The role of nitric oxide synthase 3 in hemorrhagic shock after resuscitation with stored red blood cells

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Every year, about 75 million units of blood are collected worldwide, about 5 million of them in Germany. In the United States in 2009, about 15 million units of blood were transfused, with a mean duration of storage before transfusion of 18.2 days. Transfusion of blood stored for longer than 14 days is associated with a greater incidence of multiorgan failure, extended hospitalization, and an increased mortality rate. Our hypothesis is that nitric oxide (NO) scavenging by hemoglobin released into the plasma by hemolysis and red cell breakdown during storage and after transfusion of stored blood can trigger severe adverse reactions in the recipient. These adverse reactions include vasoconstriction, inflammation, and platelet activation. In this grant application we propose to analyze if endothelial NO production by the endothelial NO synthase NOS3 is required for the inflammation and platelet activation induced by transfusion of stored blood. Reduced NO levels are associated with endothelial dysfunction, a common pre-existing disorder in patients with diabetes and atherosclerosis. We will investigate whether reduced but not absent vascular NO levels sensitize mice to the inflammatory and platelet-activating effects of stored red blood cell transfusion. Based on this, in a mouse model with hemorrhagic shock, we will test the hypothesis that transfusion of stored blood, by increasing plasma levels of NO-scavenging hemoglobin, enhances the injury associated with hemorrhagic shock and resuscitation.The proposed studies will help to elucidate the physiological and pathophysiological mechanisms responsible for the adverse effects of transfusions with stored blood. In addition, the proposed research will advance our understanding whether reduced vascular NO levels are sufficient to increase the sensitivity of mice with hemorrhagic shock to resuscitation with stored blood cells. Both projects will help to develop therapeutic strategies to protect the transfusion recipients, especially those suffering from chronic comorbidities such as diabetes, obesity, atherosclerosis, or chronic alcohol consumption, and who receive stored blood transfusions.