Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium

Zennadi, Rahima; Chien, Ai; Xu, Ke; Batchvarova, Milena; Telen, Marilyn J.

doi:10.1182/blood-2008-01-134346

Cited by 75 publications

(106 citation statements)

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“…[7][8][9][10][11][12][13][14] Binding of both red cells and leukocytes to endothelial selectins has been proposed to have a critical role in SCD VOC. 13,[15][16][17] Endothelial E-selectin expression is upregulated by inflammatory cytokines and can become a target, along with P-selectin, for leukocyte adhesion. 15,16 Cytokine-stimulated VOC in sickle transgenic mice is inhibited when mice are deficient in P-and E-selectins.…”

Section: Introductionmentioning

confidence: 99%

Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Telen

Wun

McCavit

et al. 2015

Blood

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Section: Introductionmentioning

confidence: 99%

Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Telen

Wun

McCavit

et al. 2015

Blood

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188

164

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“…8,9 Sickle cell disease (SCD) chronic lung disease and the acute chest syndrome are two of the notable causes of death in adult patients with sickle cell disease. [10][11][12] Some lung complications in SCD result from direct or indirect effects of pulmonary microvascular occlusion by sickled erythrocytes and their adhesion to the vascular endothelium, 13,14 leading to release of potent vasoactive molecules, including prostacyclin, thromboxane A 2 , and LTC 4 . 15,16 Indeed, the initiation, progression, and resolution of vaso-occlusive pain episodes due to red blood cell sickling and adhesion to endothelium in the affected tissues have been characterized as "reperfusion injury."…”

Section: Introductionmentioning

confidence: 99%

Sickle Erythrocytes and Platelets Augment Lung Leukotriene Synthesis with Downregulation of Anti‐Inflammatory Proteins: Relevance in the Pathology of the Acute Chest Syndrome

et al. 2014

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Initiation, progression, and resolution of vaso-occlusive pain episodes in sickle cell disease (SCD) have been recognized as reperfusion injury, which provokes an inflammatory response in the pulmonary circulation. Some 5-lipoxygenase (5-lox) metabolites are potent vasoconstrictors in the pulmonary circulation. We studied stimulation of production of the inflammatory eicosanoids leukotrienes (LTs) and prostaglandin E 2 (PGE 2 ) by isolated rat lungs perfused with sickle (HbSS) erythrocytes. Our hypothesis is that HbSS erythrocytes produce more LTs than normal (HbAA) erythrocytes, which can induce vaso-occlusive episodes in SCD patients. Lung perfusates were collected at specific time points and purified by high-pressure liquid chromatography, and LTC 4 and PGE 2 contents were measured by enzyme-linked immunosorbent assay (ELISA). Rat lung explants were also cultured with purified HbAA and HbSS peptides, and 5-lox, cyclooxygenase 1/2, and platelet-activating factor receptor (PAFR) proteins were measured by Western blotting, while prostacyclin and LTs produced by cultured lung explants were measured by ELISA. Lung weight gain and blood gas data were not different among the groups. HbSS-perfused lungs produced more LTC 4 and PGE 2 than HbAA-perfused lungs: 10.40 AE 0.62 versus 0.92 AE 0.2 ng/g dry lung weight (mean AE SEM; P ¼ 0.0001) for LTC 4 . Inclusion of autologous platelets (platelet-rich plasma) elevated LTC 4 production to 12.6 AE 0.96 and 7 AE 0.60 ng/g dry lung weight in HbSS and HbAA perfusates, respectively. HbSS lungs also expressed more 5-lox and PAFR. The data suggest that HbSS erythrocytes and activated platelets in patient's pulmonary microcirculation will enhance the synthesis and release of the proinflammatory mediators LTC 4 and PGE 2 , both of which may contribute to onset of the acute chest syndrome in SCD.

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“…Packed SS and AA RBCs were separated as previously described. 5 Packed RBCs were treated with various reagents to affect cAMP signaling or protein phosphorylation. Sham-treated RBCs were incubated with the same buffer and vehicle but without the active agent.…”

Section: Collection Preparation and Treatment Of Rbcsmentioning

confidence: 99%

“…We have previously shown that abnormal SS RBC interaction with the endothelium and with leukocytes can be induced via ␤ 2 adrenergic receptor (␤ 2 AR) activation by the stress hormone epinephrine. [4][5][6] Such stimulation activates the intracellular cAMP/protein kinase A (PKA) pathway. 4 ␤ 2 ARs are prototypic G-coupled receptors whose signaling properties are in part mediated by the activation of stimulatory GTP-binding proteins (G s proteins), which in turn activate adenylate cyclase (AC), leading to the generation of cAMP and the subsequent activation of PKA.…”

Section: Introductionmentioning

confidence: 99%

Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium

Zennadi¹,

Whalen

Soderblom

et al. 2012

Blood

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IntroductionSickle (homozygous hemoglobin S, SS) RBC-based adhesion and vaso-occlusive events likely initiate and/or exacerbate the profound vasculopathy present in patients with sickle cell disease (SCD). 1,2 SS RBCs possess unusually active signaling pathways that contribute to a panoply of abnormalities, including RBC adhesion to the endothelium and vaso-occlusion. [2][3][4] Cell adhesion is a multistep cellular process that is regulated by complex extracellular and intracellular signals that may differ from one cell type to another. We have previously shown that abnormal SS RBC interaction with the endothelium and with leukocytes can be induced via ␤ 2 adrenergic receptor (␤ 2 AR) activation by the stress hormone epinephrine. [4][5][6] Such stimulation activates the intracellular cAMP/protein kinase A (PKA) pathway. 4 ␤ 2 ARs are prototypic G-coupled receptors whose signaling properties are in part mediated by the activation of stimulatory GTP-binding proteins (G s proteins), which in turn activate adenylate cyclase (AC), leading to the generation of cAMP and the subsequent activation of PKA. The cAMP/PKA pathway can modulate the MAPK/ERKs cascade both directly and indirectly. 7-9 PKA has been reported to stimulate B-Raf, while inhibiting c-Raf. Therefore, the activity of downstream signaling proteins, such as MEKs and ERKs, could be either enhanced or inhibited depending on the balance of c-Raf and B-Raf activation. 10,11 The cellular functions mediated by ␤ 2 ARs can also be independent of adenylyl cyclase activation and involve other mediators instead. [12][13][14][15] The functions attributed to ERK1/2 at both the cellular and physiologic levels are diverse, including modulation of proliferation, differentiation, apoptosis, migration, and cell adhesion. [16][17][18][19] Physiologically, ERK1/2 is required for immune system development, homeostasis and antigen activation, memory formation, development of the heart, and responses to many hormones, growth factors, and insulin. Most of these previous studies have involved only nucleated cells, including erythroid cells, in which erythropoietin is the primary regulatory cytokine of this pathway. 20 However, aberrations in ERK1/2 signaling are known to occur in a wide range of pathologies, including cancer, diabetes, viral infection, and cardiovascular disease. 21,22 In preliminary studies, authors have indicated that ERK1/2 is highly abundant in both SS and normal RBCs. Yet, whether this kinase remains functional in normal or SS RBCs is unknown, and an extremely critical question in the study of SCD pathophysiology. Such a mechanism of action could represent a novel target for the treatment of SCD. Methods Endothelial cellsPrimary HUVECs were grown as monolayers in EBM2 medium (Lonza Walkersville) supplemented with EGM2 (Lonza Walkersville) as described previously. 4 All experiments were approved by the Duke University institutional review board. AntibodiesAbs used included the following monoclonal and polyclonal Abs (as purified Ig unless otherwise noted): B...

show abstract

Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium

Cited by 75 publications

References 48 publications

Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use

Sickle Erythrocytes and Platelets Augment Lung Leukotriene Synthesis with Downregulation of Anti‐Inflammatory Proteins: Relevance in the Pathology of the Acute Chest Syndrome

Erythrocyte plasma membrane–bound ERK1/2 activation promotes ICAM-4–mediated sickle red cell adhesion to endothelium

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