S-nitrosylation therapy to improve oxygen delivery of banked blood

Abstract

From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO 2 , but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO 2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O 2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.ethyl nitrite | hemoglobin cysbeta93 | nitric oxide | storage lesion

Storage of Erythrocytes Induces Suicidal Erythrocyte Death

“…Storage lesions further include oxidative injury by reactive oxygen species (superoxide, hydroxyl radical, or hydrogen peroxide) and metabolically programmed cell death [54]. Erythrocytes with storage lesions can release toxic products including lysophospholipids and free iron and may lead to decreased availability of nitric oxide [53][54][55][56]. A decrease of S-nitrosohemoglobin (SNO-Hb) in stored RBC impairs their ability to exert hypoxic vasodilation and may thus compromise tissue perfusion and oxygenation [55,56].…”

“…Erythrocytes with storage lesions can release toxic products including lysophospholipids and free iron and may lead to decreased availability of nitric oxide [53][54][55][56]. A decrease of S-nitrosohemoglobin (SNO-Hb) in stored RBC impairs their ability to exert hypoxic vasodilation and may thus compromise tissue perfusion and oxygenation [55,56]. It is noteworthy that nitric oxide is a powerful inhibitor of eryptosis [57].…”

Autologous Transfusion of Stored Red Blood Cells Increases Pulmonary Artery Pressure

“…Transfusion of blood stored for prolonged periods into either lambs or dogs produces acute pulmonary hypertension (12,(28)(29)(30). Baron and coworkers (12) developed a model of autologous blood transfusion in the awake lamb and reported that top-load transfusion of one unit of blood stored for 40 days induced transient pulmonary vasoconstriction and an increased PAP.…”

Persulfidation (S-sulfhydration) and H2S

“…(Hess and Stamler 2012;Seth and Stamler 2011;Foster et al 2009;Lima et al 2010). S-nitrosation of haemoglobin has been proposed to regulate its ability to release oxygen (Reynolds et al 2013). S-nitrosation of ryanodine receptors regulates intracellular Ca 2+ levels (Xu et al 1998) as does S-nitrosation of transient receptor potential cation channels (TRPs) (Yoshida et al 2006).…”