Inflammatory mediators promote strong sickle cell adherence to endothelium under venular flow conditions

Walmet, Paula S.; Eckman, James R.; Wick, Timothy M.

doi:10.1002/ajh.10360

Cited by 27 publications

(25 citation statements)

References 49 publications

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“…RBCs express a wide range of molecules on their surface which have been implicated in mediating adhesion to endothelial cells under different conditions. These include: (i) VLA-4 (alpha4beta1) which can bind to endothelial VCAM-1 (Walmet et al, 2003); (ii) the blood group Lutheran molecule (LU) over-expressed on sRBCs can bind to laminin present on cells or in the intercellular space (Eyler and Telen, 2006); (iii) advanced glycation end products (AGEs) present on RBCs bind to their receptor (RAGE) on endothelium (Wautier and Schmidt, 2004), activating endothelial cells; and (iv) a molecule related to blood group Rhesus, ICAM-4 (Hermand et al, 2003) binds to integrins present on leukocytes (CD11–CD18) and on platelets (alpha2beta4) offering a surface which can be involved in thrombosis (reviewed by Wautier and Wautier, 2004). Thus, although PfEMP-1 does not play a role in the induction of ICAM-1 expression seen by us, it would normally be required to bring the PRBCs and ECs together in vivo.…”

Section: Discussionmentioning

confidence: 99%

Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: Pathogenic or protective?

Chakravorty

Carret

Nash

et al. 2007

International Journal for Parasitology

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Severe malaria is associated with sequestration of Plasmodium falciparum-infected red blood cells (PRBC) in the microvasculature and elevation of intercellular adhesion molecule-1 (ICAM-1) and TNF. In vitro co-culture of human umbilical vein endothelial cells (HUVEC), with either PRBC or uninfected RBC, required the presence of low level TNF (5 pg/ml) for significant up-regulation of ICAM-1, which may contribute to increased cytoadhesion in vivo. These effects were independent of P. falciparum erythrocyte membrane protein-1 (PfEMP-1)-mediated adhesion but critically dependent on cell–cell contact. Further changes included increases in IL8 release and soluble TNF receptor shedding. Microarray analysis of HUVEC transcriptome following co-culture, using a human Affymetrix microarray chip, showed significant differential regulation of genes which defined gene ontologies such as cell communication, cell adhesion, signal transduction and immune response. Our data demonstrate that endothelial cells have the ability to mobilise immune and pro-adhesive responses when exposed to both PRBC and TNF. In addition, there is also a previously un-described positive regulation by RBC and TNF and a concurrent negative regulation of a range of genes involved in inflammation and cell-death, by PRBC and TNF. We propose that the balance between positive and negative regulation demonstrated in our study will determine endothelial pathology during a malaria infection.

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Section: Discussionmentioning

confidence: 99%

Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: Pathogenic or protective?

Chakravorty

Carret

Nash

et al. 2007

International Journal for Parasitology

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“…21, 22 The binding of sickle erythrocytes to endothelial cell-immobilized VWF could also increase hemolysis by slowing erythrocyte transit enough to induce hemoglobin deoxygenation and polymerization, consistent with the finding that sickle erythrocyte adhesion to ULVWF was highest at a fluid shear stress of 0.5 dyne/cm 2 , approximately that of postcapillary venules. 23 Hyperreactive VWF probably accumulates in SCD by a combination of increased secretion, defective clearance, and impaired processing by ADAMTS13. Impaired processing is not the result of ADAMTS13 deficiency but could reflect resistance of VWF to proteolysis, possibly because of oxidation of Met1606 at the ADAMTS13 cleavage site.…”

Section: Adamts13 Antigen and Activitymentioning

confidence: 99%

The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma

Chen

Hobbs

et al. 2011

Blood

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Vaso-occlusion, hemolysis, and oxidative stress are hallmarks of sickle cell disease (SCD). This pathology is accompanied by systemic endothelial activation, rendering the endothelium more adhesive for blood cells, including sickle erythrocytes. Activated endothelial cells display or secrete several adhesive molecules, including von Willebrand factor (VWF). We assessed several VWF parameters in SCD patients at baseline: multimer pattern, antigen concentration (VWF:Ag), activation factor (VWF:AF), and total active VWF (VWF:TA). VWF:AF was determined using a llama nanobody (AU/VWFa-11) that detects a platelet-binding conformation of the A1 domain; VWF:TA was calculated by multiplying VWF:Ag by VWF:AF. SCD plasma contained elevated VWF:Ag and ultralarge VWF multimers. VWF:TA, a measure of total VWF reactivity, correlated closely with hemolysis, as determined by serum lactate dehydrogenase. ADAMTS13 activity and antigen were normal in all patients. These findings suggest an important role for hyperreactive VWF in SCD pathology and connect SCD to other microangiopathies, particularly thrombotic thrombocytopenic purpura.

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“…During acute infections, these proteins facilitate the attachment of leukocytes to the vessel wall, ultimately resulting in transmigration into infected tissue 6. In SCA, variable TNF-α signaling might alter disease severity by activating systemic and pulmonary endothelium and by modulating rates of sickle vasoocclusion secondary to altered leukocyte-endothelial cell adhesion 7, 8. Associations between some individual clinical complications of SCA and plasma levels of VCAM-1 and ICAM-1, but not TNF-R1, have been described previously.…”

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confidence: 99%

Severe sickle cell anemia is associated with increased plasma levels of TNF‐R1 and VCAM‐1

et al. 2011

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b b-thalassemias are characterized by an imbalance of globin chains with an excess of a-chains which precipitates in erythroid precursors and red blood cells (RBCs) leading to inefficient erythropoiesis. The severity of the disease correlates with the amount of unpaired achains. Our goal was to develop a simple test for evaluation of the free a-hemoglobin pool present in RBC lysates. Alpha-Hemoglobin Stabilizing Protein (AHSP), the chaperone of a-Hb, was used to trap excess aHb. A recombinant GST-AHSP fusion protein was bound to an affinity micro-column and then incubated with hemolysates of patients. After washing, the a-Hb was quantified by spectrophotometry in the elution fraction. This assay was applied to 54 patients: 28 without apparent Hb disorder, 20 b-thalassemic and 6 a-thalassemic. The average value of free a-Hb pool was 93 ± 21 ppm (ng of free a-Hb per mg of Hb subunits) in patients without Hb disorder, while it varies from 119 to 1,756 ppm, in b-thalassemic patients and correlated with genotype. In contrast, the value of the free a-Hb pool was decreased in a-thalassemic patients (65 ± 26 ppm). This assay may help to characterize b-thalassemia phenotypes and to follow the evolution of the globin chain imbalance (a/b+c ratio) in response to treatment.b-thalassemias (b-thal) are inherited autosomal diseases characterized by a decreased or abolished b-globin chain biosynthesis [1]. During the transition of g to b globin expression in the first year of life, the clinical severity is mainly related to the ratio a/b1g which indicates the level of chain disequilibrium. b-thal are generally classified as minor, intermediate, or major phenotype, and encompass a wide clinical spectrum ranging from asymptomatic carriers to forms that can be lethal in the absence of extensive treatment. Different factors can modulate the severity of this disease [2] such as the magnitude of the decrease of the b globin synthesis, for example hemoglobin E (Hb E b26Glu?Lys) [3], or with the co-inheritance of (i) an a-thalassemia (a-thal) [4], (ii) a triplicated a-globin gene [5] or (iii) a low but variable residual capacity of g globin production which can have the phenotype of a hereditary persistence of fetal Hb (Hb F a 2 g 2 ) [6].The imbalance between a and non a-globin (g1d1b) synthesis was established by radioactive in vitro biosynthesis of globin chains from reticulocytes or of bone marrow of b-thalassemic patients [7][8][9][10]. This imbalance leads to an excess of highly unstable free a-hemoglobin (a-Hb), precipitating on the cell membrane and acting as active oxidants causing apoptosis and inefficient erythropoiesis [1,11]. The severity of b-thal is directly correlated with the degree of imbalance as quantified by the amount of unbound a-globin chain [12]. Many studies have shown that one observes a soluble a chain fraction present in the cytosolic RBC and an insoluble a chain fraction in the membrane of b-thalassemic erythrocytes [13,14]. Because of technical difficulties and the burden of using radioactive materials, ...

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Inflammatory mediators promote strong sickle cell adherence to endothelium under venular flow conditions

Abstract: Adherence of sickle erythrocytes to endothelium in venules is

Cited by 27 publications

References 49 publications

Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: Pathogenic or protective?

Altered phenotype and gene transcription in endothelial cells, induced by Plasmodium falciparum-infected red blood cells: Pathogenic or protective?

The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma

Severe sickle cell anemia is associated with increased plasma levels of TNF‐R1 and VCAM‐1

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