Appearance of dissociable and cross-linked hemoglobins in the renal hilar lymph

Matheson, Barbara; Razynska, Anna; Kwansa, Herman; Bucci, Enrico

doi:10.1067/mlc.2000.106458

Cited by 33 publications

(26 citation statements)

References 11 publications

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“…This relationship, though controversial, may be attributed to the more restricted diffusion/transition of large (polymeric or conjugated) Hbs into the subendothelial space (38,52,53). Consistent with data obtained with chemically modified Hbs of different molecular sizes (50,54), in our experiments, the most visible effect of Hb sequestration by Hp was the retention of infused Hb within the circulation, as reflected by the complete absence of renal Hb excretion in animals with high levels of endogenous or exogenously administered Hp. However, it is unlikely that the molecular weight of the Hb-Hp complex (>150 kDa) is the sole determining factor in preventing Hb-induced vasoactivity, since some larger polymeric Hbs with little or no tetramers induced a hypertensive response in animals and humans.…”

Section: Discussionsupporting

confidence: 78%

Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

Boretti¹,

Buehler²,

D’Agnillo³

et al. 2009

J. Clin. Invest.

132

178

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Release of hemoglobin (Hb) into the circulation is a central pathophysiologic event that contributes to morbidity and mortality in chronic hemolytic anemias and severe malaria. These toxicities arise from Hb-mediated vasoactivity, possibly due to NO scavenging and localized tissue oxidative processes. Currently, there is no established treatment that targets circulating extracellular Hb. Here, we assessed the role of haptoglobin (Hp), the primary scavenger of Hb in the circulation, in limiting the toxicity of cell-free Hb infusion. Using a canine model, we found that glucocorticoid stimulation of endogenous Hp synthesis prevented Hb-induced hemodynamic responses. Furthermore, guinea pigs administered exogenous Hp displayed decreased Hbinduced hypertension and oxidative toxicity to extravascular environments, such as the proximal tubules of the kidney. The ability of Hp to both attenuate hypertensive responses during Hb exposure and prevent peroxidative toxicity in extravascular compartments was dependent on Hb-Hp complex formation, which likely acts through sequestration of Hb rather than modulation of its NO-and O 2 -binding characteristics. Our data therefore suggest that therapies involving supplementation of endogenous Hb scavengers may be able to treat complications of acute and chronic hemolysis, as well as counter the adverse effects associated with Hb-based oxygen therapeutics.

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Section: Discussionsupporting

confidence: 78%

Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

Boretti¹,

Buehler²,

D’Agnillo³

et al. 2009

J. Clin. Invest.

132

178

View full text Add to dashboard Cite

show abstract

“…Tissue exposure to Hb is most evident in cases of overt hemoglobinuria after massive intravascular hemolysis, but Hb is also capable of translocating across endothelial barriers, entering the subendothelial and perivascular spaces and the lymph fluid. 2,3 …”

Section: Mechanism 1: Extravascular Translocation Of Hbmentioning

confidence: 99%

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

Schaer

Buehler

Alayash

et al. 2013

Blood

617

600

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“…To date, all animal studies carried out with OxyVita Hb have resulted in no observable vascular extravasation as determined by its absence in the renal hilar lymph after exchange transfusion experiments [15]. Additional studies have shown no evidence of this acellular HBOC in the urine of these animal studies as evaluated by visible spectral analysis [28]. These observations are consistent with our present understanding of the complex nature of the mechanisms of intracellular extravasation through the endothelial capillary walls associated with a wide range of cellular pore sizes [29].…”

Section: Resultsmentioning

confidence: 99%

Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review

Harrington

Wollocko²

2011

JFB

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OxyVita Hb is a new generation hemoglobin based oxygen carrier (HBOC) produced through modification of a zero-linked polymerization mechanism using activators which incorporate cross-linked bovine tetramer hemoglobin into “super-polymeric” macromolecules (Average molecular weight = 17 MDa) for the purpose of oxygen delivery when whole blood or packed red cells are not available. This molecular design approach was generated in order to address several fundamental biochemical and physiological weaknesses of previous generations of HBOCs. Observation during pre-clinical and clinical studies provided evidence that these early generation acellular HBOCs were directly associated with loss of retention within the circulatory system, extravasation across endothelial tissue membranes due to their small molecular size leading to arterial and venous vasoconstriction with coupled increases in mean arterial pressure (MAP). The inherent increase in molecular size and structural stability of the OxyVita Hb is a direct response to addressing these serious weaknesses that have occurred during the evolution of HBOC development within the past two decades. The nature of the zero-linked synthetic route eliminates any chemical linkers remaining in the product, eliminating side reaction concerns, such as reversibility and decomposition due to weak chemical bonds, dependency on temperature and pressure, and residual toxicity

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Appearance of dissociable and cross-linked hemoglobins in the renal hilar lymph

Cited by 33 publications

References 11 publications

Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review

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