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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2551-2555
Plasma Endothelin-1, Cytokine, and Prostaglandin E2
Levels in Sickle Cell Disease and Acute Vaso-Occlusive Sickle Crisis
By
Evangeline Graido-Gonzalez,
James C. Doherty,
Eric W. Bergreen,
Gregory Organ,
Margaret Telfer, and
Marvin A. McMillen
From the Department of Internal Medicine, the Department of Surgery,
and the Division of Hematology, Michael Reese Hospital and University
of Illinois College of Medicine at Chicago, Chicago, IL.
 |
ABSTRACT |
The relative contributions of microvascular inflammation and
vasomotor dysregulation to the development of acute vaso-occlusive crisis in sickle cell disease have been intensely studied. The present
observational study was designed to examine the levels of circulating
proinflammatory cytokines, anti-inflammatory cytokines, and vasoactive
mediators during and after acute painful crisis. In symptomatic sickle
cell patients, plasma levels of endothelin-1 and prostaglandin
E2 were elevated during crises compared with healthy
African-American controls. These levels had decreased, but not
normalized, when patients were seen 1 to 3 weeks after discharge from
hospital. Other mediators (tumor necrosis factor  [TNF],
interleukin-1 [IL-1], IL-6, IL-8, and IL-10) were neither
elevated in asymptomatic sickle cell disease nor in acute vaso-occlusive crisis. As a potent long-acting mediator of
vasoconstriction and inflammation, endothelin-1 may play a key role in
the cycle of ischemia and inflammation that initiates and sustains pain of crisis. The downregulatory effects of prostaglandin E2
on immune cell function may contribute to the increased susceptibility
to infection observed in patients with sickle cell disease.
| |
INTRODUCTION |
A CENTRAL CLINICAL ISSUE that determines
quality of life in patients with sickle cell disease is the occurrence
of painful crisis, an episodic event producing several days of
excruciating pain. Reduced deformability of hemoglobin-S
(Hgb-S)-containing red blood cells can dramatically increase the
viscosity of blood and lead to mechanical blockage of the
microcirculation,1 but the reversibility of the crisis and
the lack of widespread tissue necrosis associated with the crisis lead
to the question of whether vasospasm and inflammation might play
important roles in the pathophysiology of pain crisis.
Significant recent advances have occurred in understanding the
interactions of the irreversibly sickled cell with the
microvasculature. These have coincided with better understanding of
endothelial cell regulation of vascular smooth muscle and vasomotor
tone. The endothelial cell is a key regulator of the contractile status of vascular smooth muscle via the constitutive and regulated expression of nitric oxide (NO) and by the induced expression of endothelins and
eicosanoids.2 A major area of current study is
whether the vascular occlusion and the ischemia of sickle
cell disease may be caused by endothelial cell dysregulation mediated
by abnormal erythrocytes. Several studies have examined inflammatory
mechanisms that may mediate adhesion of sickle erythrocytes to the
endothelium. There is evidence to suggest that sickle erythrocytes may
have direct or indirect effects upon vascular tone, exclusive of
adhesion events, and that local control of vascular tone is abnormal
not only during sickle cell crisis, but also in the steady state course of the disease.3,4 Inflammatory events (cytokine production and adhesion molecular expression) may also play a role in the pathogenesis of sickle crisis.
Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory
agonist that has been shown to be elevated in sickle cell disease.5-7 The present observational study was designed to
investigate plasma levels of ET-1, proinflammatory cytokines (tumor
necrosis factor [TNF], interleukin-1 [IL-1], IL-6, and
IL-8), antiflammatory cytokines (IL-10), and counter-regulatory
prostaglandin E2 (PGE2) in asymptomatic sickle
cell disease and during pain crisis.
| |
MATERIALS AND METHODS |
Patients.
Thirteen adult homozygous sickle cell patients had an extra tube of
blood drawn at routine outpatient visits to confirm prior published
results indicating high baseline levels of ET-1,5,6 giving
a mean ET-1 level of 35 pg/mL with a range of 0 to 151 pg/mL (n = 13).
In compliance with Michael Reese Hospital Human Investigations
Committee guidelines, patients with confirmed homozygous sickle cell
anemia were invited to participate in the study. Additional blood
samples were obtained from a group of 11 comparably aged African-American consenting volunteers who were documented to be
negative for sickle or C hemoglobin. These samples served as age- and
race-matched healthy controls. For this study, blood was drawn from 13 consecutive consenting adult patients (20 to 50 years of age) with
known homozygous sickle cell disease presenting in acute pain crisis
without infection or other concurrent medical illness.
No patients were suspected to have narcotic dependency. Painful crisis
was defined as a presentation to the emergency room with severe
generalized trunk and extremity pain, defined by the patient as similar
to previous episodes, and not accompanied by cough, pharyngitis,
rhinitis, dyspnea, diarrhea, or physical evidence of pneumonia or
urinary tract infection. Fever and leukocytosis to 20,000/µL
were allowed. These patients met predetermined criteria for admission and had not responded to fluids, Dilaudid, and
intramuscular morphine in the emergency room over a 4-hour period.
In the hospital, they were placed on intravenous hydration with 5%
dextrose and 0.45 N saline and received boluses of
morphine until a Patient Control Access pump (PCA) could administer
morphine. Patients required parenteral narcotic support for 3 to 7 days before oral acetaminophen with codeine was tolerable. Blood was collected for this study on admission and each morning for 3 days thereafter. At the first posthospitalization visit to the clinic, after
a time ranging from 1 to 3 weeks, the postcrisis specimen from each
patient was drawn.
Cytokine measurement.
Blood was collected into standard 3-mL sodium-EDTA blood collection
tubes that were centrifuged to isolate plasma fractions. Plasma was
immediately frozen at  80°C for assay at a later date.
Commercially available enzyme-linked immunosorbent assay (ELISA) kits
were used to determine plasma ET-1 and PGE2 (Amersham Life
Science, Buckinghamshire, UK) and TNF, IL-1, IL-6, IL-8, and
IL-10 (Immunotech Inc, Westbrook, ME). Each kit uses a quantitative immunometric sandwich ELISA performed on a 96-well plate coated with
monoclonal antibody against the specific peptide, cytokine, or
prostanoid to be tested. During an incubation period ranging from 2 to
24 hours at 4°C to 27°C (depending on the specific assay), ET-1, TNF, IL-1, IL-6, IL-8, IL-10, and PGE2 bind to
the specific affixed monoclonal antibody. A monospecific antibody
conjugated to horseradish peroxidase is added. During an additional
incubation, the conjugate antibody binds to the affixed
antibody/peptide or antibody/cytokine complexes. Upon addition of
appropriate substrate, a peroxidase-dependent color reaction occurs
that is proportional to the amount of bound peptide, cytokine, or
prostanoid. Plates are scanned using a Bio-Whittaker Microplate Reader
2001 (Bio-Whittaker, Inc, Walkersville, MD) set at the appropriate
wavelength for the color-forming reaction. A standard curve is
generated and specimen concentrations are determined by comparing
sample optical density with the values on the standard curve. All
samples in this study were performed in duplicate, and sample variation
was estimated at approximately 5%.
Peak ET-1, cytokine, and PGE2 levels during crisis were
recorded and were compared with postcrisis and control values. Results were compared by ANOVA and the Student's unpaired two-tailed
t-test. All data are presented as the mean ± standard error
of mean.
| |
RESULTS |
Plasma ET-1 levels were significantly elevated relative to healthy
controls (0.535 ± 0.508 pg/mL) in both patients in acute pain
crisis (130.9 ± 23.1 pg/mL; P = .0002) and those at
postcrisis follow-up (23.69 ± 9.52 pg/mL; P = .04)
interpreted as their baseline symptom-free levels
(Table 1). Postcrisis levels decreased
significantly from levels drawn in crisis for all patients (P = .0001).
Plasma PGE2 levels were also significantly elevated in
crisis relative to healthy controls (316 ± 33.9 pg/mL; P < .001) and postcrisis patients (670.9 ± 61.0 pg/mL; P = .003; Table 1). Similar to the pattern observed with respect to ET-1
levels, PGE2 levels in crisis were elevated compared with
healthy controls and decreased postcrisis (P = .048). Neither
the levels of ET-1 nor those of PGE2 varied significantly
during the crisis sampling period (Fig 1).
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| Fig 1.
Plasma ET-1 and PGE2 concentrations during
the first 72 hours of hospitalization for sickle cell crisis and at
time of asymptomatic follow-up. Although plasma ET-1 (A) and
PGE2 (B) levels appear to follow similar trends, neither
varies significantly during the first 72 hours of hospitalization
(P > .05). However, the mean peak crisis levels for each are
elevated relative to those of the same patients when asymptomatic and
are elevated relative to those of healthy age- and race-matched
controls (Table 1). (ADM, admission time; 24H, 48H, and 72H indicate
24, 48, and 72 hours after admission, respectively; F/U, at time of
postcrisis outpatient appointment). ( ), Sickle cell; ( ),
control.
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Plasma levels of TNF, IL-1, IL-6, IL-8, and IL-10 were not
different between healthy controls and sickle cell patients
(P < .05), although a trend was observed in which
TNF and IL-10 remained higher than controls during and after crisis.
No difference was observed between the levels in crisis and
those of the same patients at postcrisis follow-up (P > .05;
Table 2).
| |
DISCUSSION |
The endothelins are a family of 21 amino acid peptides first
characterized by Yanagisawa in 1988.8,9 Four endothelin subtypes have been identified. ET-1, the most prevalent subtype, is the
most potent vasoconstrictor yet described. ET-1 is not only a
vasoconstrictor of large arteries and veins, but also constricts the
resistance arterioles and postcapillary venules.10 ET-1 is
rapidly internalized by its target cells, and infused pharmacologic doses are cleared from the circulation within minutes, principally by
the lungs.11 The vasoconstriction lasts as long as 1 hour. The two specific ET-1 receptors, ETR-A and ETR-B, are
G-protein-coupled membrane receptors on vascular smooth muscle cells,
and the cell response (ie, smooth muscle contraction) results from
inositol-triphosphate-mediated increases in intracellular
calcium.12 These receptors differ in their specificities
for the various endothelin subtypes and in their tissue
distribution.13 The endothelins have been found to have
elevated systemic levels in ischemic injury in acute respiratory distress syndrome, sepsis, and disseminated intravascular
coagulation.14-16 Endothelin antagonists have been
developed and are currently being evaluated.17
Endothelins are also proinflammatory agonists. Stimulation of cultured
human peripheral blood monocytes with ET-1 causes monocyte production
of inflammatory cytokines such as TNF, IL-1, IL-6, IL-8,
granulocyte-macrophage colony-stimulating factor (GM-CSF), and
substances that enhance neutrophil superoxide
production.18-20 Endothelins cause neutrophil production of
platelet-activating factor (PAF) and increase monocyte and neutrophil
chemotaxis.21-23 Endothelins upregulate endothelial cell
expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell
adhesion molecule-1 (VCAM-1), and E-selectin, adhesion molecules that
participate in the recruitment of leukocytes to sites of
inflammation.24 Neutrophil proteases play a
key role in cleaving bioactive ET-1 from its precursor
molecule.25,26
Inflammation appears to play a significant role in the vaso-occlusive
crisis in sickle cell disease. Systemic levels of TNF and IL-1
increase in sickle cell disease, as do soluble forms of ICAM-1, VCAM-1,
and E-selectin.27,28 TNF increases adherence of sickled
cells to vascular endothelium, and circulating reticulocytes in sickle
cell disease express both 41 integrin and glycoprotein IV (CD36),
adhesion molecules capable of binding to VCAM-1.29,30 Adherence of sickle erythrocytes in the microcirculation may initiate the impairment of microcirculatory blood flow.31 The
inflammatory mediators (TNF, IL-1, IL-6, and IL-8) show small
changes in our study of pain crisis that fail to reach significance,
but may play a role at the tissue level, where autocrine and paracrine effects predominate.
| |
PAIN CRISIS |
We demonstrate elevation of plasma ET-1 levels during sickle cell pain
crisis and a decrease in ET-1 levels to higher than normal in the same
patients after symptomatic recovery. Several reports have demonstrated
increased levels of ET-1 in patients with asymptomatic sickle cell
disease.5-7 We used a sensitive ELISA technology to measure
ET-1 levels, whereas the previous studies used
radioimmunoassays.6,7
The ET-1 levels observed may be derived from a variety of sources.
Hypoxia is a potent stimulus to the production and release of ET-1 by
vascular endothelial cells.32 There appears to be ET-1
production unique to sickle cell disease. Phelan et al33 demonstrated that cultured human umbilical vein endothelial cells experience a fourfold to eightfold greater transcriptional induction of
the gene encoding ET-1 when exposed to sickled cells in vitro. Cultured
bovine pulmonary artery endothelial cells transcribe increased amounts
of ET-1 mRNA and release increased ET-1 peptide when exposed to plasma
from sickle patients with acute chest syndrome and acute
crisis.7 Plasma from the same patients at the time of
symptom-free follow-up does not produce this effect.
ET-1 causes monocyte production of PGE2 in
vitro.34 PGE2 downregulates inflammatory
response by increasing intracellular cyclic AMP levels in
immunohematologic cells.35 In monocytes and macrophages,
PGE2 inhibits class II (Ia-DR) antigen expression, production of IL-1, and antigen presentation.36-38 In
lymphocytes, PGE2 impairs IL-2 production by T-helper cells
and decreases response to IL-2.39 PGE2
production by so-called suppressor macrophages may downregulate the
inflammatory process, thus preventing harmful systemic
inflammation.40 PGE2 levels increased
significantly during crisis in the present study and remained elevated
after symptoms had resolved.
Patients with sickle cell disease are at increased risk for serious
bacterial infections. This has been attributed to functional asplenia,
impaired opsonic function, and activation of the alternative complement
pathway. Defects in cell-mediated immunity have also been described,
and patients with severe variants of the disease demonstrate defective
random neutrophil migration, chemotactic activity, and lymphocyte
transformation index.41,42 These effects may be
attributable to chronic exposure to downregulatory mediators such as
PGE2 and IL-10.43
The plasma levels of ET-1 and PGE2 in this study were
elevated in 13 adult sickle cell patients in crisis compared with
aged-matched African-American controls and with their own levels on
asymptomatic follow-up. Whereas TNF, IL-1, IL-6, and IL-8 were
only variably increased, there were high levels of counterregulatory
PGE2 and IL-10. We conclude that endothelin could
contribute to both the prolonged vasospasm and to inflammation in acute
painful sickle cell crisis and that endothelin antagonist strategies
might have utility in the treatment of this complex disorder.
| |
FOOTNOTES |
Submitted November 26, 1997;
accepted June 1, 1998.
Supported in part by a faculty recruitment grant from Michael Reese
Hospital and Medical Center and by funds from Sickle Cell Anemia
Volunteer Enterprise.
Address reprint requests to Margaret Telfer, MD, Division of
Hematology/Oncology, Michael Reese Hospital and Medical Center, 2929 S
Ellis Ave-Room RC-1200, Chicago, IL 60616.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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D. K. Kaul, X. Zhang, T. Dasgupta, and M. E. Fabry
Arginine therapy of transgenic-knockout sickle mice improves microvascular function by reducing non-nitric oxide vasodilators, hemolysis, and oxidative stress
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July 1, 2008;
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L. De Franceschi, O. S. Platt, G. Malpeli, A. Janin, A. Scarpa, C. Leboeuf, Y. Beuzard, E. Payen, and C. Brugnara
Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice
FASEB J,
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[Abstract]
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W. R. Smith, L. T. Penberthy, V. E. Bovbjerg, D. K. McClish, J. D. Roberts, B. Dahman, I. P. Aisiku, J. L. Levenson, and S. D. Roseff
Daily Assessment of Pain in Adults with Sickle Cell Disease
Ann Intern Med,
January 15, 2008;
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94 - 101.
[Abstract]
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K. I. Ataga, C. G. Moore, C. A. Hillery, S. Jones, H. C. Whinna, D. Strayhorn, C. Sohier, A. Hinderliter, L. V. Parise, and E. P. Orringer
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Haematologica,
January 1, 2008;
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[Abstract]
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G. J. Kato
Novel Small Molecule Therapeutics for Sickle Cell Disease: Nitric Oxide, Carbon Monoxide, Nitrite, and Apolipoprotein A-I
Hematology,
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A. Rivera
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M. J. Telen
Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease
Hematology,
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[Abstract]
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al.
Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline.
Circulation,
March 14, 2006;
113(10):
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[Abstract]
[Full Text]
[PDF]
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al.
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Stroke,
February 1, 2006;
37(2):
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[Abstract]
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P.-L. Tharaux, I. Hagege, S. Placier, M. Vayssairat, A. Kanfer, R. Girot, and J.-C. Dussaule
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[Abstract]
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J. T. Naprawa, B. K. Bonsu, D. G. Goodman, and M. A. Ranalli
Serum Biomarkers for Identifying Acute Chest Syndrome Among Patients Who Have Sickle Cell Disease and Present to the Emergency Department
Pediatrics,
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J. M. Hibbert, L. L. Hsu, S. J. Bhathena, I. Irune, B. Sarfo, M. S. Creary, B. E. Gee, A. I. Mohamed, I. D. Buchanan, A. Al-Mahmoud, et al.
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M. T. Gladwin and G. J. Kato
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Hematology,
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K. C. Wood, R. P. Hebbel, and D. N. Granger
Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice
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J. D. Holtzclaw, D. Jack, S. M. Aguayo, J. R. Eckman, J. Roman, and L. L. Hsu
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C. R. Morris, S. M. Morris Jr., W. Hagar, J. van Warmerdam, S. Claster, D. Kepka-Lenhart, L. Machado, F. A. Kuypers, and E. P. Vichinsky
Arginine Therapy: A New Treatment for Pulmonary Hypertension in Sickle Cell Disease?
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J. D. Belcher, C. J. Bryant, J. Nguyen, P. R. Bowlin, M. C. Kielbik, J. C. Bischof, R. P. Hebbel, and G. M. Vercellotti
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G. F. Atweh, J. DeSimone, Y. Saunthararajah, H. Fathallah, R. S. Weinberg, R. L. Nagel, M. E. Fabry, and R. J. Adams
Hemoglobinopathies
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A. Khodorova, M. U. Fareed, A. Gokin, G. R. Strichartz, and G. Davar
Local Injection of a Selective Endothelin-B Receptor Agonist Inhibits Endothelin-1-Induced Pain-Like Behavior and Excitation of Nociceptors in a Naloxone-Sensitive Manner
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Z. Zhou, G. Davar, and G. Strichartz
Endothelin-1 (ET-1) Selectively Enhances the Activation Gating of Slowly Inactivating Tetrodotoxin-Resistant Sodium Currents in Rat Sensory Neurons: A Mechanism for the Pain-Inducing Actions of ET-1
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August 1, 2002;
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M. Benkerrou, C. Delarche, L. Brahimi, M. Fay, E. Vilmer, J. Elion, M.-A. Gougerot-Pocidalo, and C. Elbim
Hydroxyurea corrects the dysregulated L-selectin expression and increased H2O2 production of polymorphonuclear neutrophils from patients with sickle cell anemia
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A. Rivera, P. Jarolim, and C. Brugnara
Modulation of Gardos channel activity by cytokines in sickle erythrocytes
Blood,
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A. P. Gokin, M. U. Fareed, H.-L. Pan, G. Hans, G. R. Strichartz, and G. Davar
Local Injection of Endothelin-1 Produces Pain-Like Behavior and Excitation of Nociceptors in Rats
J. Neurosci.,
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B. K. Adler, D. E. Salzman, M. H. Carabasi, W. P. Vaughan, V. V. B. Reddy, and J. T. Prchal
Fatal sickle cell crisis after granulocyte colony-stimulating factor administration
Blood,
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J. E. Brittain, K. J. Mlinar, C. S. Anderson, E. P. Orringer, and L. V. Parise
Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin
Blood,
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[Abstract]
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K. A. Nath, J. P. Grande, J. J. Haggard, A. J. Croatt, Z. S. Katusic, A. Solovey, and R. P. Hebbel
Oxidative Stress and Induction of Heme Oxygenase-1 in the Kidney in Sickle Cell Disease
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J. D. Pomonis, S. D. Rogers, C. M. Peters, J. R. Ghilardi, and P. W. Mantyh
Expression and Localization of Endothelin Receptors: Implications for the Involvement of Peripheral Glia in Nociception
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February 1, 2001;
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K. A. Nath, V. Shah, J. J. Haggard, A. J. Croatt, L. A. Smith, R. P. Hebbel, and Z. S. Katusic
Mechanisms of vascular instability in a transgenic mouse model of sickle cell disease
Am J Physiol Regulatory Integrative Comp Physiol,
December 1, 2000;
279(6):
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[Abstract]
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A. Rivera, M. A. Rotter, and C. Brugnara
Endothelins activate Ca2+-gated K+ channels via endothelin B receptors in CD-1 mouse erythrocytes
Am J Physiol Cell Physiol,
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Abstract
Introduction
Abstract