Prostacyclin analogue (OP-2507) induces delayed ex vivo neutrophil apoptosis and attenuates reperfusion-induced hepatic microcirculatory derangement in rats

Shock. 2001 Dec;16(6):473-8. doi: 10.1097/00024382-200116060-00012.

Abstract

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.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • CD18 Antigens / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Epoprostenol / administration & dosage
  • Epoprostenol / analogs & derivatives*
  • Epoprostenol / pharmacology*
  • In Vitro Techniques
  • Liver / drug effects*
  • Liver / injuries*
  • Liver / pathology
  • Liver / physiopathology
  • Liver Circulation / drug effects*
  • Male
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Neutrophils / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology

Substances

  • CD18 Antigens
  • OP 2507
  • Epoprostenol