Sickle red blood cells stimulate endothelial cell production of eicosanoids and diacylglycerol

Setty, B. N. Yamaja; Chen, Dechun; Stuart, Marie J.

doi:10.1016/s0022-2143(96)90033-5

Cited by 20 publications

(10 citation statements)

References 27 publications

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“…Although these findings have not been reported previously, Setty et al (55) have reported in a static incubation system that AA metabolites are involved in mediating basal adhesion of normal and SRBCs to endothelium via lipoxygenase metabolites. In subsequent studies, Setty et al (53,54) found that SRBCs stimulate endothelial cell production of AA and diacylglycerol and that the lipoxygenase product 12(s)-hydroxy-5,8,10,14-eicosatetraenoic acid increased hypoxia-induced SRBC-endothelial adherence via the upregulation of VCAM-1 on endothelial cells. These studies are similar to the present study in that products of membrane phospholipids, related in part to the lipoxygenase enzyme system, appear to be involved in mediating SRBC retention/adherence.…”

Section: H127mentioning

confidence: 99%

Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids

Haynes

Obiako

2002

American Journal of Physiology-Heart and Circulatory Physiology

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This study investigates the role of the activated polymorphonuclear cell (APMN) products on sickle red blood cell (SRBC) retention/adherence in the pulmonary circulation. Isolated rat lungs were perfused with (51)Cr-labeled normal RBCs (NRBC) or SRBCs (10% hematocrit) suspensions +/- PMNs. Specific activities of lung and perfusate were measured and retention (the number of SRBC/g lung) was calculated. SRBC retention was 3.5 times greater than NRBC retention. PMN activation was required to increase SRBC retention. Supernatants from APMN increased SRBC retention, which suggested soluble products such as oxidants, PAF, and/or leukotriene (LTB(4)) are involved. Heat inactivation of PMN NADPH oxidase had no effect on retention. Whereas neither platelet-activating factor (PAF) nor LTB(4) (secreted by APMN) increased SRBC retention, PAF+LTB(4) did. The PAF antagonist, WEB-2170, attenuated SRBC retention mediated by PAF+LTB(4) and APMNs. Similarly, zileuton (5-lipoxygenase inhibitor) attenuated APMN-mediated SRBC retention. We conclude the concomitant release of PAF and LTB(4) from APMN is involved in the initiation of microvascular occlusion by SRBCs in the perfused rat lung.

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Section: H127mentioning

confidence: 99%

Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids

Haynes

Obiako

2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…15,16 Thrombocytosis and platelet activation are also well-recognized features of SCD. 4,13,14,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Thrombotic events including pulmonary embolism, deep vein thrombosis, and SCD-related stroke are common. 17,[36][37][38][39][40] SCD-associated pulmonary hypertension (PHT) is associated with endothelial cell activation (as measured by soluble vascular cell adhesion molecule-1 [sVCAM-1]), which would also support procoagulant activity.…”

Section: Introductionmentioning

confidence: 99%

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Arumugam

Mullins²,

Shanmukhappa

et al. 2015

Blood

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• Reduced prothrombin improves survival and ameliorates inflammation and end-organ damage without spontaneous bleeding in sickle cell mice.• An individual procoagulant, prothrombin, represents a novel therapeutic target that can improve sickle cell disease outcome.Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII lox/2 mice (constitutively carrying ∼10% normal FII) and FII WT mice were tracked in parallel for a year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. (Blood. 2015;126(15):1844-1855

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“…Changes in membrane lipid composition might affect red cell deformability, as recently shown in a mouse model supplemented with ω-3 PUFA (docosahexaenoic acid), 59 as well as variations in pro-inflammatory arachidonic acid incorporated into sickle erythrocytes. 60 These red cell changes may play a role in reducing the systemic pro-inflammatory environment, which contributes to the pathogenesis of vasculopathy in SCD. 6 In summary, we propose that ω-3 PUFA may limit sickle cell-related acute damage by: (i) shifting the sickle red cell membrane towards an anti-inflammatory substrate; (ii) exerting local anti-inflammatory effects in target organs for SCD (lung, liver); (iii) improving vascular dysfunction through the reduction of VCAM-1 or ET-1 or the synergistic decrease of both molecules.…”

mentioning

confidence: 99%

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

et al. 2015

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The anemia of sickle cell disease is associated with a severe inflammatory vasculopathy and endothelial dysfunction, which leads to painful and life-threatening clinical complications. Growing evidence supports the anti-inflammatory properties of ω-3 fatty acids in clinical models of endothelial dysfunction. Promising but limited studies show potential therapeutic effects of ω-3 fatty acid supplementation in sickle cell disease. Here, we treated humanized healthy and sickle cell mice for 6 weeks with ω-3 fatty acid diet (fish-oil diet). We found that a ω-3 fatty acid diet: (i) normalizes red cell membrane ω-6/ ω-3 ratio; (ii) reduces neutrophil count; (iii) decreases endothelial activation by targeting endothelin-1 and (iv) improves left ventricular outflow tract dimensions. In a hypoxia-reoxygenation model of acute vaso-occlusive crisis, a ω-3 fatty acid diet reduced systemic and local inflammation and protected against sickle cell-related end-organ injury. Using isolated aortas from sickle cell mice exposed to hypoxia-reoxygenation, we demonstrated a direct impact of a ω-3 fatty acid diet on vascular activation, inflammation, and anti-oxidant systems. Our data provide the rationale for ω-3 dietary supplementation as a therapeutic intervention to reduce vascular dysfunction in sickle cell disease. ABSTRACTmice. 16,17 The animal protocol was approved by the Animal Care and Use Committee of the University of Verona (CIRSAL). Twomonth old animals were fed for 6 weeks with either the standard AIN-93M purified rodent diet (soy-diet with n6/n3 ratio of 8:1 -Dyets Inc., Bethlehem, PA, USA), containing 140 g/kg casein, 1.8 g/kg L-cystine, 100 g/kg sucrose, 465.9 g/kg cornstarch, 155 g/kg dextrose, 40 g/kg soybean oil, 0.8 mg/kg t-butylhydroquinone, 50 g/kg cellulose, 35 g/kg mineral mix, 10 g/kg vitamin mix, and 2.5 g/kg choline bitartrate 18 or the ω-3 FD, an AIN-93M-based purified rodent diet in which all of the calories provided by fat (10%) are replaced by 7.9% from HCO and 2.1% from ω-3 oil (Dyets Inc., Bethlehem, PA, USA). At the end of the 6 weeks of FD supplementation, animals were anesthetized with isofluorane, and whole blood was collected from each mouse via retro-orbital venipuncture by heparinized microcapillaries. Mice were euthanized and organs removed immediately. The organs were divided into two and either frozen immediately in liquid nitrogen or fixed in 10% formalin and embedded in paraffin for histology. Whenever indicated, 6-week old mice were exposed to hypoxia (8% oxygen for 10 h) followed by 3 h of reoxygenation (21% oxygen) (H/R stress) to mimic an acute VOC, as previously described.

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Sickle red blood cells stimulate endothelial cell production of eicosanoids and diacylglycerol

Cited by 20 publications

References 27 publications

Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids

Activated polymorphonuclear cells increase sickle red blood cell retention in lung: role of phospholipids

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

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