Haptoglobin And Hemopexin Infusion Efficiently Activates The Nrf2/Ho-1 Axis And Inhibits Inflammation And Vaso-Occlusion In Murine Sickle Cell Disease

Free hemoglobin and hemin, released by red blood cells during intravascular hemolysis, promote vasculopathy, inflammation, thrombosis, and renal injury. Plasma haptoglobin and hemopexin tightly bind free hemoglobin and hemin, respectively, thwarting these clinical sequelae. In sickle cell disease (SCD), chronic hemolysis can deplete plasma haptoglobin and hemopexin in humans and mice. To explore mechanisms mediating this protection and provide a basis for supplementation in SCD patients, dorsal skin fold chambers were implanted onto Townes-SS mice and microvascular stasis (% non-flowing venules) was measured in response to a hemoglobin challenge. Human haptoglobin, hemopexin, or albumin was co-infused with hemoglobin or 1 hour after hemoglobin at equimolar concentrations. Sickle mice co-infused with hemoglobin/haptoglobin, hemoglobin/hemopexin or hemoglobin/haptoglobin/hemopexin had less stasis 1 to 4 hours after infusion, compared to albumin- and saline-treated mice (*p after hemoglobin, decreased stasis 2 and 3 hours after supplementation, while the venules of mice treated with albumin remained static (*p Disclosures Belcher: CSL-Behring: Research Funding; Imara: Research Funding. Chen: Imara: Research Funding. Brinkman: CSL-Behring: Employment. Vercellotti: CSL-Behring: Research Funding; Imara: Research Funding.