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

Hugelshofer, Michael; Buzzi, Raphael M; Schaer, Christian A.; Richter, Henning; Akeret, Kevin; Anagnostakou, Vania; Mahmoudi, Laleh; Vaccani, Raphael; Vallelian, Florence; Deuel, Jeremy; Kronen, Peter W; Kulcsár, Zsolt; Regli, Luca; Baek, Jin Hyen; Pires, Ivan S.; Palmer, Andre F.; Dennler, Matthias; Humar, Rok; Buehler, Paul W.; Kircher, Patrick R.; Keller, Emanuela; Schaer, Dominik J.

doi:10.1172/jci130630

Cited by 65 publications

(104 citation statements)

References 104 publications

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“…It has been recently demonstrated that secondary vasospasm (due to NO inhibition by Hb) and neurotoxicity (due to subarachnoid hemorrhage) were rescued by the infusion of Hp in the cerebral spinal fluid, by a direct inhibition and sequestration of Hb-Hp complexes (m.w. > 100 kD) [104]. With regard to intact RBCs, erythrophagocytosis by microglia [105] is usually insufficient to prevent free hemoglobin release and neurotoxicity.…”

Section: Strokementioning

confidence: 99%

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

Michel

Martı́n-Ventura

2020

IJMS

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As the main particulate component of the circulating blood, RBCs play major roles in physiological hemodynamics and impact all arterial wall pathologies. RBCs are the main determinant of blood viscosity, defining the frictional forces exerted by the blood on the arterial wall. This function is used in phylogeny and ontogeny of the cardiovascular (CV) system, allowing the acquisition of vasomotricity adapted to local metabolic demands, and systemic arterial pressure after birth. In pathology, RBCs collide with the arterial wall, inducing both local retention of their membranous lipids and local hemolysis, releasing heme-Fe++ with a high toxicity for arterial cells: endothelial and smooth muscle cells (SMCs) cardiomyocytes, neurons, etc. Specifically, overloading of cells by Fe++ promotes cell death. This local hemolysis is an event associated with early and advanced stages of human atherosclerosis. Similarly, the permanent renewal of mural RBC clotting is the major support of oxidation in abdominal aortic aneurysm. In parallel, calcifications promote intramural hemorrhages, and hemorrhages promote an osteoblastic phenotypic shift of arterial wall cells. Different plasma or tissue systems are able, at least in part, to limit this injury by acting at the different levels of this system.

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Section: Strokementioning

confidence: 99%

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

Michel

Martı́n-Ventura

2020

IJMS

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“…Recently, it was shown that cell-free Hb from cerebrospinal fluid in vascular structures is the primary cause of aneurysmal subarachnoid hemorrhage pathophysiology [116]. Indeed, RBC destruction in the subarachnoid space leads to an accumulation of cell-free Hb, exceeding haptoglobin scavenger capacity in the cerebrospinal fluid.…”

Section: Harmful Effects Of Heme On Endotheliummentioning

confidence: 99%

“…Indeed, RBC destruction in the subarachnoid space leads to an accumulation of cell-free Hb, exceeding haptoglobin scavenger capacity in the cerebrospinal fluid. This unbound Hb thus promotes spasms in cerebral arteries and smaller parenchymal arterioles [116]. In a sheep model, administration of Hp into the cerebrospinal fluid inhibited Hb-induced cerebral vasospasm and preserved vascular NO-signaling.…”

Section: Harmful Effects Of Heme On Endotheliummentioning

confidence: 99%

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

Frimat

Boudhabhay

Roumenina

2019

Toxins

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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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“…If they did, the

would immediately attack the haem ring or the adjacent amino acid residues and would be unlikely to be released into free solution [ 8 ]. Nevertheless, it is indeed the case that haem and, in the presence of H 2 O 2 , haem proteins such as myoglobin, haemoglobin and cytochrome c can be powerful pro-oxidants, a process that is important in vivo , the kidney and brain being especially sensitive targets of oxidative damage by haem proteins [ 129 , 130 ]. There are two aspects to these pro-oxidant effects ( Fig.…”

Section: Ironic Burgersmentioning

confidence: 99%

Reflections of an aging free radical

Halliwell

2020

Free Radical Biology and Medicine

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In this mini-reflection, I explain how during my doctoral work in a Botany Department I first became interested in H 2 O 2 and later in my career in other reactive oxygen species, especially the role of “catalytic” iron and haem compounds (including leghaemoglobin) in promoting oxidative damage. The important roles that H 2 O 2 , other ROS and dietary plants play in respect to humans are discussed. I also review the roles of diet-derived antioxidants in relation to human disease, presenting reasons why clinical trials using high doses of natural antioxidants have generally given disappointing results. Iron chelators and ergothioneine are reviewed as potential cytoprotective agents with antioxidant properties that may be useful therapeutically. The discovery of ferroptosis may also lead to novel agents that can be used to treat certain diseases.

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

Cited by 65 publications

References 104 publications

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases

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

Reflections of an aging free radical

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