Evaluation of renal oxygen homeostasis in a preclinical animal model to elucidate difference in blood quality after transfusion

Baek, Jin Hyen; Yalamanoglu, Ayla; Moon, So Eun; Gao, Yamei; Buehler, Paul W.

doi:10.1111/trf.14560

Cited by 7 publications

(5 citation statements)

References 33 publications

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“…The renal medulla is extremely sensitive to small shifts in tissue pO 2 and provides a relevant anatomical region to discriminate differences in efficient O 2 delivery, particularly with transfusion solutions. The present data are consistent with studies demonstrating increased hypoxia-inducible factors −1 and −2, erythropoietin production, and renal medullary hypoxia in a guinea pig model of blood transfusion . In this study, we also observed signs of cardiac dysfunction that are consistent with ischemia.…”

Section: Discussionsupporting

confidence: 93%

“…The present data are consistent with studies demonstrating increased hypoxia-inducible factors −1 and −2, erythropoietin production, and renal medullary hypoxia in a guinea pig model of blood transfusion. 49 In this study, we also observed signs of cardiac dysfunction that are consistent with ischemia. It should be stated that both the renal and cardiac signs were also apparent in the ND model, albeit to a lesser extent.…”

Section: ■ Discussionsupporting

confidence: 67%

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The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation

Lamb,

Greenfield,

Thangaraju

et al. 2023

Mol. Pharmaceutics

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Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on tissue oxygenation following hemorrhage and resuscitation in specialized animal models that challenge their resuscitative capabilities. Pre-existing conditions that compromise the vasculature and end organs, such as the liver, may limit the effectiveness of resuscitation and exacerbate the toxicity of these molecules, which is an important but minimally explored therapeutic dimension. In this study, we compared the effective oxygen delivery of intermediate molecular weight PolyhHb (PolyhHb-B3; 500−750 kDa) to high molecular weight PolyhHb (PolyhHb-B4; 750 kDa−0.2 μm) for resuscitative effectiveness in guinea pig models subjected to hemorrhagic shock. We evaluated how the size of PolyhHb impacts hemodynamics and tissue oxygenation in normal guinea pigs and guinea pigs on an atherogenic diet. We observed that while PolyhHb-B3 and -B4 equivalently restore hemodynamic parameters of normal-dieted guinea pigs, high-fat-dieted guinea pigs resuscitated with PolyhHb-B4 have lower mean arterial pressures, impaired tissue oxygenation, and higher plasma lactate levels than those receiving PolyhHb-B3. We characterized the plasma of these animals following resuscitation and found that despite similar oxygen delivery kinetics, circulating PolyhHb-B3 and -B4 demonstrated a sizedependent increase in the plasma viscosity, consistent with impaired perfusion in the PolyhHb-B4 transfusion group. We conclude that intermediate-sized PolyhHbs (such as -B3) are ideal for further research given the effective resuscitation of hemorrhagic shock based on tissue oxygenation in hypercholesterolemic guinea pigs.

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Section: Discussionsupporting

confidence: 93%

Section: ■ Discussionsupporting

confidence: 67%

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation

Lamb,

Greenfield,

Thangaraju

et al. 2023

Mol. Pharmaceutics

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“…Subsequently, Frontiers in Physiology frontiersin.org EPO accumulated in the plasma, indicating a decreased O 2 availability in the kidneys. Conversely, all variables remained at basal levels in the fresh blood group (Baek et al, 2018). Our observations in cells clearly agree with these experimental observations in this animal model.…”

Section: Discussionsupporting

confidence: 91%

Changes in hemoglobin oxidation and band 3 during blood storage impact oxygen sensing and mitochondrial bioenergetic pathways in the human pulmonary arterial endothelial cell model

Jana,

Kassa,

Wood

et al. 2023

Front. Physiol.

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Red blood cells (RBCs) undergo metabolic, oxidative, and physiological changes during storage, collectively described as the “storage lesion.” The impact of storage on oxygen homeostasis, following transfusion, is not fully understood. We show that RBC storage induces changes in oxygen binding that were linked to changes in oxygen sensing (hypoxia-inducible factor, HIF-1α) mechanisms and mitochondrial respiration in human pulmonary arterial endothelial cells (HPAECs). A decrease in oxygen affinity (P50) to approximately 20 from 30 mmHg was seen at the first week but remained unchanged for up to 42 days. This led to the suppression of HIF-1α in the first 3 weeks due to limited oxygen supplies by RBCs. Furthermore, membrane oxidative damage, band 3 alterations, and subsequent microparticle (MP) formation were also noted. Mass spectrometric analysis revealed the upregulation of transitional endoplasmic reticulum ATPase, essential for clearing ROS-damaged membrane proteins and the protein DDI1 homolog, a proteasomal shuttle chaperone. Band 3 complex proteins and superoxide dismutase were among the downregulated proteins. Mitochondrial oxygen consumption rates measured in HPAECs incubated with RBC-derived MPs (14-day and 42-day) showed a rise in maximal respiration. Intervention strategies that target intracellular hemoglobin (Hb)’s redox transitions and membrane changes may lead to the reestablishment of oxygen homeostasis in old RBCs.

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“…Red blood cells were fixed (1% glutaraldehyde in 0.1M phosphate buffer) and post-fixed with 1% osmium tetroxide for 1 h at room temperature, prior to further preparation and evaluation by scanning electron microscopy, as described (Baek et al, 2018).…”

Section: Red Blood Cell Morphological Evaluationmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

et al. 2020

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As part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics. Here we provide the first comparative metabolomics analysis of fresh and stored human (n = 21, 10 males, 11 females), olive baboon (n = 20), and rhesus macaque (n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. For example, through a combination of steady state measurements and 13 C 6 15 N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.

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Evaluation of renal oxygen homeostasis in a preclinical animal model to elucidate difference in blood quality after transfusion

Abstract: The evaluation of renal O homeostasis after transfusion represents an effective approach to defining RBC quality between predicate and novel processing. Methods are adapted from standardized techniques and ideal for preclinical evaluation.

Cited by 7 publications

References 33 publications

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation

Changes in hemoglobin oxidation and band 3 during blood storage impact oxygen sensing and mitochondrial bioenergetic pathways in the human pulmonary arterial endothelial cell model

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

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