This study examines the therapeutic value of inhaled nitric oxide (NO) in attenuating the vascular effects and organ damage resulting from intravascular hemolysis in a canine model. Hemolysis, the in vivo destruction of red blood cells, causes a flux of cell-free hemoglobin (cell-free hemoglobin or stroma-free hemoglobin) into the circulation. Cell-free hemoglobin, when present in large quantities, scavenges NO. NO is an endogenous vasodilator produced by the vascular endothelium. The balance between the production of NO by the vascular endothelium and scavenging of NO by hemoglobin during hemolysis partially determines NO bioavailability. Rapid NO scavenging by cell-free hemoglobin disrupts this balance. This disruption in NO homeostasis permits unopposed vasoconstriction to occur, which can lead to end organ injury. We have developed NO consumption methodologies that conclusively show that elevated levels of hemoglobin consume NO in vivo. By applying these methodologies to a canine model of hemolysis, we hope to determine whether the administration of inhaled NO will attenuate the systemic effects of hemolysis. This study will test our hypothesis that inhaled NO will bind cell-free hemoglobin and therefore attenuate the end organ damage incurred during acute hemolysis. If this study proves that there is a beneficial effect of NO therapy in acute hemolysis, then it will serve as the basis for future human clinical trials. The model development for producing hemolysis has been completed. An appropriate sedation protocol is being developed followed by the main study.
| Minneci, Peter C; Deans, Katherine J; Zhi, Huang et al. (2005) Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. J Clin Invest 115:3409-17 |
