Conjugated desferoxamine attenuates hepatic microvascular injury following ischemia/reperfusion.
Iron-dependent oxy radicals have been implicated in reperfusion injury. Although the iron chelator desferoxamine (DFO) is beneficial, its hemodynamic effects and short vascular retention limit its use in vivo. We tested whether DFO conjugated to a high-molecular-weight starch might ameliorate in vivo hepatic microvascular injury without adverse side effects following 120 min of ischemia. Prior to reperfusion, conjugated DFO (100 mg/kg), vehicle (Veh), or saline (I/R) was administered. After 90 min of reperfusion, blood was collected for serum transaminase determination (ALT; U/liter), and fluorescein-albumin was injected to label perfused microvessels, which were quantified in frozen sections by a point-count technique. Tissue edema was estimated by wet to dry weight ratios (W/D). Reperfusion results in hepatocyte injury (rise in ALT and W/D) and a 30% loss of perfused microvessels. Intravenous administration of conjugated DFO produces no significant change in systemic hemodynamics, whereas both ALT and tissue edema were decreased by approximately 50%. Moreover, perfused microvessels were restored virtually to nonischemic control levels. Enhanced perfusion and attenuated cell injury with DFO suggest that microvascular failure and resultant cell death are mediated, at least in part, by iron-dependent mechanisms in reperfusion.
Drugas
G T
GT
Division of Pediatric Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Paidas
C N
CN
Yahanda
A M
AM
Ferguson
D
D
Clemens
M G
MG
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D003676:Deferoxamine / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D013213:Starch / Q000031:analogs & derivatives*
D013213:Starch; D003676:Deferoxamine