Faculty Opinions recommendation of Activated neutrophil-mediated sickle red blood cell adhesion to lung vascular endothelium: role of phosphatidylserine-exposed sickle red blood cells.

Abstract Abstract 1312 Anemia affects the quality of life and the life expectancy of millions of people in the U.S. Many patients are either intolerant or unresponsive to available treatments, so alternative strategies are needed. Red blood cell production requires the action of erythropoietin (Epo) on red blood cell precursors in the bone marrow. Iron restriction results in loss of Epo-responsiveness and anemia, despite increased serum Epo levels. Iron infusion restores Epo-responsiveness suggesting that iron dominantly regulates Epo-receptor (EpoR) signaling. Understanding how iron restriction regulates EpoR signaling pathways has major clinical significance. Agonists could offer an iron-free approach that enhances the response to Epo in anemia due to iron deficiency or chronic diseases. In addition, antagonists could be used to treat polycythemia vera or other myeloproliferative disorders. We have discovered that the aconitases, multifunctional iron-sulfur cluster proteins that convert citrate into isocitrate are key in connecting iron to Epo-signaling in early erythroid progenitors (GC Bullock, et. al. Blood 2010;116:97). We also discovered that isocitrate, the downstream product of aconitase, can enhance the effectiveness of Epo during iron deficiency in vitro and in vivo in mice with IDA. These observations suggest that isocitrate or derivatives of isocitrate that synergize with erythropoiesis stimulating agents (ESAs) have important therapeutic application in the treatment of anemia. Deletion of EpoR in mice is incompatible with life, however mice and humans that express truncated EpoR show increased production of red blood cells. These observations suggest that the distal cytoplasmic domain of the EpoR inhibits production of red cells and may play a critical role in iron deficiency anemia. EpoR mutant mice lacking the distal half of the cytoplasmic domain of the EpoR (EpoR-H mice) and mice with the same EpoR truncation mutation plus an additional mutation of tyrosine 343 (EpoR-HM mice) show near normal levels of steady state erythropoiesis. To determine the role of the distal domain in erythroid suppression during iron deficiency, EpoR-H, EpoR-HM and EpoR-wildtype mice were fed a low iron diet and compared by weekly CBCs and flow cytometry. EpoR-H mutant mice continue to efficiently produce red blood cells during iron deficiency. And this occurs despite a decrease in hemoglobin. EpoR-HM mice produce fewer rbcs than EpoR-H mice, however rbc production by EpoR-HM mice resists the suppressive effects of iron restriction. Similar experiments also suggest that the distal EpoR is necessary for the isocitrate-mediated enhancement of Epo-driven erythropoiesis. In addition to aconitase/isocitrate and the distal EpoR other candidate key signaling components of this Epo-dependent, iron-responsive pathway have been identified in our recent preliminary experiments. These components include specific protein kinase C (PKC) isozymes, AKT1 and ERK1/2. These findings support a new model of iron sensing by aconitase/isocitrate that alters EpoR signaling to decrease red blood cell production and conserve iron when supplies are low. This model fits better than older “heme-deficiency” models because disorders in heme synthesis block red cell differentiation at a later stage. This model also has potential to explain changes seen in other tissues during chronic iron deficiency. Nutritional iron restriction may have unmasked a new role for the distal EpoR in red cell development and implicated new iron-responsive Epo signaling pathways that can be used to develop new therapeutic agonists and antagonists of Epo. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Microfluidic electrical impedance assessment of red blood cell mediated microvascular occlusion

Lab on a Chip ◽

10.1039/d0lc01133a ◽

2021 ◽

Author(s):

Yuncheng Man ◽

Debnath Maji ◽

Ran An ◽

Sanjay Ahuja ◽

Jane A Little ◽

...

Keyword(s):

Sickle Cell Disease ◽

Blood Cell ◽

Red Blood Cells ◽

Sickle Cell ◽

Red Blood Cell ◽

Blood Cells ◽

Electrical Impedance ◽

Cell Disease ◽

Blood Disorders

Alterations in the deformability of red blood cells (RBCs), occurring in hemolytic blood disorders such as sickle cell disease (SCD), contributes to vaso-occlusion and disease pathophysiology. However, there are few...

Download Full-text

Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease

Hematology ◽

10.1182/asheducation-2007.1.84 ◽

2007 ◽

Vol 2007 (1) ◽

pp. 84-90 ◽

Cited By ~ 27

Author(s):

Marilyn J. Telen

Keyword(s):

Sickle Cell Disease ◽

Red Blood Cells ◽

Adhesion Molecules ◽

Sickle Cell ◽

Vascular Endothelium ◽

Blood Cells ◽

Cell Disease ◽

Adhesive Interactions ◽

Lines Of Evidence

AbstractA number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.

Download Full-text

Effect of red blood cells and red blood cell ghosts on reticuloendothelial system function

Experimental and Molecular Pathology ◽

10.1016/0014-4800(84)90008-x ◽

1984 ◽

Vol 41 (1) ◽

pp. 67-73 ◽

Cited By ~ 9

Author(s):

Daniel J. Loegering ◽

Gary J. Grover ◽

Marlowe J. Schneidkraut

Keyword(s):

Blood Cell ◽

Red Blood Cells ◽

Red Blood Cell ◽

Blood Cells ◽

Reticuloendothelial System ◽

System Function

Download Full-text

Red Blood Cell Membrane Fragments but Not Intact Red Blood Cells Promote Calcium Oxalate Monohydrate Crystal Growth and Aggregation

The Journal of Urology ◽

10.1016/j.juro.2010.03.107 ◽

2010 ◽

Vol 184 (2) ◽

pp. 743-749 ◽

Cited By ~ 8

Author(s):

Somchai Chutipongtanate ◽

Visith Thongboonkerd

Keyword(s):

Crystal Growth ◽

Cell Membrane ◽

Blood Cell ◽

Calcium Oxalate ◽

Red Blood Cells ◽

Red Blood Cell ◽

Blood Cells ◽

Calcium Oxalate Monohydrate ◽

Red Blood Cell Membrane

Download Full-text

Permeation of the luminal capillary glycocalyx is determined by hyaluronan

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.2.h508 ◽

1999 ◽

Vol 277 (2) ◽

pp. H508-H514 ◽

Cited By ~ 85

Author(s):

Charmaine B. S. Henry ◽

Brian R. Duling

Keyword(s):

Blood Cell ◽

Red Blood Cells ◽

Red Blood Cell ◽

Blood Cells ◽

Enzyme Treatment ◽

Apical Surface ◽

Bright Field ◽

Endothelial Surface ◽

The Difference

The endothelial cell glycocalyx influences blood flow and presents a selective barrier to movement of macromolecules from plasma to the endothelial surface. In the hamster cremaster microcirculation, FITC-labeled Dextran 70 and larger molecules are excluded from a region extending almost 0.5 μm from the endothelial surface into the lumen. Red blood cells under normal flow conditions are excluded from a region extending even farther into the lumen. Examination of cultured endothelial cells has shown that the glycocalyx contains hyaluronan, a glycosaminoglycan which is known to create matrices with molecular sieving properties. To test the hypothesis that hyaluronan might be involved in establishing the permeation properties of the apical surface glycocalyx in vivo, hamster microvessels in the cremaster muscle were visualized using video microscopy. After infusion of one of several FITC-dextrans (70, 145, 580, and 2,000 kDa) via a femoral cannula, microvessels were observed with bright-field and fluorescence microscopy to obtain estimates of the anatomic diameters and the widths of fluorescent dextran columns and of red blood cell columns (means ± SE). The widths of the red blood cell and dextran exclusion zones were calculated as one-half the difference between the bright-field anatomic diameter and the width of the red blood cell column or dextran column. After 1 h of treatment with active Streptomyces hyaluronidase, there was a significant increase in access of 70- and 145-kDa FITC-dextrans to the space bounded by the apical glycocalyx, but no increase in access of the red blood cells or in the anatomic diameter in capillaries, arterioles, and venules. Hyaluronidase had no effect on access of FITC-Dextrans 580 and 2,000. Infusion of a mixture of hyaluronan and chondroitin sulfate after enzyme treatment reconstituted the glycocalyx, although treatment with either molecule separately had no effect. These results suggest that cell surface hyaluronan plays a role in regulating or establishing permeation of the apical glycocalyx to macromolecules. This finding and our prior observations suggest that hyaluronan and other glycoconjugates are required for assembly of the matrix on the endothelial surface. We hypothesize that hyaluronidase creates a more open matrix, enabling smaller dextran molecules to penetrate deeper into the glycocalyx.

Download Full-text

Susceptibility of density-fractionated erythrocytes to subhaemolytic mechanical shear stress

The International Journal of Artificial Organs ◽

10.1177/0391398818790334 ◽

2018 ◽

Vol 42 (3) ◽

pp. 151-157 ◽

Cited By ~ 4

Author(s):

Antony P McNamee ◽

Kieran Richardson ◽

Jarod Horobin ◽

Lennart Kuck ◽

Michael J Simmonds

Keyword(s):

Blood Cell ◽

Red Blood Cells ◽

Red Blood Cell ◽

Blood Cells ◽

Shear Stresses ◽

Mechanical Stimuli ◽

Cell Deformability ◽

Red Blood Cell Deformability ◽

Cell Age ◽

Low Shear

Introduction: Accumulating evidence demonstrates that subhaemolytic mechanical stresses, typical of circulatory support, induce physical and biochemical changes to red blood cells. It remains unclear, however, whether cell age affects susceptibility to these mechanical forces. This study thus examined the sensitivity of density-fractionated red blood cells to sublethal mechanical stresses. Methods: Red blood cells were isolated and washed twice, with the least and most dense fractions being obtained following centrifugation (1500 g × 5 min). Red blood cell deformability was determined across an osmotic gradient and a range of shear stresses (0.3–50 Pa). Cell deformability was also quantified before and after 300 s exposure to shear stresses known to decrease (64 Pa) or increase (10 Pa) red blood cell deformability. The time course of accumulated sublethal damage that occurred during exposure to 64 Pa was also examined. Results: Dense red blood cells exhibited decreased capacity to deform when compared with less dense cells. Cellular response to mechanical stimuli was similar in trend for all red blood cells, independent of density; however, the magnitude of impairment in cell deformability was exacerbated in dense cells. Moreover, the rate of impairment in cellular deformability, induced by 64 Pa, was more rapid for dense cells. Relative improvement in red blood cell deformability, due to low-shear conditioning (10 Pa), was consistent for both cell populations. Conclusion: Red blood cell populations respond differently to mechanical stimuli: older (more dense) cells are highly susceptible to sublethal mechanical trauma, while cell age (density) does not appear to alter the magnitude of improved cell deformability following low-shear conditioning.

Download Full-text