Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs
Felicitas S. Boretti, … , Abdu I. Alayash, Dominik J. Schaer
Felicitas S. Boretti, … , Abdu I. Alayash, Dominik J. Schaer
Published July 20, 2009
Citation Information: J Clin Invest. 2009;119(8):2271-2280. https://doi.org/10.1172/JCI39115.
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Research Article

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

Abstract

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 Hb-induced 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 O2-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.

Authors

Felicitas S. Boretti, Paul W. Buehler, Felice D’Agnillo, Katharina Kluge, Tony Glaus, Omer I. Butt, Yiping Jia, Jeroen Goede, Claudia P. Pereira, Marco Maggiorini, Gabriele Schoedon, Abdu I. Alayash, Dominik J. Schaer

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Figure 2

Glucocorticoid pretreatment prevents free Hb-mediated hypertension.

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Glucocorticoid pretreatment prevents free Hb-mediated hypertension. (A) ...
(A) The plasma Hb levels of conscious dogs were maintained at a concentration of approximately 100–150 μM (heme), with an initial bolus dose followed by constant infusion (top panel). The AUC for plasma heme concentrations over time did not differ between control (open circles, white bars) and prednisone-treated animals (filled circles, black bars). Blood pressure was monitored intermittently using tail artery oscillography over the 8-hour infusion period (bottom panel). A significant increase in MAP of more than 20%–25% (n = 6) was observed in control dogs but not in animals pretreated with prednisone (n = 4). The total volume of 0.9% NaCl plus Hb administered to dogs in each group was less than 5% of the total blood volume per hour. (B) Plasma heme concentration levels of anesthetized dogs were maintained with a Hb infusion protocol of 30 ml/h (0–30 minutes), 60 ml/h (30–60 minutes), 90 ml/h (60–90 minutes), and 120 ml/h (90–120 minutes) (top panel). The incremental increases in Hb did not differ between groups. The increase in MAP with elevated plasma heme concentrations is shown, with divergence between the 2 groups occurring at 60 minutes and corresponding to a heme plasma concentration of approximately 100–150 μM. The AUC0–120min for MAP was 5-fold greater in control (n = 5), compared with prednisone-treated animals (n = 5). Data are presented as mean ± SEM.