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Hemopexin and Haptoglobin: Allies Against Heme Toxicity from Hemoglobin Not Contenders

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Hemopexin and Haptoglobin: Allies Against Heme Toxicity from Hemoglobin Not Contenders View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 30 June 2015 doi: 10.3389/fphys.2015.00187 Hemopexin and haptoglobin: allies against heme toxicity from hemoglobin not contenders Ann Smith 1* and Russell J. McCulloh 2, 3 1 School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO, USA, 2 Pediatric and Adult Infectious Diseases, Children’s Mercy-Kansas City, Kansas City, MO, USA, 3 School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA 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 Edited by: Magnus Gram, of HPX and haptoglobin (Hp) is presented, updating how these two proteins and Lund University, Sweden their respective receptors act simultaneously to protect the body in clinical conditions Reviewed by: that entail hemolysis and/or systemic intravascular (IVH) inflammation. Evidence from Jozsef Balla, University of Debrecen, Hungary longitudinal studies in patients supports that HPX plays a Hp-independent role in genetic Bo Akerstrom, and non-genetic hemolytic diseases without the need for global Hp depletion. Evidence Lund University, Sweden also supports that HPX has an important role in the prognosis of complex illnesses Joris Delanghe, Ghent University, Belgium characterized predominantly by the presence of hemolysis, such as SCD, sepsis, *Correspondence: hemolytic-uremic syndrome, and conditions involving IVH and extravascular hemolysis Ann Smith, (EVH), such as that generated by extracorporeal circulation during cardiopulmonary MBB-School of Biological Sciences, University of Missouri-Kansas City, bypass (CPB) and from blood transfusions. We propose that quantitating the amounts 5007 Rockhill Road, Kansas, MO of plasma heme, HPX, Hb-Hp, heme-HPX, and heme-albumin levels in various disease 64110, USA states may aid in the diagnosis and treatment of the above-mentioned conditions, which [email protected] is crucial to developing targeted plasma protein supplementation (i.e., “replenishment”) Specialty section: therapies for patients with heme toxicity due to HPX depletion. This article was submitted to Oxidant Physiology, Keywords: hemopexin, heme, haptoglobin, iron, plasma protein therapeutics, hemolytic index, hemolysis, a section of the journal erythrophagocytosis Frontiers in Physiology Received: 31 March 2015 Accepted: 11 June 2015 Published: 30 June 2015 Abbreviations: Mr, Apparent Molecular weight; CPB, Cardiopulmonary bypass; CD91/LRP1, CD163, Cluster of differentiation; DF, Dengue fever; DHF, Dengue hemorrhagic fever; EVH, Extravascular hemolysis; FLVCR, Feline leukemia Citation: virus Sub group C receptor; FPN, Ferroportin; Hp, Haptoglobin; HO, Heme oxygenase; HPX, Hemopexin; HIV, Human Smith A and McCulloh RJ (2015) immunodeficiency virus; IVH, Intravascular hemolysis; IL-6, interleukin-6; MetHb, Methemoglobin; Mb, Myoglobin; NQO1, Hemopexin and haptoglobin: allies NADP(H):quinone oxido-reductase 1; NET, Neutrophil extracellular trap; NO, Nitric oxide; NOS, Nitric oxide synthase; against heme toxicity from hemoglobin PMVEC, Pulmonary artery endothelial cell; PMVEC, Pulmonary microvasculature endothelial cell; PHP, pyridoxalated Hb not contenders. Front. Physiol. 6:187. polyoxethylene conjugate; ROS, Reactive oxygen species; RBC, red blood cell; SCD, Sickle cell disease; TNF, tumor necrosis doi: 10.3389/fphys.2015.00187 factor; VWF, Von Willibrand Factor. Frontiers in Physiology | www.frontiersin.org 1 June 2015 | Volume 6 | Article 187 Smith and McCulloh Hemopexin and haptoglobin are allies not contenders Introduction et al., 2002), heme being derived from ruptured plaques (Nagy et al., 2010) and LDL from the extracellular intima. The low, essentially constant leakage of hemoglobin (Hb) from Interest in the protective role of HPX has rapidly increased red blood cells (RBCs), termed trivial hemolysis, is well-tolerated; during the past 5 years because the causative role of heme however, both intravascular (IVH) and extravascular (EVH) in the pathophysiology of sepsis, sickle cell disease (SCD), hemolysis induce severe inflammation and potential tissue other hemolytic conditions and also in atherosclerosis (Balla dysfunction. This pathology is due to heme (iron-protoporphyrin et al., 1991a; Nagy et al., 2010) has become accepted (Larsen IX) released from methemoglobin (metHb, Bunn and Jandl, et al., 2010; Smith, 2011a,b; Ghosh et al., 2013; Schaer et al., 1968). Unless bound to proteins, the redox-active heme-iron 2013; Smith, 2013; Belcher et al., 2014; Schaer et al., 2014; participates in oxygen radical reactions that covalently modify Jung et al., 2015). Insights into how HPX acts in clinical protein, lipid, carbohydrate and/or nucleotides, which then lead IVH and EVH have been obtained primarily through primate- to tissue damage. Cellular heme toxicity, first described in 1991 , rat-, mouse-, and human-based studies. While HPX’s role in (Balla et al., 1991b), derives partly from heme alone and also protection against heme-mediated inflammation and oxidative through heme-mediated sensitization of cells to subsequent damage is established, further studies are needed to confirm the stimuli including reactive oxygen species from activated human Hp-independent activity of HPX in hemolysis in various clinical neutrophils, inflammatory cytokines, and NO. Cells rely on disease states in humans. We have therefore summarized and “extracellular antioxidants,” i.e., the proteins in biological fluids reviewed both historical and recent observations on the HPX and to prevent such radical chemistry by sequestering the heme and Hp systems in relevant human conditions and diseases. Finally, its iron (Halliwell and Gutteridge, 1990). Thus, haptoglobin (Hp) we propose future research avenues related to heme metabolism binds Hb, the source of heme that is bound by hemopexin in human health and disease. These include quantitating the (HPX), and transferrin binds iron. In plasma, HPX targets amounts of plasma heme, HPX, Hb-Hp, heme-HPX, and heme to the liver parenchymal cells for heme catabolism, iron heme-albumin levels in various disease states to aid in the storage, and re-distribution. In barrier tissues, HPX targets heme diagnosis and treatment of diseases prominently characterized to brain neurons (Hahl et al., 2013). Normally, HPX recycles by hemolysis and investigating the use of targeted plasma after heme delivery whereas the Hp-Hb complex is degraded in protein supplementation (i.e., “replenishment”) therapies for macrophages. Documented changes in plasma Hp and free Hb patients with heme toxicity due to HPX depletion. Although not levels provide clues as to the extent of hemolysis; but only HPX addressed here, α-1 microglobulin binds heme and free radicals and heme levels demonstrate problems with heme clearance. protecting particularly EVH sites (Akerstrom and Gram, 2014), Our purpose is to provide a new perspective on the roles of the and when infused minimized pre-eclampsia-like symptoms from HPX and Hp systems in human diseases in which they protect Hb in perfused human placenta (May et al., 2011); and treated against Hb-derived heme toxicity and body iron loss. HPX is pre-eclampsia in sheep (Wester-Rosenlof et al., 2014). not an acute phase protein in humans, as is Hp, and because of additional differences between these systems in humans and in Structure and Function of Hemopexin and mice, we focus on reviewing in vivo data from human subjects and rhesus monkey research, and in vitro data from cultured Haptoglobin and their Role in Heme and human cells. Throughout this review, we have used italic font to Hemoglobin Clearance in Intravascular emphasize key points and conclusions. Hemolysis Our goal is to describe current understanding of heme metabolism and the deleterious effects of “free” heme on The lysis of 1 ml of blood containing 5 billion RBCs each with immunological processes, endothelial function, systemic ∼289 million Hb molecules (Sears, 1999) could release ∼ 1.45 × inflammation, and various end-organ tissues (e.g., kidney, 1018 Hb molecules, which is 1000-fold higher than 20 µM plasma lung, liver, etc.), with particular attention paid to the protective Hp molecules (6.82 × 1015) in the immediate plasma (550 µl). role of HPX. We propose that the model of a linear pathway Given that total body plasma Hp would be ∼2.8×1019 molecules for the development of heme toxicity with HPX as a backup (and HPX on average an additional 1.8 × 1019 molecules if at system for Hp, i.e., acting only when Hp becomes depleted, 12.4 µM (Drabkin, 1971), it is clear that Hb and heme loads does not represent many situations in vivo. Examples from can be massive. Endothelial cells lack HPX receptors (Smith patients and experimental animals provide evidence that HPX and Morgan, 1979) and unregulated heme diffusion into and and Hp act simultaneously in various niches of the body when metabolism by these cells, estimated to be ∼60 trillion cells in hemolysis occurs, both
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