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Impact of acellular hemoglobin‐based oxygen carriers on brain apoptosis in rats
Author(s) -
Vandegriff Kim D.,
Malavalli Ashok,
Lohman Jeff,
Young Mark A.,
Terraneo Laura,
Virgili Eleonora,
Bianciardi Paola,
Caretti Anna,
Samaja Michele
Publication year - 2014
Publication title -
transfusion
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.045
H-Index - 132
eISSN - 1537-2995
pISSN - 0041-1132
DOI - 10.1111/trf.12643
Subject(s) - apoptosis , hemoglobin , terminal deoxynucleotidyl transferase , cytoprotection , extracellular , reactive oxygen species , kinase , hypoxia (environmental) , p50 , phosphorylation , medicine , chemistry , oxygen , endocrinology , pharmacology , andrology , immunology , tunel assay , biochemistry , transcription factor , organic chemistry , gene
Background Extracellular hemoglobin ( Hb )‐based oxygen carriers ( HBOCs ) are under extensive consideration as oxygen therapeutics. Their effects on cellular mechanisms related to apoptosis are of particular interest, because the onset of proapoptotic pathways may give rise to tissue damage. Study Design and Methods The objective was to assess whether the properties of the Hb that replaces blood during an isovolemic hemodilution would modulate apoptotic‐response mechanisms in rat brain and whether such signaling favors cytoprotection or damage. We exposed rats to exchange transfusion (ET; 50% blood volume and isovolemic replacement with H extend [negative colloid control], MP 4 OX [ PEG ylated HBOC with high oxygen affinity], and αα H b [αα‐cross‐linked HBOC with low oxygen affinity; n = 4‐6/group]). Sham rats acted as control. Animals were euthanized at 2, 6, and 12 hours after ET; brain tissue was harvested and processed for analysis. Results In MP 4 OX animals, the number of neurons that overexpressed the hypoxia‐inducible factor ( HIF )‐1α was higher than in αα H b, particularly at the early time points. In addition, MP 4 OX was associated with greater phosphorylation of protein kinase B ( A kt), a well‐known cytoprotective factor. Indeed, the degree of apoptosis, measured as terminal deoxynucleotidyl transferase–positive neurons and caspase‐3 cleavage, ranked in order of MP 4 OX < H extend < αα H b. Conclusion Even though both HBOC s showed increased levels of HIF ‐1α compared to shams or H extend‐treated animals, differences in signaling events resulted in very different outcomes for the two HBOC s. αα H b‐treated brain tissue showed significant neuronal damage, measured as apoptosis. This was in stark contrast to the protection seen with MP 4 OX , apparently due to recruitment of A kt and neuronal specific HIF ‐1α pathways.