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Comparative Study
. 1997 Feb-Mar;29(1-2):1333-4.
doi: 10.1016/s0041-1345(96)00581-7.

Comparison of various lazaroid compounds for protection against ischemic liver injury

N Ishizaki  1 , Y Zhu, S Zhang, A Nemoto, Y Kobayashi, V M Subbotin, R G Lee, T E Starzl, S Todo
Affiliations
Comparative Study

Comparison of various lazaroid compounds for protection against ischemic liver injury

N Ishizaki et al. Transplant Proc. 1997 Feb-Mar.

Abstract

Lazaroids are a group of 21 -aminosteroids that lack steroid action but have a potent cytoprotective effect by inhibiting iron-dependent lipid peroxidation. However, there have been conflicting reports on the effectiveness and potency of the various lazaroid compounds. In this study, we compared the effectiveness of three major lazaroids on warm liver ischemia in dogs using a 2-hr hepatic vascular exclusion model. The agents were given to the animals intravenously for 30 min before ischemia. The animals were divided into 5 groups: Control (n=10), no treatment; Group F (n=6), U-74006F (10 mg/kg); Group G (n=6), U-74389G (10 mg/kg); Group A1 (n=6), U-74500A (10 mg/kg); Group A2 (n=6), U-74500A (5 mg/kg). The effect of treatment was evaluated by two-week animal survival, hepatic tissue blood flow, liver function tests, blood and tissue biochemistry, and histological analyses. Animal survival in all treated groups was significantly improved compared with the control (83–100% versus 30%). Elevation of liver enzymes after reperfusion was markedly attenuated in treated groups, except for an early significant increase in Group G. Postreperfusion hepatic tissue blood flow was much higher in all treated animals (50% of the preischemic level vs. 25% in the control). Lazaroids, particularly U-74500A at 5 mg/kg (Group A2), suppressed adenine nucleotide degradation during ischemia and enhanced the resynthe-sis of high-energy phosphates after reperfusion. Although structural abnormalities in postreperfusion liver tissues were markedly ameliorated in all treated groups, Group A2 showed significantly less neutrophil infiltration. Liver injury from warm ischemia and reperfusion was attenuated with all lazaroid compounds, of which U-74500A at 5 mg/kg exhibited the most significant protective activity.

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Figures

Figure 1
Figure 1
(A) Changes in lactate dehydrogenase (LDH) after reperfusion: * P<0.05 vs. Control, Groups F, A1, A2; ** P<0.05 vs. Groups F, A1, A2; # P<0.05 vs. Groups F, G, A1, A2. (B) Changes in alanine aminotransferase (ALT) after reperfusion: * P<0.05 vs. Groups F, A1, A2; ** P<0.05 vs. Groups F, G, A1, A2.
Figure 2
Figure 2
Tissue blood flow in the liver during ischemia and after reperfusion. Values are expressed as a percentage of the preischemic level. * P<0.05 vs. Control, Groups F, G; ** P<0.05 vs. Control, Groups F, G, A1.
Figure 3
Figure 3
Changes in plasma malodialdehide (MDA) at the end of warm ischemia and after reperfusion. * P<0.05 vs. Control.
FIGURE 4
FIGURE 4
(A) Control group liver tissue 60 min after reperfusion. Hepatocytes necrosis and vacuolation were found at pericentral area and other scattered areas. Hemorrhage and sinusoidal congestion were found at the site of parenchymal necrosis. Parenchymal damage was associated with neutrophil infiltration. (H&E; X200). (B) Group A2 liver tissue 60 min after reperfusion. Liver architecture was well preserved. Liver parenchymal damage was not significant, with only single cell necrosis or vacuolation. Hemorrhage and sinusoidal congestion were rare. Neutrophil infiltration was reduced compared to Control. (H&E; X200).
FIGURE 5
FIGURE 5
Number of neutrophils in the liver 60 min after reperfusion: * P<0.05 vs. Control, Groups F, G, A1; ** Average numbers in 10 power fields (x100).
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References

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