TY - JOUR
T1 - Effect of PJ-34 PARP-Inhibitor on Rat Liver Microcirculation and Antioxidant Status
AU - Szijártó, Attila
AU - Batmunkh, Enkhjargal
AU - Hahn, Oszkár
AU - Mihály, Zoltán
AU - Kreiss, Adám
AU - Kiss, András
AU - Lotz, Gábor
AU - Schaff, Zsuzsa
AU - Váli, László
AU - Blázovics, Anna
AU - Geró, Domokos
AU - Szabó, Csaba
AU - Kupcsulik, Péter
N1 - Funding Information:
The authors would like to thank Rita Stangl, Judit Tamás, Tamás Halasi for the excellent technical assistance during this study. We gratefully acknowledge Simon Fischer for his help. The work of C.S. and G.D. was supported by the Office of National Research and Technology, Hungary.
PY - 2007/9
Y1 - 2007/9
N2 - Background: Ischemia-reperfusion (I-R) injury during liver resection leads to the production of toxic free radicals and oxidants that influence the microcirculation. DNA single-strand breaks can be induced by these reactive species. In response to excessive DNA damage, PARP [poly(ADP-ribose) polymerase] becomes overactivated, which can lead to cellular ATP depletion and cell death. The aim of our study was to evaluate whether PARP is expressed in post-ischemic liver, and to examine the effect of the administration of PJ-34 PARP inhibitor on liver function, histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) reaction, and the oxidative state of the liver after injury. Methods: Male Wistar rats (weighing 250 g) underwent 60 min of normothermic, segmental liver ischemia followed by 30 min of reperfusion. The animals (n = 45) were divided into three groups: sham operated; I-R (control) treated with saline; and PJ-34 pre-treated (10 mg/kg i.v.). Hepatic microcirculation was monitored by a laser Doppler flowmeter. The reperfusion was characterized as the integral of the reperfusion area (RA) and the maximal plateau (PM). Histological alterations, TUNEL-reaction, serum, and liver tissue antioxidant levels, as well as serum ALT and AST levels were measured. Results: Upon reperfusion, the PJ-34 group had significantly (P < 0.05) higher flow rates than control groups (PMPJ-34: 58%, PMcontrol: 37%; RAPJ-34.: 48%, RAcontrol: 25%). At the end of the 30 min reperfusion, PJ-34 resulted in significantly (P < 0.05) lower serum ALT and AST levels and chemiluminescent intensity (free radicals) of the liver. The liver's free SH-group concentration and H-donor ability of the plasma was elevated in the PARP-inhibitor treated group. Positive staining for TUNEL, after PJ-34 pre-treatment was significantly increased (P < 0.05); in contrast, the control tissues were less positively stained for TUNEL but necrotic tissue was abundant. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.
AB - Background: Ischemia-reperfusion (I-R) injury during liver resection leads to the production of toxic free radicals and oxidants that influence the microcirculation. DNA single-strand breaks can be induced by these reactive species. In response to excessive DNA damage, PARP [poly(ADP-ribose) polymerase] becomes overactivated, which can lead to cellular ATP depletion and cell death. The aim of our study was to evaluate whether PARP is expressed in post-ischemic liver, and to examine the effect of the administration of PJ-34 PARP inhibitor on liver function, histopathology, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) reaction, and the oxidative state of the liver after injury. Methods: Male Wistar rats (weighing 250 g) underwent 60 min of normothermic, segmental liver ischemia followed by 30 min of reperfusion. The animals (n = 45) were divided into three groups: sham operated; I-R (control) treated with saline; and PJ-34 pre-treated (10 mg/kg i.v.). Hepatic microcirculation was monitored by a laser Doppler flowmeter. The reperfusion was characterized as the integral of the reperfusion area (RA) and the maximal plateau (PM). Histological alterations, TUNEL-reaction, serum, and liver tissue antioxidant levels, as well as serum ALT and AST levels were measured. Results: Upon reperfusion, the PJ-34 group had significantly (P < 0.05) higher flow rates than control groups (PMPJ-34: 58%, PMcontrol: 37%; RAPJ-34.: 48%, RAcontrol: 25%). At the end of the 30 min reperfusion, PJ-34 resulted in significantly (P < 0.05) lower serum ALT and AST levels and chemiluminescent intensity (free radicals) of the liver. The liver's free SH-group concentration and H-donor ability of the plasma was elevated in the PARP-inhibitor treated group. Positive staining for TUNEL, after PJ-34 pre-treatment was significantly increased (P < 0.05); in contrast, the control tissues were less positively stained for TUNEL but necrotic tissue was abundant. Conclusion: PARP plays a pathogenetic role in the deterioration of the hepatic microcirculation and promotes hepatocellular necrosis in liver reperfusion injury.
KW - PARP
KW - PJ-34
KW - apoptosis
KW - ischemia
KW - laser Doppler flowmeter
KW - liver
KW - reperfusion
UR - https://www.scopus.com/pages/publications/34547947626
UR - https://www.scopus.com/pages/publications/34547947626#tab=citedBy
U2 - 10.1016/j.jss.2006.08.003
DO - 10.1016/j.jss.2006.08.003
M3 - Article
C2 - 17612561
AN - SCOPUS:34547947626
SN - 0022-4804
VL - 142
SP - 72
EP - 80
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -