P-selectin and sickle cell disease: a balancing act.
Ontology highlight
ABSTRACT:
SUBMITTER: Manwani D
PROVIDER: S-EPMC9635525 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
Publications
Similar Datasets
Project description: Not available
| S-EPMC6988409 | biostudies-literature
Project description:Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin-deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin-deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.
| S-EPMC8120139 | biostudies-literature
Project description:BackgroundThe vascular endothelium is markedly disrupted in sickle cell disease (SCD) and is the converging cascade of the complex pathophysiologic processes linked to sickle cell vasculopathy. Circulating endothelial activation and/or apoptotic markers may reflect this endothelial activation/damage that contributes to the pathophysiology of the SCD vascular complications.MethodsPlasmatic levels of circulating endothelial cells (CECs), E-selectin, progenitor's endothelial cells (EPCs), and circulating extracellular vesicles (EVs) were evaluated in 50 SCD patients, 16 with vasculopathy. The association between these markers and the occurrence of disease-related microvascular injuries of the eye (retinopathy), kidney (nephropathy), and skin (chronic active ulcers) was explored.ResultsAmong the endothelial activation markers studied, only higher plasma levels of E-selectin were found in SCD patients with vasculopathy (p = .015). Increased E-selectin levels were associated with retinopathy (p < .001) but not with nephropathy or leg ulcers. All patients, at steady state, with or without vasculopathy, did not display a high count of CEC and EPC, markers of endothelial injury and repair. We did not show any significant differences in EVs levels between vasculopathy and not vasculopathy SCD patients.ConclusionsFurther studies will be required to determine whether the E-selectin could be used as an early biomarker of retinopathy sickle cell development.
| S-EPMC10100354 | biostudies-literature
Project description:Sickle cell disease (SCD) is a monogenic disorder estimated to affect more than three million people worldwide. Acute systemic painful vaso-occlusive episode (VOE) is the primary reason for emergency medical care among SCD patients. VOE may also progress to acute chest syndrome (ACS), a type of acute lung injury and one of the primary reasons for mortality among SCD patients. Recently, P-selectin monoclonal antibodies were found to attenuate VOE in SCD patients and lung vaso-occlusion in transgenic humanized SCD mice, highlighting the therapeutic benefit of P-selectin inhibition in SCD. Here, we use quantitative fluorescence intravital lung microscopy (qFILM) to illustrate that tandem P-selectin-glycoprotein ligand-immunoglobulin (TSGL-Ig) fusion molecule containing four P-selectin binding sites, significantly attenuated intravenous (IV) oxyhemoglobin triggered lung vaso-occlusion in SCD mice. These findings highlight the therapeutic potential of TSGL-Ig in preventing VOE and ACS in SCD.
| S-EPMC7237323 | biostudies-literature
Project description:ObjectiveTo determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in sickle cell disease (SCD).Methods and resultsBoth platelet and neutrophil activation occur in SCD, but the interdependence of these events is unknown. Platelet activation and binding to leukocytes were measured in mice and patients with SCD and in controls. Relative to controls, blood obtained from mice or patients with SCD contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multispectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild-type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in PNAs in mice with SCD and additional activation of both platelets and neutrophils. The pretreatment of mice with SCD with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability.ConclusionsOur findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. The inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises.
| S-EPMC3058044 | biostudies-literature
Project description:Adhesive interactions between circulating sickle red blood cells (RBCs), leukocytes, and endothelial cells are major pathophysiologic events in sickle cell disease (SCD). To develop new therapeutics that efficiently inhibit adhesive interactions, we generated an anti-P-selectin aptamer and examined its effects on cell adhesion using knockout-transgenic SCD model mice. Aptamers, single-stranded oligonucleotides that bind molecular targets with high affinity and specificity, are emerging as new therapeutics for cardiovascular and hematologic disorders. In vitro studies found that the anti-P-selectin aptamer exhibits high specificity to mouse P-selectin but not other selectins. SCD mice were injected with the anti-P-selectin aptamer, and cell adhesion was observed under hypoxia. The anti-P-selectin aptamer inhibited the adhesion of sickle RBCs and leukocytes to endothelial cells by 90% and 80%, respectively. The anti-P-selectin aptamer also increased microvascular flow velocities and reduced the leukocyte rolling flux. SCD mice treated with the anti-P-selectin aptamer demonstrated a reduced mortality rate associated with the experimental procedures compared with control mice. These results demonstrate that anti-P-selectin aptamer efficiently inhibits the adhesion of both sickle RBCs and leukocytes to endothelial cells in SCD model mice, suggesting a critical role for P-selectin in cell adhesion. Anti-P-selectin aptamer may be useful as a novel therapeutic agent for SCD.
| S-EPMC3031491 | biostudies-literature
Project description:Upregulated expression of P-selectin on activated endothelium and platelets significantly contributes to the initiation and progression of vaso-occlusive crises (VOC), a major cause of morbidity in sickle cell disease (SCD). Crizanlizumab (ADAKVEO®), a humanized monoclonal antibody against P-selectin, primarily inhibits the interaction between leukocytes and P-selectin, and has been shown to decrease the frequency of VOCs in clinical trials. However, the lack of reliable in vitro assays that objectively measure leukocyte adhesion to P-selectin remains a critical barrier to evaluating and improving the therapeutic treatment in SCD. Here, we present a standardized microfluidic BioChip whole blood adhesion assay to assess leukocyte adhesion to P-selectin under physiologic flow conditions. Our results demonstrated heterogeneous adhesion by leukocytes to immobilized P-selectin, and dose-dependent inhibition of this adhesion following pre-exposure to Crizanlizumab. Importantly, treatment with Crizanlizumab following adhesion to P-selectin promoted detachment of rolling, but not of firmly adherent leukocytes. Taken together, our results suggest that the microfluidic BioChip system is a promising in vitro assay with which to screen patients, monitor treatment response, and guide current and emerging anti-adhesive therapies in SCD.
| S-EPMC7246173 | biostudies-literature
Project description:Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte-endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis.
| S-EPMC3293645 | biostudies-literature
Project description: Not available
| S-EPMC3906328 | biostudies-literature
Project description:Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.
| S-EPMC9832386 | biostudies-literature