Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders

Abstract

The goal here is to describe our current understanding of heme metabolism and the deleterious effects of “free” heme on immunological processes, endothelial function, systemic inflammation, and various end-organ tissues (e.g., kidney, lung, liver, etc.), with particular attention paid to the role of hemopexin (HPX). Because heme toxicity is the impetus for much of the pathology in sepsis, sickle cell disease (SCD), and other hemolytic conditions, the biological importance and clinical relevance of HPX, the predominant heme binding protein, is reinforced. A perspective on the function of HPX and haptoglobin (Hp) is presented, updating how these two proteins and their respective receptors act simultaneously to protect the body in clinical conditions that entail hemolysis and/or systemic intravascular (IVH) inflammation. Evidence from longitudinal studies in patients supports that HPX plays a Hp-independent role in genetic and non-genetic hemolytic diseases without the need for global Hp depletion. Evidence also supports that HPX has an important role in the prognosis of complex illnesses characterized predominantly by the presence of hemolysis, such as SCD, sepsis, hemolytic-uremic syndrome, and conditions involving IVH and extravascular hemolysis (EVH), such as that generated by extracorporeal circulation during cardiopulmonary bypass (CPB) and from blood transfusions. We propose that quantitating the amounts of plasma heme, HPX, Hb-Hp, heme-HPX, and heme-albumin levels in various disease states may aid in the diagnosis and treatment of the above-mentioned conditions, which is crucial to developing targeted plasma protein supplementation (i.e., “replenishment”) therapies for patients with heme toxicity due to HPX depletion.

Heme Synthesis and Acquisition in Bacterial Pathogens

“…To prevent excess heme toxicity, eukaryotic heme synthesis is highly regulated and heme homeostasis and sequestration are well orchestrated. When Hb is released from erythrocytes or otherwise exists extracellularly, it is rapidly bound by haptoglobin (Hp) [27]. The abundance of cell-free Hb is thought to be very low in healthy adults, but a variety of genetic disorders, infections, and other disease states can increase the concentration of free Hb [28].…”

Sustained treatment of sickle cell mice with haptoglobin increases HO‐1 and H‐ferritin expression and decreases iron deposition in the kidney without improvement in kidney function

“…Twice weekly Hp (90 mg/kg) over 5 weeks was recently tested in a mouse model of chronic extracellular Hb-mediated progression of pulmonary hypertension and decreased iron accumulation in lung and heart tissue was documented in conjunction with decreases in pulmonary vascular inflammation and resistance and right-ventricular hypertrophy (Irwin, et al 2015). There is increased interest in clinical trials in SCD patients of the use of haptoglobin and haemopexin, the scavenger for free haem (Quimby, et al 2015, Smith and McCulloh 2015). To assess the possible utility of Hp replacement in SCD, we administered Hp thrice weekly at doses of 200 and 400 mg/kg to sickle cell mice for a period of 3 months and examined the effect of Hp administration on the extent of decreases in organ damage.…”

Hepatic Overexpression of Hemopexin Inhibits Inflammation and Vascular Stasis in Murine Models of Sickle Cell Disease

“…In this study we treated the NY1DD and Townes-SS sickle mouse models with Hpx gene transfer targeted to the liver and evaluated the effects on cytoprotective pathways and Hb-and heme-induced vasoocclusion in a dorsal skin-fold chamber (DSFC) model. Our results suggest that hepatic overexpression of Hpx in sickle mice inhibits inflammation and microvascular stasis in the DSFC model by delivering heme to CD91/LRP1 on the liver and increasing nuclear Nrf2 activation and HO-1 expression in the liver (24,36,37).…”

“…Other hemoglobin-binding proteins are also likely to be beneficial, such as haptoglobin (26,36,78,79). Perhaps a combination of plasma Hpx and haptoglobin infusions would be particularly effective.…”