Effects of Physiological Factors on Oxygen Transport in an in Vitro Capillary System

Lemon, Douglas D.; Boland, Emma; Nair, P. K.; Olson, John S.; Hellums, J. D.

doi:10.1007/978-1-4615-9510-6_4

Cited by 2 publications

(2 citation statements)

References 8 publications

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“…The optimum parameters for oxygen transport by Hb in human red blood cells appear to be a P 50 = 30-50 lM (20-40 mm Hg) at 37°C and association (k¢ O2 ) and dissociation (k O2 ) rate constants ‡ 1 lM (22,35,63,76,93,104,150). The mechanisms that govern O 2 binding have been established in detail and used to design recombinant Hb molecules with P 50 values that range from £ 0.2 to ‡ 200 lM, using both allosteric and active site mutations (14,35,83).…”

Section: Controlling O 2 Affinity and Nodmentioning

confidence: 98%

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Varnado

Mollan

Birukou

et al. 2013

Antioxidants & Redox Signaling

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Significance: The worldwide blood shortage has generated a significant demand for alternatives to whole blood and packed red blood cells for use in transfusion therapy. One such alternative involves the use of acellular recombinant hemoglobin (Hb) as an oxygen carrier. Recent Advances: Large amounts of recombinant human Hb can be expressed and purified from transgenic Escherichia coli. The physiological suitability of this material can be enhanced using protein-engineering strategies to address specific efficacy and toxicity issues. Mutagenesis of Hb can (i) adjust dioxygen affinity over a 100-fold range, (ii) reduce nitric oxide (NO) scavenging over 30-fold without compromising dioxygen binding, (iii) slow the rate of autooxidation, (iv) slow the rate of hemin loss, (v) impede subunit dissociation, and (vi) diminish irreversible subunit denaturation. Recombinant Hb production is potentially unlimited and readily subjected to current good manufacturing practices, but may be restricted by cost. Acellular Hb-based O 2 carriers have superior shelf-life compared to red blood cells, are universally compatible, and provide an alternative for patients for whom no other alternative blood products are available or acceptable. Critical Issues: Remaining objectives include increasing Hb stability, mitigating iron-catalyzed and iron-centered oxidative reactivity, lowering the rate of hemin loss, and lowering the costs of expression and purification. Although many mutations and chemical modifications have been proposed to address these issues, the precise ensemble of mutations has not yet been identified. Future Directions: Future studies are aimed at selecting various combinations of mutations that can reduce NO scavenging, autooxidation, oxidative degradation, and denaturation without compromising O 2 delivery, and then investigating their suitability and safety in vivo. Antioxid. Redox Signal. 18, 2314-2328.

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Section: Controlling O 2 Affinity and Nodmentioning

confidence: 98%

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Varnado

Mollan

Birukou

et al. 2013

Antioxidants & Redox Signaling

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“…High concentration of cell-free hemoglobin once filtered by the kidney, would cause renal tubular damage and glomerular filtration rate (GFR) decrease (Bunn and Jandl 1968, Chang 1971, DeVenuto and Zegna 1982, Dudziak and Bonhard 1980). Technology has allowed for the design and production of recombinant hemoglobin (rHb) that can be planned with specific characteristics, including O 2 affinity (P 50 –O 2 ) (Dou et al 2002, Huang and Olsen 1994, Lemon et al 1988, Varnado et al 2013) and nitric oxide scavenging properties (i.e., the bimolecular rate constant for NO dioxygenation, k′ NOD ) (Tsai et al 2006, Vermeulen Windsant et al 2014, Yu et al 2008, 2009, 2010), but only a few studies have shown how these rHbs affect kidney function or kidney structure. Understanding how the solutions characteristics of these rHbs will differentially affect the microcirculation and the kidney (Palmer and Intaglietta 2014) will aid in determining the importance of these characteristics in developing this class of Hb-based oxygen carrying (HBOC) therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Acute kidney function and morphology following topload administration of recombinant hemoglobin solution

Martucci

Cabrales

et al. 2016

Artificial Cells, Nanomedicine, and Biotechnology

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There is a 0.138% incidence of adverse reactions related to blood transfusion. Transfusion-related acute lung injury, immunosuppression, fever, pathogen transmission, and hemolytic transfusion reactions are the most common ones. Synthetic oxygen carriers have been developed to deal with blood shortages and for use in the field where stored blood was not available. They were also designed to be pathogen free, including unknown viruses. In this study, we used Male Golden Syrian Hamsters implemented with a dorsal window chamber to determine how infusion of three different, genetically crosslinked recombinant acellular hemoglobin (rHb) solutions with different oxygen affinities and nitric oxide kinetics affect mean arterial pressure (MAP), heart rate (HR), kidney function, and kidney structure. We found that the administration of all three rHb solutions caused mild hypertension and bradycardia 30 minutes after infusion. However, acute changes in glomerular filtration rate (GFR) were not detected, even though histological analysis was performed 72 hours after treatment revealed some structural changes. All the rHb solutions resulted in hypertension 30 minutes after a 10% topload administration. Regardless of their properties, the presence of acellular Hb causes significant alterations to kidney tissue.

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Effects of Physiological Factors on Oxygen Transport in an in Vitro Capillary System

Cited by 2 publications

References 8 publications

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Development of Recombinant Hemoglobin-Based Oxygen Carriers

Acute kidney function and morphology following topload administration of recombinant hemoglobin solution

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