scholarly journals Sickle erythrocytes inhibit human endothelial cell DNA synthesis

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2146-2152 ◽  
Author(s):  
R Weinstein ◽  
MA Zhou ◽  
A Bartlett-Pandite ◽  
K Wenc
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Function ◽  
Dna Synthesis ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Inhibitory Effect ◽  
Human Endothelial Cell ◽  
Endothelial Monolayers ◽  
Sickle Erythrocytes

Abstract Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level, and the clinical presentation of vascular events is heterogeneous, suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis, human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes, with or without autologous plasma, had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute, 10 minutes, or 1 hour and then removed, subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions, the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence, human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers, and persists for at least 6 hours of 3H-thymidine labeling. These results indicate that interaction between sickle erythrocytes and the endothelium may result in altered endothelial function. This altered endothelial function may contribute to the development of vascular occlusive phenomena in patients with sickle cell anemia.

scholarly journals Sickle erythrocytes inhibit human endothelial cell DNA synthesis

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2146-2152
Author(s):  
R Weinstein ◽  
MA Zhou ◽  
A Bartlett-Pandite ◽  
K Wenc
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Function ◽  
Dna Synthesis ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Inhibitory Effect ◽  
Human Endothelial Cell ◽  
Endothelial Monolayers ◽  
Sickle Erythrocytes

Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level, and the clinical presentation of vascular events is heterogeneous, suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis, human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes, with or without autologous plasma, had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute, 10 minutes, or 1 hour and then removed, subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions, the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence, human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers, and persists for at least 6 hours of 3H-thymidine labeling. These results indicate that interaction between sickle erythrocytes and the endothelium may result in altered endothelial function. This altered endothelial function may contribute to the development of vascular occlusive phenomena in patients with sickle cell anemia.

Measuring the Direct Effects of Sickle Cell Vaso-Occlusion on Endothelial Cells Using Microfluidic Technology

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 897-897
Author(s):  
David R Myers ◽  
Yumiko Sakurai ◽  
Prasanthi Chappa ◽  
Gilda Barabino ◽  
David R. Archer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Sickle Cell Disease ◽  
Endothelial Function ◽  
Sickle Cell ◽  
Endothelial Cell Dysfunction ◽  
Cell Disease ◽  
Cell Dysfunction ◽  
Sickle Erythrocytes

Abstract Abstract 897 Sickle cell disease is a complex process involving biophysical and biological phenomenon such as microvascular occlusion due to rigid sickle erythrocytes, hemolysis, and aberrant cellular interactions involving endothelial cells and sickle erythrocytes and leukocytes. Indeed, a key aspect of sickle cell pathophysiology is endothelial cell dysfunction. Cardiovascular research in recent years has shown that endothelial cells biologically respond to the local mechanical environment, particularly to the changes in the applied shear stresses (Chiu and Chien, Physiological Reviews, 2011). Interestingly, no studies investigating how the biophysical alterations in sickle cell disease may directly affect endothelial function have been published. The classic view has been that vaso-occlusion is simply due to sickled erythrocytes becoming stuck in microvasculature at low oxygen tensions leading to decreased blood flow and tissue ischemia. However, the mechanical aspects of sickle cell vaso-occlusion themselves, that is, the physical phenomenon of sickling erythrocytes tightly packed in an occluded blood vessel, may directly affect endothelial biology and lead to dysfunction. We hypothesize that these pathologic forces induced by sickling erythrocytes directly lead to dysfunction of endothelial cells, which are mechanosensitive, and contribute to sickle cell pathophysiology. However, these sickling-induced forces and their effects on endothelial cells have been difficult to measure, in part due to a lack of available tools. To that end, we have developed two microfluidic tools to assess the role of sickle-cell vaso-occlusion on endothelial cells. The first device is an in vitro microfluidic platform featuring microchannels the size of post-capillary venules (30 μm) with human endothelial cells cultured within and completely lining the entire inner surface of those microchannels (Figure 1A). This “microvasculature-on-a-chip” enables the visualization of blood cell-endothelial cell interactions during vaso-occlusion under a controlled hemodynamic environment and provides a platform to study the effect of vaso-occlusion on endothelial cells. To date we have characterized this “endothelialized” microfluidic device, showing that endothelial cells are confluent using anti-VE-cadherin immunostaining and adequately generate nitric oxide. Furthermore, we have flowed blood samples from patients with sickle cell disease and found that hydroxyurea treatment both reduces the number of occlusions and increases the mean velocity of the blood traveling through the device, as expected (Figure 1B–E). To decouple whether it is a biochemical or biophysical phenomenon that causes endothelial cell dysfunction during vaso-occlusion, a second micromechanical device was created to quantitatively measure the forces generated by sickling events. The device captures whole blood and will deform outward when forces are applied by the sickle erythrocytes as shown in Figure 2. The membrane above the sickle cells has been coated with 2 μm fluorescent beads which will change focus during deflection. Deflections of one or two beads indicates that a single sickle cell is locally applying force, whereas deflections of large numbers of beads indicates that the cells are collectively applying a pressure to the membrane. The device has been fully fabricated and loaded with blood cells. An accompanying experimental setup enabling the deoxygenation of the device coupled with microscopy has also been created and preliminary tests show successful deoxygenation of sickle erythrocytes from patients with hemoglobin SS disease and the Berkeley sickle cell mouse model. By combining insights gained from each device, future work will determine how the mechanical process of sickling and vaso-occlusion directly affect endothelial function and will lead to a new understanding of sickle cell pathophysiology. Sickle cell vaso-occlusion will be induced in the “endothelialized” microfluidic device while monitoring nitric oxide production and the upregulation of inflammatory markers, such as adhesion molecules and free radicals. The second device will provide quantitative numbers of forces produced by sickling erythrocytes, leading to experiments in which these forces are applied to endothelial cells while monitoring the same metrics. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Adhesion of sickle red blood cells and damage to interleukin-1 beta stimulated endothelial cells under flow in vitro

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4845-4852 ◽  
Author(s):  
M Natarajan ◽  
MM Udden ◽  
LV McIntire
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Blood Cells ◽  
Prolonged Exposure ◽  
Sickle Cells ◽  
Sickle Erythrocytes ◽  
Sickle Red Blood Cells

Two factors that are hypothesized to contribute to vasoocclusive crises in sickle cell anemia are increased sickle red blood cell-endothelial cell interactions and damage to endothelium. Despite considerable study, the mechanisms by which erythrocyte-endothelial interactions occur and the role of endothelial damage have not yet been fully elucidated. In this report, we demonstrate that adhesion and damage may be related in a model of vasoocclusion in sickle cell anemia. Phase contrast microscopy coupled to digital image processing was used to determine the adhesion of sickle red blood cells to 1-, 4-, and 24-hour interleukin-I beta (IL-1 beta) stimulated endothelial calls in a parallel plate flow chamber. Morphological alterations to activated endothelial cells after the perfusion of sickle erythrocytes were also identified. Pretreatment of monolayers with 50 pg/mL of IL-1 beta for 1, 4, and 24 hours caused approximately 16-fold increases in adhesion of sickle cells to activated endothelium at all time points. Results with an Arginine-glycine aspartic acid (RGD) peptide and monoclonal antibodies indicated a role for three different endothelial cell receptors: alpha v beta 3 after 1 hour of IL-1 beta stimulation; E- selectin after 4 hours of IL-1 beta stimulation; and vascular cell adhesion molecule-1 after prolonged exposure to cytokines. Perfusion of sickle, but not normal, erythrocytes resulted in alteration of endothelial morphology. Approximately 6% to 8% damage was observed on 4- and 24-hour IL-1 beta stimulated endothelial cells after the perfusion of sickle cells. Damage to 24-hour activated endothelial cells showed a positive correlation (r = .899) with the number of adherent sickle erythrocytes.

Lactadherin Enhances the Adhesion of Sickle Cells to Vascular Endothelial Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2341-2341
Author(s):  
Prasenjit Guchhait ◽  
Swapan K. Dasgupta ◽  
Jose A. Lopez ◽  
Perumal Thiagarajan
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Milk Fat ◽  
Calcium Ionophore ◽  
Shear Stresses ◽  
Ionophore A23187 ◽  
Αvβ3 Integrin ◽  
Dependent Manner ◽  
Sickle Erythrocytes

Abstract Adherence of red blood cells to the endothelium initiates vaso-occlusion in sickle cell anemia. The increased adhesiveness of sickle erythrocytes is accompanied by several changes in the lipids of the erythrocyte membrane, including increased expression of phosphatidylserine (PS). One important PS-binding protein is lactadherin (also known as milk fat globule-EGF factor 8), a 45-kDa glycoprotein containing an Arg-Gly-Asp (RGD) sequence. Lactadherin is secreted by many cell types, including macrophages, and is known to have a role in the clearance of apoptotic lymphocytes by binding PS on the cell surface and thus presenting a binding site for macrophage integrins, including αvβ3. We recently showed that lactadherin, added exogenously to both normal and sickle erythrocytes, enhances phagocytosis of these cells by macrophages. Here, we investigated the effect of bovine lactadherin on the adhesion of sickle erythrocytes to the endothelium in flowing blood. Lactadherin (100 nM) promoted the adhesion of sickle erythrocytes to histamine-stimulated human umbilical vein endothelial cells (HUVECs) at shear stresses from 2.5 to 10 dyne/cm2. Adhesion was inhibited significantly by abciximab (10μ g/ml), an antibody against αvβ3 (P<0.05). Normal erythrocytes were induced to adhere to stimulated HUVEC in a lactadherin-dependent manner by treatment with 10 mM N-ethylmaleamide and 4 μ M calcium ionophore A23187—treatment that exposes phosphatidylserine on the erythrocyte surface. These results indicate that lactadherin mediates sickle cell adhesion to the endothelium by bridging PS on erythrocytes to αvβ3 integrin on the endothelium. We propose that sickle erythrocytes acquire lactadherin as they traverse macrophage-rich zones such as spleen, liver, and lymph nodes. Those that are not ingested immediately will become more adhesive for endothelium. Thus, lactadherin appears to be involved in both hemolysis and vaso-occlusion in sickle cell anemia.

A Monoclonal Antibody to Lactadherin Inhibits Sickle Red Blood Cell Adhesion to Vascular Endothelial Cells in a Plasma Milieu.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1236-1236
Author(s):  
Swapan K. Dasgupta ◽  
Prasenjit Guchhait ◽  
Anhquyen Le ◽  
Sarvari Yellapragada ◽  
Jose Lopez ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Blood Cells ◽  
Dependent Manner ◽  
Sickle Erythrocytes ◽  
Sickle Red Blood Cells

Abstract Adherence of red blood cells to the endothelium initiates vaso-occlusion in sickle cell anemia. The increased adhesiveness of sickle erythrocytes is accompanied by several changes in the lipids of the erythrocyte membrane, including increased expression of phosphatidylserine (PS). One important PS-binding protein is lactadherin (also known as milk fat globule-EGF factor 8), a 45-kDa glycoprotein containing an Arg-Gly-Asp (RGD) sequence. It is secreted by macrophages and is present in normal plasma. Lactadherin promotes phagocytosis of PS-expressing apoptotic lymphocytes and sickle red blood cells by anchoring them to integrins on macrophages. Here, we investigated the role of endogenous lactadherin in adhesion of sickle erythrocytes to the endothelium. We developed a murine monoclonal antibody to human lactadherin, called L688, and investigated its effect on the adhesion of sickle red blood cells to histamine-stimulated human umbilical vein endothelial cells under hydrodynamic flow. In three experiments using washed erythrocytes resuspended in autologous plasma from three different patients with sickle cell anemia, L688 (20 μg/ml) inhibited adhesion by 24–30% (p<0.01). Further evidence for an important role for lactadherin in sickle erythrocyte adhesion to endothelial cells was provided by the observation that exogenous lactadherin enhanced adhesion in a concentration-dependent manner. Lactadherin-mediated adhesion was also inhibited by monoclonal antibody abciximab, (c7E3, 10 μg/ml) which targets the β3 integrin subunit common to both αIIbβ3 and αVβ3. Control antibodies had no effect. Finally, the lactadherin-dependent adhesion of sickle erythrocytes to activated endothelium was inhibited by PS vesicles but not by phosphatidylcholine vesicles, confirming an important role for PS in sickle cell adhesion. Consistent with this, normal erythrocytes can be induced to adhere to stimulated HUVEC in a lactadherin-dependent manner by treatment with N-ethylmaleimide (10 mM) and calcium ionophore A23187 (4 μM) — treatment that exposes PS on the outer leaflet of the red cell membrane. Together, these results indicate that lactadherin mediates sickle cell adhesion to the endothelium by bridging PS on the erythrocytes with αVβ3 integrin on the endothelium. We propose that anemia in sickle cell disease is at least partially due to phagocytosis of lactadherin-coated sickle erythrocytes in the spleen, liver, and lymph nodes. Those erythrocytes that are not ingested immediately by macrophages will become more adhesive for endothelium. Thus, lactadherin appears to be involved both in sickle cell clearance from the circulation and in adhesion to endothelium.

Increased Erythrocyte Rigidity Is Sufficient to Cause Endothelial Dysfunction in Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 818-818 ◽  
Author(s):  
Robert Mannino ◽  
David R Myers ◽  
Yumiko Sakurai ◽  
Russell E. Ware ◽  
Gilda Barabino ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Adhesion Molecule ◽  
Endothelial Cell Dysfunction ◽  
Cell Disease ◽  
Cell Dysfunction ◽  
Sickle Erythrocytes

Abstract Abstract 818 Endothelial dysfunction is a major component of sickle cell disease (SCD) pathophysiology. Interestingly, previous cardiovascular research has definitively shown that endothelial cells biologically respond to mechanical forces and aberrations in these forces cause endothelial dysfunction via pro-inflammatory pathways that are also involved in SCD. While endothelial dysfunction in SCD has been well characterized biologically, little research has focused on the direct biophysical effects of SCD blood on endothelium. As endothelial cells are in constant contact with flowing “stiffened” sickle erythrocytes, we propose that the direct mechanical interactions between the physically altered sickle erythrocytes and endothelial cells are an additional cause of endothelial dysfunction in SCD (Figure 1A). Endothelial dysfunction in SCD is thought to be caused by the downstream effects of vaso-occlusion and/or hemolysis. Our laboratory has recently developed and published a description of an in vitro microvasculature model comprised of endothelial cells that are cultured throughout the entire 3D inner surface of a microfluidic system designed for investigating cellular interactions in hematologic diseases (Tsai, et al, JCI, 2012), (Figure 1B-D). This microvasculature-on-a-chip recapitulates an ensemble of physiological processes and biophysical properties, including adhesion molecule expression, blood cell-endothelial cell interactions, cell deformability, cell size/shape, microvascular geometry, hemodynamics, and oxygen levels (Myers et al. JoVE, 2012), all of which may contribute to endothelial dysfunction in SCD. We hypothesize that the mechanical interactions between sickle erythrocytes and endothelial cells alone are sufficientto cause endothelial dysfunction in our microvasculature-on-a-chip. To test our hypothesis, we flowed different suspensions of healthy red blood cells (RBCs), and stiffened RBCs, through our microvasculature on a chip cultured with HUVECs. We suspended fresh human RBCs in media at a low hematocrit recapitulating the anemic conditions typically seen in SCD patients as a control. The experimental conditions used the same solution as the control, but also contained glutaraldehyde-stiffened RBCs, which are of the same stiffness as irreversibly sickled cells (ISCs), at approximately the same concentrations as ISCs in SCD patients. The stiffened RBC suspension was washed multiple times to eliminate all traces of glutaraldehyde and to ensure that any endothelial cell dysfunction in our system was due to mechanical effects between the endothelium and RBCs. After 4 hours of perfusion, the number of occlusions in our microsystem was counted and the cells were fixed and stained for Vascular Cell Adhesion Molecule 1 (VCAM-1). VCAM-1 been shown to be a marker of endothelial cell dysfunction and is a biomarker for severe vasculopathy in SCD (Dworkis, Am J Hematol, 2011). Immunofluorescence staining in our microsystem confirmed that VCAM1 is upregulated (Figure 2) in HUVECs when exposed to flowing stiffened RBCs compared to control RBCs. VCAM-1 upregulation appears to be diffuse throughout the length of the device. After experimentation, endothelial cells in our system can be isolated for further RT-PCR or microarray analysis. As such, ongoing work involves investigating and quantifying the expression of other pro-inflammatory molecules to elucidate the underlying mechanisms of this biomechanical process involving RBCs and endothelial cells. Additional experiments complementary experiments using endothelial cells from other anatomic areas, SCD patient samples, and murine SCD models are also underway. Our data indicates that purely physical interactions between endothelial cells and stiffened RBCs are sufficient to cause some degree of endothelial dysfunction, even in the absence of vaso-occlusion, ischemia, or oxidative stress due to hemolysis. As sickle RBCs and ISCs are constantly circulating in the blood of SCD patients, our results have profound implications for SCD pathophysiology and may help explain why SCD patients develop chronic diffuse vasculopathy over time. Disclosures: No relevant conflicts of interest to declare.

Heme and the Vasculature: How the Endothelium Protects Itself Against Toxic Iron

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Gregory M. Vercellotti ◽  
John D Belcher
Keyword(s):  
Oxidative Stress ◽  
Carbon Monoxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Mouse Models ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Sleeping Beauty ◽  
Heme Oxygenase 1

Abstract Abstract SCI-25 Iron-derived reactive oxygen species (ROS) are involved in the pathogenesis of numerous vascular disorders. Heme-derived iron plays an instrumental role in the pathology of intravascular hemolytic diseases including malaria, sickle cell anemia, transfusion reactions, DIC and PNH. Heme catalyzed oxidative stress promotes a pro-inflammatory/prothrombogenic endothelium, diminution of bio-available nitric oxide (NO) and attraction of leukocytes and platelets. The vasculature is protected against heme-catalyzed injury by plasma proteins including haptoglobin, hemopexin, albumin, alpha-1-microglobulin and by scavenger receptors for heme complexes including CD163 and CD91. Heme and its concomitant oxidative stress induces the cytoprotective and rate-limiting enzyme in heme catabolism, heme oxygenase-1 (HO-1). In the process, HO-1 releases three enzymatic byproducts: carbon monoxide (CO), biliverdin/bilirubin, and iron, which stimulates ferritin synthesis. These HO-1 by-products have established anti-oxidant and anti-inflammatory properties. Human patients and mouse models elevate HO-1 in response to chronic hemolysis. Of all sites in the body, the endothelium may be at greatest risk of exposure to heme. Heme greatly potentiates endothelial cell killing mediated by leukocytes and other sources of ROS. As a defense against heme, endothelial cells upregulate HO-1 and ferritin. If cultured endothelial cells are briefly pulsed with heme and are then incubated for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with induction of both HO-1 and ferritin. H-ferritin with its ferroxidase activity is especially cytoprotective. In animal models, increased expression of HO-1 has been shown to protect tissues against ischemia-reperfusion injury, oxidative stress, inflammation, transplant rejection, apoptosis, and cell proliferation. Conversely, HO-1 null mice (hmox-1−/−) and human patients deficient in HO-1 are especially prone to oxidative stress and inflammation. Sickle cell anemia is an archetypal example of heme-induced oxidative stress and cytoprotective adaptation. The sickle patient and sickle mouse models defend and adapt to hemolysis by increasing their defenses against heme. HO-1 plays an essential role in the inhibition and resolution of vaso-occlusion in sickle cell anemia. HO-1 and its products, carbon monoxide and biliverdin, modulate vaso-occlusion through multiple mechanisms including reducing oxidative stress, inhibiting NF-kB, down-regulating endothelial cell adhesion molecules, decreasing red blood cell hemolysis and altering vascular tone. However, sickle cell patients often have adaptive increases in HO-1 activity which are insufficient to completely handle the excessive heme burden, particularly during acute bouts of hemolysis. HO-1 gene therapy in sickle mice using Sleeping Beauty-mediated transposition of an HO-1 transgene provides a promising non-viral approach to significantly enhance HO-1 expression in sickle cell anemia. Strategies to minimize heme-iron activation of the vasculature including increasing HO-1 and its products, anti-oxidants, iron chelators, increasing haptoglobin, hemopexin and/or their receptors CD163/CD91 should be explored in hemolytic disease states. Disclosures: Vercellotti: Sangart: Consultancy, Research Funding. Belcher:Sangart: Research Funding.

scholarly journals Double-stranded RNA induces sickle erythrocyte adherence to endothelium: a potential role for viral infection in vaso-occlusive pain episodes in sickle cell anemia

Blood ◽  
1995 ◽  
Vol 85 (10) ◽  
pp. 2945-2950 ◽  
Author(s):  
PA Smolinski ◽  
MK Offermann ◽  
JR Eckman ◽  
TM Wick
Keyword(s):  
Endothelial Cells ◽  
Viral Infection ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sendai Virus ◽  
Rna Virus ◽  
Poly I:C ◽  
Double Stranded Rna ◽  
Sickle Erythrocyte ◽  
Sickle Erythrocytes

Vaso-occlusive pain episodes in sickle cell anemia are hypothesized to be precipitated by adherence of sickle erythrocytes to vascular endothelium in the microcirculation. Febrile episodes, thought to be viral in etiology, are frequently associated with vaso-occlusion; however, a direct link between viral infection and vascular occlusion has not yet been established. Many pathogenic viruses contain double-stranded RNA or replicate through double-stranded RNA intermediates. Double-stranded RNA has been shown to induce vascular cell adhesion molecule-1 (VCAM-1) protein expression on endothelial cells. Recently, a new adhesion pathway has been described between VCAM-1 expressed on cytokine stimulated endothelium and the alpha 4 beta 1 integrin complex expressed on sickle reticulocytes. Based on these observations, the hypothesis was developed that viral infection, through double-stranded RNA intermediates, increases endothelial VCAM-1 expression leading to sickle erythrocyte adhesion to endothelium via an alpha 4 beta 1-VCAM-1- -dependent mechanism. In support of this hypothesis, endothelial cells exposed to the synthetic double-stranded RNA poly(I:C) or the RNA virus parainfluenza 1 (Sendai virus) express increased levels of VCAM-1 and support increased sickle erythrocyte adherence under continuous flow at 1.0 dyne/cm2 shear stress as compared with unstimulated endothelium. Blocking antibodies directed against either VCAM-1 on the endothelium or alpha 4 beta 1 on sickle erythrocytes inhibit nearly all of the increased sickle cell adherence caused by poly(I:C) or Sendai virus. These results support the hypothesis that viruses, through double-stranded RNA elements, can induce sickle erythrocyte adherence to endothelium through alpha 4 beta 1-VCAM-1--mediated adhesion and provide a potential link between viral infection and microvascular occlusion precipitating sickle cell pain episodes.

scholarly journals The Senegal DNA haplotype is associated with the amelioration of anemia in African-American sickle cell anemia patients

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1371-1375 ◽  
Author(s):  
RL Nagel ◽  
S Erlingsson ◽  
ME Fabry ◽  
H Croizat ◽  
SM Susuka ◽  
...  
Keyword(s):  
New York ◽  
Gene Cluster ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Inhibitory Effect ◽  
Hemoglobin F ◽  
Globin Gene Cluster ◽  
Alpha Gene ◽  
Hbf Level

Abstract We have previously determined that in African sickle cell anemia (SS) patients three different beta-like globin gene cluster haplotypes are associated with different percent G gamma (one of the two types of non- alpha chains comprising hemoglobin F [HbF]), mean percent HbF, and percent dense cells. We report now that in adult New York SS patients, the presence of at least one chromosome with the Senegal haplotype is associated with higher Hb levels (1.2 g/dL higher) than is found for any other non-Senegal haplotype (P less than .004). The percent reticulocytes and the serum bilirubin levels were lower in these patients. When the effect of alpha-gene number was analyzed by examining a sample of SS patients with concomitant alpha-thalassemia, the same results were obtained. Because the HbF level is significantly higher among the Senegal haplotype carriers in this sample, the inhibitory effect on sickling of this Hb variant may be one of the reasons for the haplotype effect. We conclude that the Senegal beta- like globin gene cluster haplotype is associated with an amelioration of the hemolytic anemia that characterizes sickle cell disease.

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