Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0002895 (sickle cell disease)
11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydroxyurea therapy reduces the rates of vaso-occlusive crisis in patients with sickle cell anaemia and recent data suggest that hydroxyurea treatment can generate nitric oxide (NO). Nitric oxide has been proposed as a novel therapy for sickle cell disease via a number of pathways. We therefore sought to determine whether hydroxyurea has NO donor properties in patients with sickle cell anaemia and explore potential mechanisms by which NO production could be therapeutic. Venous blood was collected from 19 fasting sickle cell anaemia patients, on chronic hydroxyurea therapy, at baseline and 2 and 4 h after a single morning dose of hydroxyurea, as well as 10 patients not taking hydroxyurea. The plasma and red cell NO reaction products nitrate, nitrite and nitrosylated- haemoglobin were measured using ozone-based chemiluminescent assays (using vanadium, KI and I3- reductants respectively). Consistent with NO release from hydroxyurea, baseline levels of total nitrosylated haemoglobin increased from 300 nmol/l to 500 nmol/l (P = 0.01). Plasma nitrate and nitrite levels also significantly increased with peak levels observed at 2 h. Glutathionyl-haemoglobin levels were unchanged, while plasma secretory vascular cellular adhesion molecule-1 levels were reduced in patients taking hydroxyurea (419 +/- 40 ng/ml) compared with control patients with sickle cell anaemia (653 +/- 55 ng/ml; P = 0.003), and were inversely correlated with fetal haemoglobin levels (r = -0.72; P = 0.002). These results demonstrate that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of NO. The role of NO in the induction of fetal haemoglobin and possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored.
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PMID:Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. 1184 49

Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n = 15); (2) patients with a history of vasoocclusive events (n = 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n = 9). Unstimulated PMNs showed decreased L selectin expression and increased H(2)O(2) production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H(2)O(2) production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H(2)O(2) production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H(2)O(2) production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug.
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PMID:Hydroxyurea corrects the dysregulated L-selectin expression and increased H(2)O(2) production of polymorphonuclear neutrophils from patients with sickle cell anemia. 1189 59

Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.
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PMID:No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease. 1222 77

Inflammation may play an essential role in vaso-occlusion in sickle cell disease. Sickle patients have high white counts and elevated levels of serum C-reactive protein (CRP), cytokines, and adhesion molecules. In addition, circulating endothelial cells, leukocytes, and platelets are activated. We examined 4 transgenic mouse models expressing human alpha- and sickle beta-globin genes to determine if they mimic the inflammatory response seen in patients. These mouse models are designated NY-S, Berk-S(Antilles), NY-S/S(Antilles) (NY-S x Berk-S(Antilles)), and Berk-S. The mean white counts were elevated 1.4- to 2.1-fold (P </=.01) in the Berk-S(Antilles), NY-S/S(Antilles), and Berk-S mice, but not in the NY-S mice compared with controls. Serum amyloid P-component (SAP), an acute-phase response protein with 60% to 70% sequence homology to CRP, was elevated 8.5- to 12.1-fold (P </=.001) in transgenic sickle mice. Similarly, serum interleukin-6 (IL-6) was elevated 1.6- to 1.9-fold (P </=.05). Western blots, confirming immunohistochemical staining, showed vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and platelet-endothelial cell adhesion molecule (PECAM) were up-regulated 3- to 5-fold (P </=.05) in the lungs of sickle mice. Ribonuclease protection assays (RPAs) demonstrated VCAM mRNA also was elevated in sickle mice 1.2- to 1.4-fold (P </=.01). Nuclear factor kappaB (NF-kappaB), a transcription factor critical for the inflammatory response, was elevated 1.9-fold (P </=.006) in NY-S sickle mouse lungs. We conclude that transgenic sickle mice are good models to study vascular inflammation and the potential benefit of anti-inflammatory therapies to prevent vaso-occlusion in sickle cell disease.
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PMID:Transgenic sickle mice have vascular inflammation. 1254 57

Microvascular complications in sickle cell disease occur as a result of obstruction of small vessels by deoxygenated sickle cells. Cerebrovascular complications are also common and result from obstruction of large blood vessels by thrombosis with changes in vessels that have some similarity to those found in arteriosclerotic vascular disease. Endothelial damage and activation from sickle cell-endothelial interactions may contribute to both. We find that endothelial cells have increased expression of VCAM-1, E-selectin, and ICAM-1 when exposed to sickle blood cells. The concentration-dependent, sickle-induced, adhesion molecule expression is significantly greater than that promoted by normal cells. The time course of Cell Adhesion Molecule (CAM) expression is similar to that induced by TNF-alpha and IL1. Studies after white cell enrichment and reduction suggest leukocytes are the primary mediators. CAM expression by endothelial cells appears stimulated by soluble factors. Antibody inhibition studies support TNF-alpha and IL-1, produced by sickle leukocytes, as the primary soluble factors responsible for the observed CAM expression. Both the induction of endothelial CAM expression and subsequent endothelial adherence of sickle erythrocytes may play significant roles in the pathophysiology of sickle-related complications, and reduction in CAM expression may provide a new approach to treatment.
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PMID:Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. 1267 44

Possible pathogenetic processes in sickle cell disease include antioxidants, endothelial and platelet changes, and hypercoagulability. Hypothesizing relationships between these processes, we recruited 47 young adult patients (mean age 19 years) with homozygous sickle cell disease and 40 age-, race- and sex-matched healthy controls and measured plasma markers representative of these processes. We found raised plasma von Willebrand factor (P = 0.001) and intercellular adhesion molecule (P = 0.016, both marking endothelial perturbation, but the latter also marking inflammation), raised soluble P selectin (P = 0.002) (marking platelet activation) and inflammation marker C reactive protein (P = 0.021), but reduced antioxidant capacity (P = 0.002) in patients compared with controls. There was no difference in fibrinogen and there was no significant correlation between any of the indices. Our data suggest that changes in endothelial and platelet function in sickle cell disease are unrelated to reduced antioxidant capacity.
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PMID:Platelet activation and endothelial cell dysfunction in sickle cell disease is unrelated to reduced antioxidant capacity. 1269 48

Intercellular adhesion molecule-4 (ICAM-4, syn. LW glycoprotein) interacts with the integrins alpha(L)beta(2), alpha(M)beta(2), A(4)beta(1), the alpha(V) family, and alpha(IIb)beta(3). Systematic mutagenesis of surface-exposed residues conserved between human and murine ICAM-4 defined 12 single amino-acid changes that affect the interaction of ICAM-4 with alpha(V) integrins. Mutation of 10 of these residues, 8 of which are spatially close on the surface of the molecule, led to a reduction in adhesion. Moreover, peptides corresponding to regions of ICAM-4 involved in its interaction with alpha(V) integrins inhibited these interactions. The other 2 mutations increased the extent of interaction of ICAM-4 with alpha(V) integrins. These mutations appear to prevent glycosylation of N160, suggesting that changes in glycosylation may modulate ICAM-4-alpha(V) integrin interactions. The region of ICAM-4 identified as the binding site for alpha(V) integrins is adjacent to the binding sites for alpha(L)beta(2) and alpha(M)beta(2). Selective binding of ICAM-4 to different integrins may be important for a variety of normal red cell functions and also relevant to the pathology of thrombotic disorders and vasoocclusive events in sickle cell disease. Our findings suggest the feasibility of developing selective inhibitors of ICAM-4-integrin adhesion of therapeutic value in these diseases.
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PMID:Identification of critical amino-acid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to alpha V integrins. 1455 Nov 35

In addition to its mediation of vascular relaxation and neurotransmission, nitric oxide (*NO) potently modulates oxygen radical reactions and inflammatory signaling. This participation of *NO in free radical and oxidative reactions will yield secondary oxides of nitrogen that display frequently-undefined reactivities and unique signaling properties. In sickle cell disease (SCD) inflammatory-derived oxidative reactions impair *NO-dependent vascular function. A combination of clinical and knockout-transgenic SCD mouse studies show increased rates of xanthine oxidase-dependent superoxide (O2*-) production and reveal the presence of an oxidative and nitrative inflammatory milieu in the sickle cell vasculature, kidney and liver. Considering the critical role of endothelial *NO production in regulating endothelial adhesion molecule expression, platelet aggregation, and both basal and stress-mediated vasodilation, the O2*- mediated reduction in *NO bioavailability can significantly contribute to the vascular dysfunction and organ injury associated with SCD.
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PMID:Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease--mechanisms and consequences. 1504 Apr 33

Erythrocytes in normal conditions have weak interactions with other blood cells and endothelial cells while in pathological circumstances they can adhere to endothelium and aggregate or agglutinate to blood cells. Erythrocyte adhesion was found to be abnormal in sickle cell anemia and diabetes mellitus and correlated to the vascular complications. Further studies demonstrated that VLA-4 adhesion molecule (alpha4beta1) present on erythrocytes bound to vascular cell adhesion molecule (VCAM-1) of the endothelium. In addition, the blood group Lutheran molecule (LU) overexpressed on sickle erythrocytes bind to laminin present on cells or in the intercellular space. In diabetes mellitus the formation of advanced glycation end products (AGE) by reaction between carbohydrates and free aminogroups of lysine is responsible for red blood cell membrane glycation. AGEs present on RBCs bind to the receptor for AGE (RAGE) on endothelium, activating endothelial cells. A molecule related to blood group Rhesus was demonstrated to belong to the intercellular adhesion molecule (ICAM) family. ICAM-4 binds to integrins present on leukocytes (CD11-CD18) and on platelets (alpha2beta4) offering a surface, which can be involved in thrombosis. The identification of erythrocytes adhesion molecules open a new way to understand thrombotic processes and vascular dysfunction.
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PMID:Erythrocytes and platelet adhesion to endothelium are mediated by specialized molecules. 1525 42

The possible role of physiologic stress hormones in enhancing adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs) in sickle cell disease (SCD) has not been previously explored. We have now found that up-regulation of intracellular cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) by epinephrine significantly increased sickle but not normal erythrocyte adhesion to both primary and immortalized ECs. Inhibition of serine/threonine phosphatases also enhanced sickle erythrocyte adhesion at least partially through a PKA-dependent mechanism. Adhesion was mediated through LW (intercellular adhesion molecule-4 [ICAM-4], CD242) blood group glycoprotein, and immunoprecipitation studies showed that LW on sickle but not on normal erythrocytes undergoes increased PKA-dependent serine phosphorylation as a result of activation. The major counter receptor for LW was identified as the alphavbeta3 integrin on ECs. These data suggest that adrenergic hormones such as epinephrine may initiate or exacerbate vaso-occlusion and thus contribute to the association of vaso-occlusive events with physiologic stress.
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PMID:Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. 1530 66


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