/phospholipid ratio.From the