Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction

John D. Belcher, Chunsheng Chen, Julia Nguyen, Fuad Abdulla, Ping Zhang, Hao Nguyen, Phong Nguyen, Trevor Killeen, Sylvia M. Miescher, Nathan Brinkman, Karl A. Nath, Clifford J. Steer, Gregory M. Vercellotti

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During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (± equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-ĸB phospho-p65, and vaso-occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Wei-bel-Palade body mobilization of P-selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS-mice induces cytoprotective cellular responses is linked to increased HO-1 activity.

Original languageEnglish (US)
Article numbere0196455
JournalPloS one
Issue number4
StatePublished - Apr 2018

Bibliographical note

Funding Information:
The research was supported by a grant from the National Heart, Lung and Blood Institute R01 HL114567-05 to GMV and JDB and a grant from CSL Behring to JDB and GMV. The funder (CSL Behring) provided support in the form of salaries for authors [SMM NB]. These authors [SMM NB] provided input on research aims and goals, provided hemopexin and haptoglobin, and assisted with writing, review and editing of the manuscript. The authors would like to thank Dr. Bo Hedlund for helpful discussions.

Publisher Copyright:
© 2018 Belcher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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