Is methemoglobin an inert bystander, biomarker or a mediator of oxidative stress—The example of anemia?

Acute anemia increases the risk for perioperative morbidity and mortality in critically ill patients who experience blood loss and fluid resuscitation (hemodilution). Animal models of acute anemia suggest that neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) is adaptive and protects against anemia-induced mortality. During acute anemia, we have observed a small but consistent increase in methemoglobin (MetHb) levels that is inversely proportional to the acute reduction in Hb observed during hemodilution in animals and humans. We hypothesize that this increase in MetHb may be a biomarker of anemia-induced tissue hypoxia. The increase in MetHb may occur by at least two mechanisms: (1) direct hemoglobin oxidation by increased nNOS-derived NO within the perivascular tissue and (2) by increased deoxyhemoglobin (DeoxyHb) nitrite reductase activity within the vascular compartment. Both mechanisms reflect a potential increase in NO signaling from the tissue and vascular compartments during anemia. These responses are thought to be adaptive; as deletion of nNOS results in increased mortality in a model of acute anemia. Finally, it is possible that prolonged activation of these mechanisms may lead to maladaptive changes in redox signaling. We hypothesize, increased MetHb in the vascular compartment during acute anemia may reflect activation of adaptive mechanisms which augment NO signaling. Understanding the link between anemia, MetHb and its treatments (transfusion of stored blood) may help us to develop novel treatment strategies to reduce the risk of anemia-induced morbidity and mortality.

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► Anemia is a risk for increased morbidity and mortality in surgical patients.
► Neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) is adaptive in animal models of anemia.
► Decreasing hemoglobin levels leads to progressive tissue hypoxia and an associated increase in methemoglobin (MetHb) levels in peripheral blood.
► The increase in MetHb levels may be a biomarker of anemic tissue hypoxia.
► The mechanism for increased MetHb during anemia may include direct oxidation of Hb by NO and increased deoxyhemoglobin (DeoxyHb) nitrite reductase activity.
► Tissue nNOS and vascular DeoxyHb nitrite reductase may act cooperatively to generate increased levels of biologically active NO.