Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Jin Hyen Baek, … , Dominik J. Schaer, Paul W. Buehler
Published May 5, 2017; First published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e93577. https://doi.org/10.1172/jci.insight.93577.
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Research Article Hematology Vascular biology

Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood

Abstract

Non–transferrin-bound iron (NTBI) and free hemoglobin (Hb) accumulate in circulation following stored RBC transfusions. This study investigated transfusion, vascular disease, and mortality in guinea pigs after stored RBC transfusion alone and following cotransfusion with apo-transferrin (apo-Tf) and haptoglobin (Hp). The effects of RBC exchange transfusion dose (1, 3, and 9 units), storage period (14 days), and mortality were evaluated in guinea pigs with a vascular disease phenotype. Seven-day mortality and the interaction between iron and Hb as cocontributors to adverse outcome were studied. Concentrations of iron and free Hb were greatest after transfusion with 9 units of stored RBCs compared with fresh RBCs or stored RBCs at 1- and 3-unit volumes. Nine units of stored RBCs led to mortality in vascular diseased animals, but not normal animals. One and 3 units of stored RBCs did not cause a mortality effect, suggesting the concomitant relevance of NTBI and Hb on outcome. Cotransfusion with apo-Tf or Hp restored survival to 100% following 9-unit RBC transfusions in vascular diseased animals. Our data suggest that increases in plasma NTBI and Hb contribute to vascular disease–associated mortality through iron-enhanced Hb oxidation and enhanced tissue injury.

Authors

Jin Hyen Baek, Ayla Yalamanoglu, Yamei Gao, Ricardo Guenster, Donat R. Spahn, Dominik J. Schaer, Paul W. Buehler

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Figure 5

Systemic vascular and renal tissue injury following 9-unit stored red blood cell (S-RBC) transfusion following coadministration of apo-transferrin (apo-Tf) or haptoglobin (Hp).

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Systemic vascular and renal tissue injury following 9-unit stored red bl...
(A) H&E staining of thoracic aorta tissue of guinea pigs transfused with 9 units S-RBCs and stained for non-heme iron. Left: Original magnification, ×100. Scale bars: 500 μm. Right: The arrow (top image) represents the region of the high-magnification image (bottom) showing iron deposition within the vascular wall. Original magnification, ×100 (top) and ×960 (bottom). Scale bars, 500 μm (top) and 50 μm (bottom). A, adventitia; M, media; I, intima. The effect of apo-Tf and Hp infusions are shown (magnification, ×100; scale bar, 500 μm). (B) Aortic injury severity score for each transfusion dose group (n = 10 animals). ANOVA with a multiple comparisons test was performed and results are as follows. Comparison with sham control (0 units): 0 units versus 9 units S-RBCs (n = 10, P = 0.0001). Comparison with 9 units S-RBCs: 9 units S-RBCs versus 9 units S-RBCs + apo-Tf (n = 10, P = 0.0001); 9 units S-RBCs versus 9 units S-RBCs + Hp (n = 10, P = 0.0001). (C) Light microscopy images of renal cortical tissue from 9-unit S-RBC–transfused stained with H&E. Original magnification, ×200. Scale bars: 200 μm. The solid arrows show necrotic tubules with absence of nuclei, lacking intact lumen. The effect of apo-Tf and Hp dosing are shown. (D) Renal LCN2 (NGAL) mRNA expression in kidney tissues is presented as fold induction relative to the expression in control animals. Comparison with sham control (0 units): 0 units versus 9 units S-RBCs (n = 5, P = 0.0002). Comparison between 9 units S-RBCs: 9 units S-RBCs versus 9 units S-RBCs + apo-Tf (n = 5, P = 0.005); 9 units S-RBCs versus 9 units S-RBCs +Hp (n = 5, P = 0.0008). All data are presented as individual values with the mean ± SD. *Indicates significant between-group differences. Magnification = ocular lens (×10) × objective.