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.
View: Text | PDF
Research Article Article has an altmetric score of 3

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

×

Figure 6

Absence of high-affinity Hb-Hp interactions with αα–cross-linked Hb (αα-DBBF) leads to hypertension, despite high Hp availability.

Options: View larger image (or click on image) Download as PowerPoint
Absence of high-affinity Hb-Hp interactions with αα–cross-linked Hb (αα-...
(A) Plasma heme concentrations of anesthetized dogs with a Hb and αα–cross-linked Hb (αα-DBBF) were maintained with an infusion protocol of 30 ml/h (0–30 minutes), 50 ml/h (30–60 minutes), 90 ml/h (60–90 minutes), and 120 ml/h (90–120 minutes) in control (open circles, Hb) and prednisone-treated dogs (black circles, αα-DBBF) (top panel). MAP responses to Hb (open circles) in control dogs (low Hp) and to αα–cross-linked Hb (gray circles) in prednisone-treated (high Hp) dogs (bottom panel). The AUC0–120 min for MAP was similar for both groups. Data are presented as mean ± SEM (n = 5). (B) The blood pressure response of conscious guinea pigs to dose escalation with αα–cross-linked Hb in HES (open circles) or Hp (filled circles) at a 1:1 ratio (Hb to HES or Hp). Data are presented as mean ± SEM (n = 6).