Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging

Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Decreased deformability of RBCs is, therefore, one of the factors that can contribute to the elimination of aged or damaged RBCs from the circulation. This process can also cause impaired oxygen delivery, which contributes to the pathology of a number of diseases. Studies from our laboratory have shown that oxidative stress plays a significant role in damaging the RBC membrane and impairing its deformability. RBCs are continuously exposed to both endogenous and exogenous sources of reactive oxygen species (ROS) like superoxide and hydrogen peroxide (H(2)O(2)). The bulk of the ROS are neutralized by the RBC antioxidant system consisting of both non-enzymatic and enzymatic antioxidants including catalase, glutathione peroxidase and peroxiredoxin-2. However, the autoxidation of hemoglobin (Hb) bound to the membrane is relatively inaccessible to the predominantly cytosolic RBC antioxidant system. This inaccessibility becomes more pronounced under hypoxic conditions when Hb is partially oxygenated, resulting in an increased rate of autoxidation and increased affinity for the RBC membrane. We have shown that a fraction of peroxyredoxin-2 present on the RBC membrane may play a major role in neutralizing these ROS. H(2)O(2) that is not neutralized by the RBC antioxidant system can react with the heme producing fluorescent heme degradation products (HDPs). We have used the level of these HDP as a measure of RBC oxidative Stress. Increased levels of HDP are detected during cellular aging and various diseases. The negative correlation (p < 0.0001) between the level of HDP and RBC deformability establishes a contribution of RBC oxidative stress to impaired deformability and cellular stiffness. While decreased deformability contributes to the removal of RBCs from the circulation, oxidative stress also contributes to the uptake of RBCs by macrophages, which plays a major role in the removal of RBCs from circulation. The contribution of oxidative stress to the removal of RBCs by macrophages involves caspase-3 activation, which requires oxidative stress. RBC oxidative stress, therefore, plays a significant role in inducing RBC aging

The Pathophysiology of Extracellular Hemoglobin Associated with Enhanced Oxidative Reactions

Hemoglobin (Hb) continuously undergoes autoxidation producing superoxide which dismutates into hydrogen peroxide (H2O2) and is a potential source for subsequent oxidative reactions. Autoxidation is most pronounced under hypoxic conditions in the microcirculation and for unstable dimers formed at reduced Hb concentrations. In the red blood cell (RBC), oxidative reactions are inhibited by an extensive antioxidant system. For extracellular Hb, whether from hemolysis of RBCs and/or the infusion of Hb-based blood substitutes, the oxidative reactions are not completely neutralized by the available antioxidant system. Un-neutralized H2O2 oxidizes ferrous and ferric Hbs to Fe(IV)-ferrylHb and oxyferrylHb, respectively. FerrylHb further reacts with H2O2 producing heme degradation products and free iron. OxyferrylHb, in addition to Fe(IV) contains a free radical that can undergo additional oxidative reactions. Fe(III)Hb produced during Hb autoxidation also readily releases heme, an additional source for oxidative stress. These oxidation products are a potential source for oxidative reactions in the plasma, but to a greater extent when the lower molecular weight Hb dimers enter cells and tissues. Heme and oxyferryl have been shown to have a proinflammatory effect further increasing their potential for oxidative stress. These oxidative reactions contribute to a number of pathological situations including atherosclerosis, kidney malfunction, sickle cell disease and malaria. The toxic effects of extracellular Hb are of particular concern for increased hemolysis due to hemolytic anemia. Hemolysis is further exacerbated in various diseases and their treatments. Blood transfusions are required whenever there is an appreciable decrease in RBCs due to hemolysis or blood loss. It is, therefore, essential that transfused blood, whether stored RBCs or blood obtained by an Autologous Blood Recovery System from the patient, does not further increase extracellular Hb

Olfactory dysfunction in aging and neurodegenerative diseases

Alterations in olfactory functions are proposed to be early biomarkers for neurodegeneration. Many neurodegenerative diseases are age-related, including two of the most common, Parkinson’s disease (PD) and Alzheimer’s disease (AD). The establishment of biomarkers that promote early risk identification is critical for the implementation of early treatment to postpone or avert pathological development. Olfactory dysfunction (OD) is seen in 90% of early-stage PD patients and 85% of patients with early-stage AD, which makes it an attractive biomarker for early diagnosis of these diseases. Here, we systematically review widely applied smelling tests available for humans and some animal models and the relationships between OD and normal aging, PD, AD, and other conditions. The utility of OD as a biomarker for neurodegenerative disease diagnosis and future research directions are also discussed

Alterations in the red blood cell membrane proteome in alzheimer's subjects reflect disease-related changes and provide insight into altered cell morphology

Abstract Background Our earlier studies have shown that red blood cell (RBC) morphology in Alzheimer's disease (AD) subjects was altered (> 15% of the RBCs were elongated as compared to 5.9% in normal controls (p Results The data suggest, (1) RBC shape/morphology changes in AD subjects are possibly attributed primarily to the changes (elevation or decrease) in the level of a series of membrane/cytoskeleton proteins involved in regulating the stability and elasticity of the RBC membrane, and (2) changes (elevation or decrease) in the level of a second series of proteins in the RBC membrane proteome reflect similar changes reported earlier by various investigators in AD or animal model of AD. Of particular interest, elevation of oxidative stress response proteins such as heat shock 90 kDa protein 1 alpha in AD subjects has been confirmed by western blot analysis in the RBC membrane proteome. Conclusions The results suggest that this study provides a potential link between the alterations in RBC membrane proteome in AD subjects and AD pathology.</p

Potential Modulation of Vascular Function by Nitric Oxide and Reactive Oxygen Species Released From Erythrocytes

The primary role for erythrocytes is oxygen transport that requires the reversible binding of oxygen to hemoglobin. There are, however, secondary reactions whereby the erythrocyte can generate reactive oxygen species (ROS) and nitric oxide (NO). ROS such as superoxide anion and hydrogen peroxide are generated by the autoxidation of hemoglobin. NO can be generated when nitrite reacts with hemoglobin forming an HbNO+ intermediate. Both of these reactions are dramatically enhanced under hypoxic conditions. Within the erythrocyte, interactions of NO with hemoglobin and enzymatic reactions that neutralize ROS are expected to prevent the release of any generated NO or ROS. We have, however, demonstrated that partially oxygenated hemoglobin has a distinct conformation that enhances hemoglobin-membrane interactions involving Band 3 protein. Autoxidation of the membrane bound partially oxygenated hemoglobin facilitates the release of ROS from the erythrocyte. NO release is made possible when HbNO+, the hemoglobin nitrite-reduced intermediate, which is not neutralized by hemoglobin, is bound to the membrane and releases NO. Some of the released ROS has been shown to be transferred to the vasculature suggesting that some of the released NO may also be transferred to the vasculature. NO is known to have a major effect on the vasculature regulating vascular dilatation. Erythrocyte generated NO may be important when NO production by the vasculature is impaired. Furthermore, the erythrocyte NO released, may play an important role in regulating vascular function under hypoxic conditions when endothelial eNOS is less active. ROS can react with NO and, can thereby modulate the vascular effects of NO. We have also demonstrated an inflammatory response due to erythrocyte ROS. This reflects the ability of ROS to react with various cellular components affecting cellular function