Modeling and Quantitative Analysis Of The Role Of Nitric Oxide In Methemoglobin Anemia

摘要

Methemoglobin anemia is a disorder of the blood caused by abnormally high levels of methemoglobin in the red blood cell (RBC). Methemoglobin is produced in the rbc by irreversible oxidation of the oxygen-carrying ferrous ion (Fe~(2+)) of the heme group of the hemoglobin molecule to its non-oxygen binding ferric state (Fe~(3+)). The oxidation is induced by Nitric Oxide (NO), which is directly inhaled by the patient or synthesized in excess by L-Arginine present in endothelial cells, or is produced from oxidizing nitrates ingested through drinking water and/or pharmaceutical agents.In this work, we study the role of NO in the pathophysiology of methemoglobin anemia and perform quantitative analysis of the relation between levels of NO inhaled/ingested/produced by the patient and the severity of the disease. Reactions of NO occurring in the rbc with both oxy- and deoxy-hemoglobin are considered in conjunction with the reaction between oxygen and deoxyhemoglobin to form oxyhemoglobin and that for the reconversion of methemoglobin to deoxyhemoglobin. Our model captures the dynamics of different reactive species in the rbc, such as NO, oxygen, oxy-, deoxy-, met- and nitrosyl-hemoglobin for the case of normal as well as diseased humans, by allowing for pulmonary uptake of inhaled NO and/or diffusional transport of endothelial-derived NO. Our results indicate that an eight-fold increase in rate of endothelial production of NO over normal may be considered to be critical for the patient since it decreases oxygen saturation level to below 95%, leading to significant hypoxemia. We also study the effect of oxygen therapy on methemoglobin and oxygen saturation levels in the blood and quantify the severity of hypoxemia by stratifying patients who are oxygen responsive from those who fail to respond to pure oxygen.