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J Appl Physiol (January 19, 2006). doi:10.1152/japplphysiol.01374.2005
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Submitted on October 28, 2005
Accepted on January 13, 2006

Salvage of focal cerebral ischemic damage by transfusion of high O2-affinity recombinant hemoglobin polymers in mouse

Masaaki Nemoto1, Toshiaki Mito1, William S. Brinigar2, Clara Fronticelli1, and Raymond C. Koehler1*

1 Department of Anesthesiology and Critical Care Medicine, The Johns Hpokins University, Baltimore, Maryland, USA
2 Department of Chemistry, Temple University, Philadelphia, Pennsylvania, USA

* To whom correspondence should be addressed. E-mail: rkoehler{at}jhmi.edu.

Cell-free hemoglobin solutions with high oxygen affinity might be beneficial for selectively delivering oxygen to ischemic tissue. A recombinant hybrid hemoglobin molecule was designed using the human {alpha}-subunit and the bovine {beta}-subunit, with placement of surface cysteines to permit disulfide bond polymerization of the tetramers. The resulting protein generated from an E. coli expression system had a molecular weight > 1 MDa, a P50 of approximately 3 Torr, and a cooperativity of n = 1.0. Anesthetized mice were transfused during 2-h occlusion of the middle cerebral artery. Compared to transfusion with 5% albumin, cerebral infarct volume was reduced by 41% with transfusion of a 3% solution of the high oxygen-affinity hemoglobin polymer and by 50% with transfusion of a 6% solution of the polymer. Transfusion of a 6% solution of a 500-KDa polymer possessing a P50 of 17 Torr and a cooperativity of n = 2.0 resulted in a 66% reduction of infarct volume. These results indicate that cell-free Hb polymers with P50 values much lower than that of red blood cell hemoglobin are highly capable of salvaging ischemic brain. The assumption that the P50 of blood substitutes should be similar to that of blood might not be warranted when used during ischemic conditions.




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