Prostacyclin analogue (OP-2507) induces delayed ex vivo neutrophil apoptosis and attenuates reperfusion-induced hepatic microcirculatory derangement in rats.
Leukocyte-endothelial adherence and changes of blood flow in microcirculation are associated with the development of ischemia-reperfusion injury in the liver. Polymorphonuclear neutrophil (PMN) apoptosis is essential to maintain homeostasis and plays a major role in limiting the reperfusion-related systemic effects. This study investigates the effects of a prostacyclin analogue (OP-2507) on hepatic ischemia-reperfusion injury. Adult, male Sprague-Dawley rats were used. Five groups were evaluated: (1) sham-operated control, n = 8; (2) ischemia control (1-h ischemia, 5-h reperfusion), n = 8; (3) intravenous infusion with OP-2507 ([15 cis-14-propylcyclohexyl]-16,17,18,19,20-pentanor-9-deoxy-9alpha,6-ni-trilo-PGF, methyl eater) at a dose of 1 microg/kg/min plus ischemia, n = 8; (4) intravenous infusion with OP-2507 at a dose of 0.1 microg/kg/min plus ischemia, n = 8, and (5) sham-operated control and intravenous infusion with OP-2507 at a dose of 1 microg/kg/min, N =8. Laser-Doppler flowmetry and an in vivo microscopy were used to investigate hepatic microcirculation. PMN apoptosis was quantitated by flow-cytometric labeling of DNA strand breaks. Tissue malondialdehyde and adenosine triphosphate were determined at the end of the experiment. Compared with the ischemia control group, OP-2507 significantly improved harmful insults following ischemia-reperfusion. The changes of mean systemic arterial pressure following ischemia-reperfusion have been significantly attenuated by OP- 2507 at both doses. OP-2507 lessened adherent leukocyte count in the post-sinusoid venules, and improved flow velocity in these areas. OP-2507 at both doses reduced malondialdehyde and increased adenosine triphosphate levels and this effect was dose-related. The activity of delayed ex vivo PMN apoptosis was significantly lower in the ischemia group than that of control and treatment groups. OP-2507 induced the activity of PMN apoptosis and its effect is dose-related, also. The PMN apoptosis activity is strongly correlated with parenchymal damages. This study demonstrates that OP-2507 treatment with ischemia may ameliorate the ischemia-reperfusion injury of the liver in the rat model, and increase spontaneous neutrophil apoptosis ex vivo.
Chen
M F
MF
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
Chen
J C
JC
Chiu
D F
DF
Ng
C J
CJ
Shyr
M H
MH
Chen
H M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018821:CD18 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D018821:CD18 Antigens; C049453:OP 2507; D011464:Epoprostenol