Hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) are currently being developed as red blood cell (RBC) substitutes for use in transfusion medicine. Despite significant commercial development, recent late stage clinical results of polymerized hemoglobin (PolyHb) solutions (i.e. Hemopure? (OPK Biotech, Cambridge, MA), a glutaraldehyde polymerized bovine Hb;and PolyHeme? (Northfield Laboratories Inc., Evanston, IL), a glutaraldehyde polymerized pyridoxylated human Hb) hamper further development. Both of these commercial products elicit vasoconstriction at the microcirculatory level, and lead to the development of systemic hypertension and oxidative tissue damage. These side-effects are hypothesized to occur either by a nitric oxide (NO) scavenging or oxygen (O2) oversupply mechanism and are both exacerbated by PolyHb extravasation into the tissue space. In light of these 2 potential mechanisms, it is apparent that PolyHb size will have a profound impact on the extent of vasoconstriction, systemic hypertension and oxidative tissue toxicity. Since, increasing the size of the HBOC will prevent its extravasation through endothelial cell-cell junctions, decreasing the magnitude of the HBOC diffusion coefficient and thus decreasing both the extent of NO scavenging and hyper-oxygenation of the blood vessel wall. Using this simple approach, our team demonstrated that increasing the molecular size of PolyHb eliminated vasoconstriction and hypertension in two different animal species. Prevention of HBOC extravasation should also decrease ROS-induced tissue oxidative damage by preventing the HBOC from coming into intimate contact with tissues. Therefore in this application, we hypothesize that HBOC size will regulate oxidative damage to tissues and organs as well as myocardial function. In order to test the central hypothesis of this application, we propose 2 specific aims:
Specific Aim 1 : Analyze the role of endothelial function on PolyHb toxicokinetics.
Specific Aim 2 : Analyze the role of PolyHb on myocardial function. The proposed work is both significant and innovative, since it seeks to develop safe and efficacious PolyHbs for use in transfusion medicine. In addition, state-of-the-art biophysical techniques and two unique animal models will be used to understand PolyHb physiological responses and determine the clinical potential of these novel materials.
The U.S. blood supply is at risk due to the presence of emerging infectious diseases. In order to preserve the blood supply and protect the population, this application seeks to develop novel oxygen carrying solutions consisting of polymerized hemoglobins that are safe and efficacious by using an animal model with similar antioxidant status to humans.