Vasoactive, pro-inflammatory and pro-coagulant effects of hemoglobin-based oxygen carriers in a murine model of hemorrhagic shock

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In Germany in 2007, road accidents claimed nearly 5,000 lives and caused life-threatening trauma to more than 430,000 people. Many of these individuals had hemorrhagic shock and required fluid resuscitation. As compared to clear fluids, cell-free hemoglobin-based oxygen carriers (HBOC) carry oxygen and could provide effective metabolic support for the organs of the injured patient with hemorrhagic shock when typematched blood is unavailable. This goal of a safe and effective use of HBOC has been pursued for years without success, most recently due to an excess of myocardial infarction and death in patients receiving HBOCs. Many believe that this noxious side-effect is due to NO scavenging by HBOC. In the present project, we will focus on studying the vasoactive, pro-inflammatory, and pro-coagulant side effects of HBOCs and their prevention by inhaled NO supplementation. Specifically, we will (i) characterize and compare the proinflammatory and pro-coagulant effects of HBOC, tetrameric hemoglobin, and whole blood in both wild-type mice and mice congenitally deficient in endothelial NO synthase (NOS3-/-), (ii) test whether breathing NO can prevent these noxious HBOC-induced side effects, and (iii) investigate the efficacy of the combination of inhaled NO and HBOC infusion on hemodynamic and biochemical responses, as well as key organ tissue oxygenation, cell death and inflammation in a well-characterized murine hemorrhagic shock model. In this manner we hope to open a pathway to the safe and effective use of HBOCs when blood is unavailable, while preventing noxious side-effects.