Poly(ADP-ribose) polymerase triggers the microvascular mechanisms of hepatic ischemia-reperfusion injury.
Activation of poly(ADP-ribose) polymerase (PARP) mediates oxidative stress-induced cell injury. We tested the hypothesis that PARP contributes to ischemia-reperfusion (I/R) damage of the liver by triggering the mechanisms of microcirculatory failure. Leukocyte- and platelet-endothelial cell interactions as well as sinusoidal perfusion were analyzed by intravital fluorescence microscopy after lobar hepatic I/R (90 min/30 min) in C57BL/6 x 129/Sv wild-type (PARP+/+) and PARP-deficient (PARP-/-) mice. Hepatic I/R induced leukocyte/platelet-endothelial cell interactions and tissue injury in PARP+/+ mice, as indicated by impaired sinusoidal perfusion and increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) serum activities. In PARP-/- mice, however, the postischemic increase in the numbers of rolling/adherent leukocytes and platelets was significantly lower. In addition, I/R-induced translocation of CD62P as well as mRNA expression of CD62E, CD54, and CD106 were attenuated. The degree of perfusion failure was reduced and the increase in the ALT/AST activities was lower in PARP-/- mice compared with PARP+/+ mice. We conclude that PARP contributes to hepatic microvascular injury by triggering the expression/translocation of adhesion molecules and modulating leukocyte/platelet-endothelial cell interactions.
Institute for Surgical Research, University of Munich, D-81377 Munich, Germany.
Andrej
A
Khandoga
Georg
G
Enders
Peter
P
Biberthaler
Fritz
F
Krombach
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001792:Blood Platelets / Q000502:physiology; D002450:Cell Communication; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005260:Female; D007511:Ischemia / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology; D008099:Liver / Q000201:enzymology; D008102:Liver Circulation; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D008833:Microcirculation / Q000502:physiology; D019007:P-Selectin / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000503:physiopathology*
D019007:P-Selectin; D012333:RNA, Messenger; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase