Extracellular Hb Enhances Cardiac Toxicity in Endotoxemic Guinea Pigs: Protective Role of Haptoglobin

Abstract

Endotoxemia plays a major causative role in the myocardial injury and dysfunction associated with sepsis. Extracellular hemoglobin (Hb) has been shown to enhance the pathophysiology of endotoxemia. In the present study, we examined the myocardial pathophysiology in guinea pigs infused with lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, and purified Hb. We also examined whether the administration of the Hb scavenger haptoglobin (Hp) could protect against the effects observed. Here, we show that Hb infusion following LPS administration, but not either insult alone, increased myocardial iron deposition, heme oxygenase-1 expression, phagocyte activation and infiltration, as well as oxidative DNA damage and apoptosis assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunostaining, respectively. Co-administration of Hp significantly attenuated the myocardial events induced by the combination of LPS and Hb. These findings may have relevant therapeutic implications for the management of sepsis during concomitant disease or clinical interventions associated with the increased co-exposures to LPS and Hb, such as trauma, surgery or massive blood transfusions.

Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm

“…The protective physiological effect of haptoglobin during systemic hemolysis has been related to the large molecular size of the Hb-haptoglobin complex (15,43). The complex is too large to be filtered by the kidney or to extravasate from blood into the wall structures of coronary arteries or the interstitial space of the myocardium (15,48). These observations helped to resolve the enigma that the biochemical reactivity, which was recognized as the source of cell-free Hb toxicity, was not substantially different in the case of the Hb-haptoglobin complex compared with unbound Hb.…”

Haptoglobin-2 variant increases susceptibility to acute respiratory distress syndrome during sepsis

“…Human plasma-derived Hp is approved in Japan for the treatment of severe hemolysis during extracorporeal cardiopulmonary bypass, severe burn injuries, or massive transfusion following trauma (57-61), but this product is not approved in the United States. Additional experimental stud- ies have reported that Hp reduces CFH-induced vasoconstriction, hemoglobinuria, and renal dysfunction following massive transfusion (18,62,63); cardiotoxicity following lipopolysaccharide and CFH administration (64); and organ dysfunction following experimental Staphylococcus aureus pneumonia with massive exchange transfusion (65). These experimental studies used either mixed pooled human Hp (18,62) or specifically HP2-1 and HP2-2 human Hp (63)(64)(65), and the clinical trials used commercial pooled human Hp derived from populations with a high prevalence of HP2-1 and HP2-2 genotypes (27,(57)(58)(59)(60)(61).…”

Hemopexin counteracts systolic dysfunction induced by heme-driven oxidative stress

“…It has been shown that free hemoglobin affects heart function in rabbits and exacerbates cardiotoxicity of LPS in experimental models of sepsis [47][48][49]. The heme moiety of hemoglobin, which is released following hemoglobin oxidation in the pro-oxidant plasma milieu, is thought to mediate hemoglobin toxicity [50].…”