Hemolysis Derived Products Toxicity and Endothelium: Model of the Second Hit

Vascular diseases are multifactorial, often requiring multiple challenges, or ‘hits’, for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, hemolysis derived-products are rapidly neutralized by numerous defense systems, including haptoglobin and hemopexin which scavenge hemoglobin and heme, respectively. Likewise, cellular defense mechanisms are involved, including heme-oxygenase 1 upregulation which metabolizes heme. However, in cases of intra-vascular hemolysis, those systems are overwhelmed. Heme exerts toxic effects by acting as a damage-associated molecular pattern and promoting, together with hemoglobin, nitric oxide scavenging and ROS production. In addition, it activates the complement and the coagulation systems. Together, these processes lead to endothelial cell injury which triggers pro-thrombotic and pro-inflammatory phenotypes. Moreover, among endothelial cells, glomerular ones display a particular susceptibility explained by a weaker capacity to counteract hemolysis injury. In this review, we illustrate the ‘multiple-hit’ theory through the example of intra-vascular hemolysis, with a particular focus on cell-free heme, and we advance hypotheses explaining the glomerular susceptibility observed in hemolytic diseases. Finally, we describe therapeutic options for reducing endothelial injury in hemolytic diseases.

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The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Frontiers in Immunology ◽

10.3389/fimmu.2020.561917 ◽

2021 ◽

Vol 11 ◽

Author(s):

Oluwabukola T. Gbotosho ◽

Maria G. Kapetanaki ◽

Gregory J. Kato

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Phenotypic Variability ◽

Major Complication ◽

Heme Oxygenase 1 ◽

Pathological Feature ◽

Cell Disease ◽

Protective Mechanisms ◽

Molecular Pattern ◽

Free Heme

Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.

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Heme Oxygenase-1/CO as Protective Mediators in Cigarette Smoke- Induced Lung Cell Injury and Chronic Obstructive Pulmonary Disease

Current Pharmaceutical Biotechnology ◽

10.2174/138920112800399338 ◽

2012 ◽

Vol 13 (6) ◽

pp. 769-776 ◽

Cited By ~ 20

Author(s):

Tamas Dolinay ◽

Augustine M.K. Choi ◽

Stefan W. Ryter

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Heme Oxygenase ◽

Cell Injury ◽

Chronic Obstructive ◽

Heme Oxygenase 1 ◽

Obstructive Pulmonary Disease

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Cellular Defense Mechanisms: Activation of Macrophages . Proceedings of a conference, Günzburg, Germany, Oct. 1973. W.-H. Wagner, H. Hahn, and R. Evans, Eds. Excerpta Medica, Amsterdam, and Elsevier, New York, 1974. xii, 346 pp., illus. $34.60. Workshop Conferences Hoechst, vol. 2.

Science ◽

10.1126/science.189.4205.790-a ◽

1975 ◽

Vol 189 (4205) ◽

pp. 790-790

Author(s):

S. Gordon

Keyword(s):

New York ◽

Defense Mechanisms ◽

Cellular Defense

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Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria

Infection and Immunity ◽

10.1128/iai.05933-11 ◽

2012 ◽

Vol 80 (4) ◽

pp. 1445-1454 ◽

Cited By ~ 44

Author(s):

Vitor R. R. Mendonça ◽

Nívea F. Luz ◽

Nadja J. G. Santos ◽

Valéria M. Borges ◽

Marilda S. Gonçalves ◽

...

Keyword(s):

Heme Oxygenase ◽

Inflammatory Marker ◽

Plasma Concentrations ◽

Soluble Form ◽

Heme Oxygenase 1 ◽

Asymptomatic Malaria ◽

Symptomatic Malaria ◽

Free Heme ◽

Main Components ◽

Genetic Profiles

ABSTRACTIntravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of theHMOX1andHpgenes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)nrepeats in the microsatellite polymorphism region of theHMOX1gene, theHp2allele, and theHp2.2genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria.

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Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury

Diabetes & Metabolism Journal ◽

10.4093/dmj.2011.35.5.469 ◽

2011 ◽

Vol 35 (5) ◽

pp. 469 ◽

Cited By ~ 14

Author(s):

Eun-Mi Lee ◽

Young-Eun Lee ◽

Esder Lee ◽

Gyeong Ryul Ryu ◽

Seung-Hyun Ko ◽

...

Keyword(s):

Protective Effect ◽

Heme Oxygenase ◽

High Glucose ◽

Cell Injury ◽

Heme Oxygenase 1 ◽

Pancreatic Β Cell ◽

Β Cell

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The role of corneal crystallins in the cellular defense mechanisms against oxidative stress

Seminars in Cell and Developmental Biology ◽

10.1016/j.semcdb.2007.10.004 ◽

2008 ◽

Vol 19 (2) ◽

pp. 100-112 ◽

Cited By ~ 63

Author(s):

Natalie Lassen ◽

William J. Black ◽

Tia Estey ◽

Vasilis Vasiliou

Keyword(s):

Oxidative Stress ◽

Defense Mechanisms ◽

Cellular Defense

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Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

Blood ◽

10.1182/blood-2011-08-375303 ◽

2012 ◽

Vol 119 (10) ◽

pp. 2368-2375 ◽

Cited By ~ 135

Author(s):

Guilherme B. Fortes ◽

Leticia S. Alves ◽

Rosane de Oliveira ◽

Fabianno F. Dutra ◽

Danielle Rodrigues ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Critical Role ◽

Membrane Integrity ◽

Iron Chelation ◽

Heme Oxygenase 1 ◽

Cytotoxic Effects ◽

Interacting Protein ◽

Free Heme ◽

Necrosis Factor

Abstract Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.

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