Protection by glycyrrhizin against warm ischemia-reperfusion-induced cellular injury and derangement of the microcirculatory blood flow in the rat liver.
OBJECTIVE
The mechanism by which ischemia-reperfusion (I/R)-induced derangement of the hepatic microcirculation leads to tissue injury is not fully understood. We postulated that alterations to the hepatic microcirculation, including hemodynamic derangement and increased leukocyte-endothelium interaction, play a role, and that glycyrrhizin exerts its hepatoprotective effects, in part, by reducing these microcirculatory changes.


METHODS
Wistar rats were subjected to 30-60 minutes segmental hepatic ischemia, followed by 120 minutes of reperfusion. Glycyrrhizin was administered prior to ischemia. Using intravital fluorescence microscopy, the administration of fluorescein isothiocyanate-conjugated erythrocytes allowed the measurement of erythrocyte-velocity (RBC(vel)), lobular, and sinusoidal perfusion. Bleb formation was observed by electron microscopy. Blood and tissue were taken for the assessment of liver injury.


RESULTS
Glycyrrhizin reduced I/R-induced liver injury (histology, liver enzymes) and reduced hepatocyte apoptosis (TUNEL, caspase-3 activity). Glycyrrhizin inhibited hepatocyte bleb formation and reversed the I/R-induced reductions in lobular perfusion and RBC(vel). Leukocyte rolling and adherence in postsinusoidal venules and neutrophil infiltration were reduced by glycyrrhizin. I/R-induced elevation in HMGB1 was prevented by glycyrrhizin.


CONCLUSIONS
Early bleb formation with deranged microcirculatory flow and leukocyte-endothelium interaction would appear to contribute to I/R-induced hepatocellular injury. Glycyrrhizin exerts its hepatoprotective effect by preventing these changes, in addition to a direct cellular effect.
Mabuchi
Ayako
A
Microcirculation Research Laboratory, Department of Physiology, University of Otago, Dunedin, New Zealand.
Wake
Kenjiro
K
Marlini
Muhamad
M
Watanabe
Hitomi
H
Wheatley
Antony M
AM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D001783:Blood Flow Velocity / Q000187:drug effects*; D002448:Cell Adhesion; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D036904:Leukocyte Rolling; D008102:Liver Circulation / Q000187:drug effects*; D008833:Microcirculation; D018715:Microscopy, Video; D020556:Neutrophil Infiltration; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*
D000893:Anti-Inflammatory Agents; D020011:Protective Agents; D019695:Glycyrrhizic Acid