The possible mechanisms by which modified hemoglobins cause microvascular damage are summarized in Figure 3. It is obvious that in order to prevent oxidative tissue damage by hemoglobin-based blood substitutes during transfusion, the formation of, and the effects of, different nitrogen-and oxygen-derived radicals must be prevented. To prevent formation of such radicals it is necessary to reduce the tendency of the hemoglobin to oxidize, either by chemical modification during manufacture, or by adding an appropriate reducing agent at the time of infusion. Ideally, a therapeutic agent would scavenge all deleterious radicals, whether or not their production is catalyzed by iron, and would be able to cross biological membranes. One possible candidate that has been suggested is Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N oxyl), a stable nitroxide that attenuates the effects of peroxynitrite and oxygen-derived free radicals such as superoxide anions and hydroxyl radicals . Unlike recombinant superoxide dis-mutase, which is not able to cross biological membranes, Tempol permeates biological membranes and accumulates in the cell cytosol. Future studies using molecules such as Tempol, in conjunction with a range of Hb-based blood substitutes with various oxygen affinities and NO scavenging capacities, may lead to a product that both is nontoxic and delivers oxygen at a rate suitable for the conditions.
Auto-oxidation: The removal of electrons from a molecule. In the case of Hb, Fe2+, or ferrous Hb, is auto-oxidized to form Fe3+, or ferric (met) Hb.
Reactive oxygen species: A cluster of atoms, including oxygen, which contains an unpaired electron in its outermost shell. This is an extremely unstable configuration that reacts quickly with other molecules to achieve the stable configuration of four pairs of electrons in the outer shell.
Redox: Changes in the redox status of a molecule involve the addition (reduction) or removal (oxidation) of electrons to or from the molecule.
Shear stress: The intensity of force per unit area acting tangentially to the area.
Vasopressor: A substance that causes an increase in blood pressure by constricting the arteries.
1. Alayash, A. I. (1999). Hemoglobin-based blood substitutes: Oxygen carriers, pressor agents, or oxidants? Nat. Biotech. 17, 545-549. This review provides a summary of the different types of hemoglobin-based blood substitutes for which clinical trials are underway, and provides some insights into the complex redox chemistry of hemoglobin.
2. Sloan, E. R., Koenigsberg, M., Gens, D., Cipolle, M., Runge, J., Mullory, M., and Rodman, G. (1999). Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhage shock: Arandomized controlled efficacy trial. JAMA 282,1857-1864.
3. McCarthy, M. R., Vandergriff, K. D., and Winslow, R. M. (2001). The role of facilitated diffusion in oxygen transport by cell-free hemoglobins: Implications for the design of hemoglobin-based oxygen carriers. Biophys. Chem. 92, 247-117.
4. Moison, R. M. W., van Hoof, E. J. H. A., Clahsen, P. C., van Zoeren Grobben, D., and Berger, H. M. (1996). Influence of plasma preparations and donor red blood cells on the antioxidant capacity of blood from newborn babies: An in vitro study. Acta Paediatr. 85, 220-224.
5. Baldwin, A. L., and Wiley, E. B. (2002). Selenium reduces hemoglobin-induced damage to intestinal mucosa. Art. Cells Blood Subs. Immob. Biotech. 30(1), 1-22.
6. Lee, R., Neya, K., Svizzero, T. A., and Vlahakes, G. J. (1995). Limitations of the efficacy of hemoglobin-based oxygen carrying solutions. J. Appl. Physiol. 79, 236-242.
7. Baldwin, A. L. (1999). Modified hemoglobins produce venular interendothelial gaps and albumin leakage in the rat mesentery. Am. J. Physiol. 277, H650-H659. This paper is one of a series in which fluorescence microscopy is used to demonstrate the focal microvascular leakage caused by intravascular injection of DBBF-Hb.
8. D'Agnillo, F., and Chang, T. M. (1993). Cross-linked hemoglobin-superoxide dismutase-catalase scavenges oxygen-derived free-radicals and prevents methemoglobin formation and iron release. Biomat. Artif. Cells, Immobil. Biotech. 21(5), 609-621.
9. Saetzler, R. K., Arfors, K. E., Tuma, R. F., Vasthare, U., Ma, L., Hsia, C. J. C., and Lehr, H.-A. (1999). Polynitroxylated hemoglobin-based oxygen carrier: Inhibition of free radical-induced microcirculatory dysfunction. Free Radical Biol. Med. 27(1/2), 1-6.
10. Thiemermann, C., McDonald, M. C., and Cuzzocrea, S. (2001). The stable nitroxide, Tempol, attenuates the effects of peroxynitrite and oxygen-derived free radicals. Crit. Care Med. 29(1), 223-224.
Dr. Baldwin is a Professor of Physiology at the University of Arizona and is currently Treasurer of the Microcirculatory Society. Her work on reactive oxygen species and hemoglobin-induced microvascular damage has been supported by NIH for the past 8 years.
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