Protein-Based Blood Substitutes: Recent Attempts at Controlling Pro-Oxidant Reactivity with and Beyond Hemoglobin

Abstract

Reviewed here are recent attempts to produce protein-based artificial oxygen carriers (“blood substitutes”). Most of these involve chemical or physical modifications on hemoglobin, although a recent line of research using hemerythrin instead of hemoglobin is also described. The focus is set on the extent to which these modifications alter the redox reactivity of the proteins, and on ways in which this can be done systematically and purposefully, within the framework of a working hypothesis where redox side-reactions hold an important role in the physiological outcome of experimental transfusions with artificial oxygen carriers.

Periodate-oxidized alginate as polycondensation reagent for hemoglobin

“…Conditions: 10 µM protein, 80 µM peroxide, PBS, room temperature illustrates oxygen binding curves for copolymerized and native hemoglobin. It may be seen that the cooperativity effect disappears in derivatized Hb while affinity towards oxygen increases compared with native hemoglobin, in line with observations previously noted for most other polycondensates based on hemoglobin or other related proteins [10,[16][17][18][19][20][21][22].…”

Artificial Oxygen Carriers—Past, Present, and Future—a Review of the Most Innovative and Clinically Relevant Concepts

“…Encasing in any type of membrane by crosslinking between monomers (to obtain stable tetramers) as well as tetramers (to affect O 2 affinity or size) (Centis and Vermette, 2009), can reduce these side effects. Furthermore increasing knowledge on the Dissociation into dimers (Chang, 1988;Elmer et al, 2012) • Overloading the renal tubular cells (renal failure) Nitric oxide (NO) stealing property mainly from the endothelial cell layer (Doherty et al, 1998;Olson et al, 2004;Cabrales and Friedman, 2013;Alayash, 2014) • Systemic and pulmonary vasoconstriction (myocardial damage pulmonary hypertension) • Lack of mediator of thrombocyte aggregation and adhesion (impaired clotting) • Gastrointestinal side effects Local hyperoxia due to decreased oxygen affinity (no diffusion barrier existent) (McCarthy et al, 2001;Alayash, 2014) • Systemic hypertension Auto-oxidation (Buehler et al, 2010;Scurtu et al, 2013;Alayash, 2014) • Nonfunctional hemoglobin • Formation of superoxide ions • Altering transcriptional activity of heme oxygenase and other antioxidant enzymes In organ transplantation, the major goal of AOCs is organ retention and quality improvement prior to transplantation. The use of AOCs allows for normothermic perfusion without RBC concentrates.…”

Comparative In Vivo Effects of Hemoglobin-Based Oxygen Carriers (HBOC) with Varying Prooxidant and Physiological Reactivity

“…Beyond instructive insight into the biochemistry and into the in vitro behaviour of HBOCs and of their components[ 25 ], the still-extant clinical side-effects are an argument for more detailed exploration of HBOC performance in animal models–in the hope of paving the way for better-informed choices in the design of better HBOC candidates[ 3 , 26 – 34 ]. We have previously reported upon the preparation of a range of HBOCs based on bovine Hb with wide differences in prooxidant reactivities[ 5 , 7 , 25 , 35 – 38 ], and on their effects on human cell cultures (human umbilical vein endothelial cells, HUVEC, and to some extent lymphocytes)[ 5 , 25 , 36 – 38 ]. All of these preparations have large molecular weights–the main differences consisting in the autooxidation rates and in the varying abilities to resist damage inflicted by hydrogen peroxide.…”