RESUMEN
Psychological stress has adverse effects on various human diseases, including those of the cardiovascular system. However, the mechanisms by which stress influences disease activity remain unclear. Here, using vaso-occlusive episodes (VOEs) of sickle cell disease as a vascular disease model, we show that stress promotes VOEs by eliciting a glucocorticoid hormonal response that augments gut permeability, leading to microbiota-dependent interleukin-17A (IL-17A) secretion from T helper 17 (Th17) cells of the lamina propria, followed by the expansion of the circulating pool of aged neutrophils that trigger VOEs. We identify segmented filamentous bacteria as the commensal essential for the stress-induced expansion of aged neutrophils that enhance VOEs in mice. Importantly, the inhibition of glucocorticoids synthesis, blockade of IL-17A, or depletion of the Th17 cell-inducing gut microbiota markedly reduces stress-induced VOEs. These results offer potential therapeutic targets to limit the impact of psychological stress on acute vascular occlusion.
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Anemia de Células Falciformes/patología , Microbioma Gastrointestinal/inmunología , Interleucina-17/metabolismo , Estrés Psicológico/patología , Células Th17/inmunología , Anemia de Células Falciformes/psicología , Animales , Bacterias/inmunología , Línea Celular , Vida Libre de Gérmenes , Glucocorticoides/biosíntesis , Factor Estimulante de Colonias de Granulocitos/metabolismo , Células HEK293 , Humanos , Sistema Hipotálamo-Hipofisario/metabolismo , Inflamación/inmunología , Inflamación/psicología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunologíaRESUMEN
While neutrophils are the main effectors of protective innate immune responses, they are also key players in inflammatory pathologies. Sickle cell disease (SCD) is a genetic blood disorder in which red blood cells (RBCs) are constantly destroyed in the circulation which generates a highly inflammatory environment that culminates in vascular occlusions. Vaso-occlusion is the hallmark of SCD and a predictor of disease severity. Neutrophils initiate and propagate SCD-related vaso-occlusion through adhesive interactions with the activated and dysfunctional endothelium, sickle RBCs, and platelets, leading to acute and chronic complications that progress to irreversible organ damage and ultimately death. The use of SCD humanized mouse models, in combination with in vivo imaging techniques, has emerged as a fundamental tool to understand the dynamics of neutrophils under complex inflammatory contexts and their contribution to vascular injury in SCD. In this review, we discuss the various mechanisms by which circulating neutrophils sense and respond to the wide range of stimuli present in the blood of SCD patients and mice. We argue that the central role of neutrophils in SCD can be rationalized to develop targets for the management of clinical complications in SCD patients.
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Anemia de Células Falciformes , Enfermedades Vasculares , Lesiones del Sistema Vascular , Humanos , Ratones , Animales , Neutrófilos , Lesiones del Sistema Vascular/complicaciones , Lesiones del Sistema Vascular/metabolismo , Anemia de Células Falciformes/complicaciones , Enfermedades Vasculares/complicaciones , Enfermedades Vasculares/patología , Eritrocitos/metabolismoRESUMEN
Viscosity-vaso-occlusion (VVO) and haemolysis-endothelial dysfunction (HED) are pathophysiological mechanisms and clinical subphenotypes of sickle cell disease (SCD). Recurrent vaso-occlusive crises (VOC) may lead to neuroplastic changes and pain sensitization. Among 257 SCD participants, we assessed the relationship of subphenotypes with pain sensitivity using quantitative sensory testing to identify heat pain thresholds (HPT) and pressure pain thresholds (PPT). VOC history and sleep, social and emotional functioning were assessed using the adult sickle cell quality of life measurement information system. The 'elbow method' determined the optimal number of clusters as three. Clustering was performed using K-prototypes. Among clusters 2 and 3, VOC frequency and severity were higher. Clusters 1 and 3 had lower haemoglobin, higher reticulocytes and lactate dehydrogenase and more leg ulcers. In multivariate regression, cluster 3 was associated with approximately 13.6% lower PPT compared to cluster 1, and female sex was associated with decreases in PPT and HPT at the hands and feet (p < 0.001). Hydroxyurea use and unit increases in sleep functioning and age were associated with approximately 20.1% higher foot-PPT, 6.8% higher hand-PPT and 2.5% higher hand-HPT and foot-HPT respectively. Findings suggest that a third subphenotype with mixed VVO and HED features and worse pain sensitization may exist.
RESUMEN
INTRODUCTION: Sickle cell disease (SCD) is the most common inherited hemoglobinopathy, affecting approximately 100 000 patients in United States and millions worldwide. Although the mainstay of pain management for VOC remains systemic opioids, given the potential for adverse effects including respiratory depression and hypoxemia, there remains interest in the use of regional anesthetic techniques (neuraxial or peripheral nerve blockade). METHODS: A systematic search of pubMed, Scopus, and Google Scholar was conducted using the terms sickle cell disease, sickle cell crisis, pain crisis, vaso-occlusive crisis, regional anesthesia, peripheral nerve blockade, and neuraxial anesthesia. RESULTS: We identified 7 publications, all of which were retrospective case series or single case reports, outlining the use of neuraxial anesthesia in a total of 26 patients with SCD. Additionally, we identified 4 publications, including one retrospective case series and 3 single case reports, entailing the use of peripheral blockade in patients with VOC and SCD. DISCUSSION: The available literature, albeit all retrospective or anecdotal, suggests the potential utility of regional anesthesia to treat pain in patients with SCD. Additional benefits have included avoidance of the potential deleterious physiologic effects of systemic opioids and in one case series, an improvement in respiratory function as judged by pulse oximetry. The anecdotal and retrospective nature of the available reports with an absence of prospective trials limits the evidence based medicine available from which to develop to guidlines for the optimal local anesthetic agent to use, its concentration, the rate of infusion, and the choice of adjunctive agents.
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Anemia de Células Falciformes , Anestesia de Conducción , Compuestos Orgánicos Volátiles , Humanos , Niño , Estudios Retrospectivos , Estudios Prospectivos , Anemia de Células Falciformes/complicaciones , Dolor/etiología , Anestesia de Conducción/efectos adversos , Analgésicos OpioidesRESUMEN
Haemoglobin S polymerization in the red blood cells (RBCs) of individuals with sickle cell anaemia (SCA) can cause RBC sickling and cellular alterations. Piezo1 is a mechanosensitive protein that modulates intracellular calcium (Ca2+ ) influx, and its activation has been associated with increased RBC surface membrane phosphatidylserine (PS) exposure. Hypothesizing that Piezo1 activation, and ensuing Gárdos channel activity, alter sickle RBC properties, RBCs from patients with SCA were incubated with the Piezo1 agonist, Yoda1 (0.1-10 µM). Oxygen-gradient ektacytometry and membrane potential measurement showed that Piezo1 activation significantly decreased sickle RBC deformability, augmented sickling propensity, and triggered pronounced membrane hyperpolarization, in association with Gárdos channel activation and Ca2+ influx. Yoda1 induced Ca2+ -dependent adhesion of sickle RBCs to laminin, in microfluidic assays, mediated by increased BCAM binding affinity. Furthermore, RBCs from SCA patients that were homo-/heterozygous for the rs59446030 gain-of-function Piezo1 variant demonstrated enhanced sickling under deoxygenation and increased PS exposure. Thus, Piezo1 stimulation decreases sickle RBC deformability, and increases the propensities of these cells to sickle upon deoxygenation and adhere to laminin. Results support a role of Piezo1 in some of the RBC properties that contribute to SCA vaso-occlusion, indicating that Piezo1 may represent a potential therapeutic target molecule for this disease.
Asunto(s)
Anemia de Células Falciformes , Calcio , Humanos , Calcio/metabolismo , Laminina/metabolismo , Eritrocitos/metabolismo , Eritrocitos Anormales/metabolismoRESUMEN
Sickle cell disease is characterized by painful vaso-occlusive crises, in which poorly deformable sickle cells play an important role in the complex vascular obstruction process. Existing techniques are mainly based on optical microscopy and video processing of sickle blood flow under normoxic condition, for measuring vaso-occlusion by a small fraction of dense sickle cells of intrinsic rigidity but not the vaso-occlusion by the rigid, sickled cells due to deoxygenation. Thus, these techniques are not suitable for rapid, point-of-care testing. Here, we integrate electrical impedance sensing and Polydimethylsiloxane-microvascular mimics with controlled oxygen level into a single microfluidic chip, for quantification of vaso-occlusion by rigid, sickled cells within 1 min. Electrical impedance measurements provided a label-free, real-time detection of different sickle cell flow behaviors, including steady flow, vaso-occlusion, and flow recovery in response to the deoxygenation-reoxygenation process that are validated by microscopic videos. Sensitivity of the real part and imaginary part of the impedance signals to the blood flow conditions in both natural sickle cell blood and simulants at four electrical frequencies (10, 50, 100, and 500 kHz) are compared. The results show that the sensitivity of the sensor in detection of vaso-occlusion decreases as electrical frequency increases, while the higher frequencies are preferable in measurement of steady flow behavior. Additional testing using sickle cell simulants, chemically crosslinked normal red blood cells, shows same high sensitivity in detection of vaso-occlusion as sickle cell vaso-occlusion under deoxygenation. This work enables point-of-care testing potentials in rapid, accurate detection of steady flow and sickle cell vaso-occlusion from microliter volume blood specimens. Quantification of sickle cell rheology in response to hypoxia, may provide useful indications for not only the kinetics of cell sickling, but also the altered hemodynamics as obseved at the microcirculatory level.
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Anemia de Células Falciformes , Humanos , Impedancia Eléctrica , Microcirculación , Anemia de Células Falciformes/diagnóstico , Microfluídica , Dispositivos Laboratorio en un ChipRESUMEN
BACKGROUND: Sickle cell anemia (SCA) is a genetic disease with great clinical heterogeneity and few viable strategies for treatment; hydroxyurea (HU) is the only widely used drug. Thus, the study of single nucleotide polymorphisms (SNPs) and the gene expression of MMPs 1, 2, 9, 7 and TIMPs 1 and 2, which are involved in the regulation of extracellular matrix, inflammation, and neuropathies, may provide further insights into the pathophysiology of the disease and elucidate biomarkers and molecules as potential therapeutic targets for patients with SCA. METHODS AND RESULTS: We evaluated 251 young individuals with SCA from northeastern Brazil. The groups were divided according to vaso-occlusive crisis (VOC) and cerebrovascular disease (CVD), compared to control individuals. SNP detection and gene expression assays were performed by real-time PCR, TaqMan system®. Both the expression levels of MMP1 gene, and the SNP MMP1-1607 1G/2G were associated with the risk of cerebral ischemic stroke (IS), and the expression of MMP1 was also associated with a higher frequency of VOC/year. Expression levels of MMP7, TIMP1, and TIMP2 were increased in patients conditioned to IS. The SNP 372T>C (rs4898) TIMP1 T alleles were more frequent in patients with > 5 VOC events/year. The SNP rs17576 of MMP9 showed differences in gene expression levels; it was increased in the genotypes AG, and AG+GG. CONCLUSION: The findings of this study, the SNPs, and expression provide initial support for understanding the role of MMPs-TIMPs in the pathophysiology of SCA in young patients.
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Anemia de Células Falciformes , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Compuestos Orgánicos Volátiles , Humanos , Metaloproteinasa 1 de la Matriz/genética , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Accidente Cerebrovascular/genética , Isquemia , Polimorfismo de Nucleótido Simple/genética , Metaloproteinasas de la Matriz/genética , Expresión GénicaRESUMEN
Sickle cell disease (SCD) is characterized by frequent and unpredictable vaso-occlusive crises (VOCs). Sickle erythrocytes (SSRBCs) contribute to VOCs by participating in a series of adhesive events with blood cells and the vascular endothelium. Adhesion assays have been used to evaluate the relationship between SSRBC adhesion and SCD severity. We developed a standardized, clinical flow adhesion assay of whole blood to vascular cell adhesion molecule (FA-WB-VCAM). The objective of this study was to assess the variability and clinical predictive value of FA-WB-VCAM in a six-month longitudinal, observational study (ELIPSIS) in SCD subjects during at-home, steady-state and self-reported VOCs, and following VOC resolution. We observed a strong relationship between FA-WB-VCAM and SCD severity. Adhesion indices were significantly lower in SCD subjects on hydroxycarbamide and increased during VOCs; at-home VOCs had significantly higher FA-WB-VCAM than steady-state and contact VOCs. SCD subjects with a high frequency of self-reported VOCs had a pro-adhesive phenotype at steady state and were stratified into a high-adhesive phenotype cohort; two years prospectively we observed a higher frequency of VOCs in the high-adhesion cohort. This study supports stratifying SCD subjects based on steady-state FA-WB-VCAM and suggests that FA-WB-VCAM may be a plausible surrogate end-point for SCD severity.
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Anemia de Células Falciformes/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Estudios de Casos y Controles , Humanos , Estudios LongitudinalesRESUMEN
Occlusive nonvasculitic vasculopathy is a process characterized clinically by retiform purpura and potential ulceration and necrosis of affected areas, secondary to blockage of small vessels without associated inflammatory vasculitis. Intravascular injection of foreign material is known to cause distal ischemia and necrosis due to thrombosis, local vasoconstriction, or microemboli formation. A 27-year-old male presented with retiform purpura and worsening distal fingertip necrosis of the right upper extremity accompanied by suspicious intravascular polarizable foreign material identified on skin, muscle, and vascular biopsies. We report a case that highlights concerning complications and dermatopathologic findings of intravascular injection of oral opioid tablets.
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Analgésicos Opioides/efectos adversos , Embolia/diagnóstico , Enfermedades Cutáneas Vasculares/patología , Vasculitis/patología , Adulto , Analgésicos Opioides/administración & dosificación , Biopsia , Embolia/etiología , Fasciotomía/métodos , Resultado Fatal , Dedos/patología , Cuerpos Extraños/diagnóstico , Reacción a Cuerpo Extraño/diagnóstico , Reacción a Cuerpo Extraño/cirugía , Humanos , Inyecciones Intravenosas , Masculino , Necrosis/diagnóstico , Necrosis/etiología , Cooperación del Paciente/psicología , Púrpura/diagnóstico , Púrpura/etiología , Piel/patología , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/patología , Comprimidos/administración & dosificación , Vasculitis/cirugíaRESUMEN
Rationale: Intraerythrocytic polymerization of Hb S promotes hemolysis and vasoocclusive events in the microvasculature of patients with sickle cell disease (SCD). Although platelet-neutrophil aggregate-dependent vasoocclusion is known to occur in the lung and contribute to acute chest syndrome, the etiological mechanisms that trigger acute chest syndrome are largely unknown.Objectives: To identify the innate immune mechanism that promotes platelet-neutrophil aggregate-dependent lung vasoocclusion and injury in SCD.Methods:In vivo imaging of the lung in transgenic humanized SCD mice and in vitro imaging of SCD patient blood flowing through a microfluidic system was performed. SCD mice were systemically challenged with nanogram quantities of LPS to trigger lung vasoocclusion.Measurements and Main Results: Platelet-inflammasome activation led to generation of IL-1ß and caspase-1-carrying platelet extracellular vesicles (EVs) that bind to neutrophils and promote platelet-neutrophil aggregation in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro. The inflammasome activation, platelet EV generation, and platelet-neutrophil aggregation were enhanced by the presence of LPS at a nanogram dose in SCD but not control human blood. Inhibition of the inflammasome effector caspase-1 or IL-1ß pathway attenuated platelet EV generation, prevented platelet-neutrophil aggregation, and restored microvascular blood flow in lung arterioles of SCD mice in vivo and SCD human blood in microfluidics in vitro.Conclusions: These results are the first to identify that platelet-inflammasome-dependent shedding of IL-1ß and caspase-1-carrying platelet EVs promote lung vasoocclusion in SCD. The current findings also highlight the therapeutic potential of targeting the platelet-inflammasome-dependent innate immune pathway to prevent acute chest syndrome.
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Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/inmunología , Vesículas Extracelulares/inmunología , Inflamasomas/inmunología , Lesión Pulmonar/etiología , Lesión Pulmonar/fisiopatología , Agregación Plaquetaria/inmunología , Síndrome Torácico Agudo/etiología , Síndrome Torácico Agudo/fisiopatología , Anemia de Células Falciformes/fisiopatología , Animales , Humanos , Ratones , Ratones Transgénicos , Modelos Animales , Neutrófilos/inmunologíaRESUMEN
Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.
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Anemia de Células Falciformes/patología , Anemia de Células Falciformes/fisiopatología , Citoprotección , Hemopexina/metabolismo , Animales , Humanos , Inmunomodulación , Lipoproteínas/metabolismo , Microvasos/patologíaRESUMEN
Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso-occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18-30 years) 1:1:1 to twice-daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient-reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non-major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary-reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.
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Anemia de Células Falciformes , Dolor , Inhibidores de Agregación Plaquetaria , Ticagrelor , Adolescente , Adulto , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Femenino , Humanos , Masculino , Dolor/sangre , Dolor/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/farmacocinética , Ticagrelor/administración & dosificación , Ticagrelor/farmacocinética , Adulto JovenRESUMEN
Pain is the main complication of sickle cell disease (SCD). Individuals with SCD experience acute pain episodes and chronic daily pain, both of which are managed with opioids. Opioids have deleterious side effects and use-associated stigma that make them less than ideal for SCD pain management. After recognizing the neuropathic qualities of SCD pain, clinically-approved therapies for neuropathic pain, including gabapentin, now present unique non-opioid based therapies for SCD pain management. These experiments explored the efficacy of gabapentin in relieving evoked and spontaneous chronic pain, and hypoxia/reoxygenation (H/R)-induced acute pain in mouse models of SCD. When administered following H/R, a single dose of gabapentin alleviated mechanical hypersensitivity in SCD mice by decreasing peripheral fibre activity. Gabapentin treatment also alleviated spontaneous ongoing pain in SCD mice. Longitudinal daily administration of gabapentin failed to alleviate H/R-induced pain or chronic evoked mechanical, cold or deep tissue hypersensitivity in SCD mice. Consistent with this observation, voltage-gated calcium channel (VGCC) α2 δ1 subunit expression was similar in sciatic nerve, dorsal root ganglia and lumbar spinal cord tissue from SCD and control mice. Based on these data, gabapentin may be an effective opioid alternative for the treatment of chronic spontaneous and acute H/R pain in SCD.
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Anemia de Células Falciformes , Dolor Crónico , Gabapentina/farmacología , Hiperalgesia , Hipoxia , Nervio Ciático , Enfermedad Aguda , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/metabolismo , Anemia de Células Falciformes/patología , Animales , Canales de Calcio Tipo L/genética , Canales de Calcio Tipo L/metabolismo , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Dolor Crónico/metabolismo , Dolor Crónico/patología , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/genética , Hiperalgesia/metabolismo , Hiperalgesia/patología , Hipoxia/tratamiento farmacológico , Hipoxia/genética , Hipoxia/metabolismo , Hipoxia/patología , Ratones , Ratones Transgénicos , Nervio Ciático/metabolismo , Nervio Ciático/patologíaRESUMEN
BACKGROUND: Sickle cell anemia (SCA), a disorder with an important inflammatory component, where vasoocclusion is major contributor to the disease pathophysiology. Pro-inflammatory cytokines play an important regulatory role in the process of inflammation. We investigated the expression TL1A/DR3/DcR3 cytokine signaling pathway in peripheral blood mononuclear cells (PBMC) and their corresponding plasma levels in SCA subjects who presented with acute painful episodes. MATERIALS AND METHODS: PBMC were isolated from the blood of SCA subjects and normal healthy controls. RNA isolated from PBMC was used for real time gene expression of TL1A/DR3/DcR3. Gene expression was compared in subgroups within SCA subjects with co-inherited fetal hemoglobin (HbF) or alpha-globin gene deletions. Plasma prepared from blood was used for determination of TL1A/DR3/DcR3 proteins by ELISA assays. RESULTS: In the PBMC of SCA subjects, expression of TL1A and DcR3 is elevated, while DR3 expression is lowered in comparison to normal control PBMC. In SCA subjects with HbFâ¯>â¯10%, TL1A/DcR3 expression is lower, while HbFâ¯<â¯10% is associated with increased TL1A/DcR3 expression. Moreover, subjects with HbFâ¯>â¯10% appear to have significantly fewer pain episodes in comparison to those with HbFâ¯<â¯10%. Deletion of alpha-globin genes appears to have no significant effect on TL1A/DR3/DcR3 expression. Circulating levels of TL1A, DR3 and DcR3 in plasma were significantly elevated in SCA subjects. CONCLUSIONS: Elevated TL1A and DcR3 expression in PBMC of SCA subjects during painful vasoocclusive crisis, suggest an altered TL1A expression may contribute to the pathophysiology of vasoocclusive crisis in SCA. HbFâ¯>â¯10% appears to moderate TL1A elevation, while HbFâ¯<â¯10% exacerbates TL1A/DcR3 responses. Furthermore, subjects with HbFâ¯>â¯10% have significantly lower pain episodes reported as compared to subjects with HbFâ¯<â¯10%.
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Anemia de Células Falciformes/sangre , Regulación de la Expresión Génica , Leucocitos Mononucleares/metabolismo , Miembro 25 de Receptores de Factores de Necrosis Tumoral/sangre , Miembro 6b de Receptores del Factor de Necrosis Tumoral/sangre , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Adolescente , Adulto , Anemia de Células Falciformes/patología , Femenino , Humanos , Leucocitos Mononucleares/patología , MasculinoRESUMEN
Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the ß-globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell-derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA-approved therapy to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L-glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.
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Anemia de Células Falciformes/etiología , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/metabolismo , Animales , Antidrepanocíticos/farmacología , Antidrepanocíticos/uso terapéutico , Biomarcadores , Coagulación Sanguínea , Moléculas de Adhesión Celular/metabolismo , Micropartículas Derivadas de Células/metabolismo , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Membrana Eritrocítica/metabolismo , Eritrocitos Anormales/metabolismo , Genotipo , Hemoglobina Falciforme/genética , Hemólisis , Humanos , Hidroxiurea/farmacología , Hidroxiurea/uso terapéutico , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Mutación , Óxido Nítrico/metabolismo , Globinas beta/genéticaRESUMEN
Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.
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Apolipoproteína L1/genética , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Rechazo de Injerto/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Adulto , Aloinjertos/patología , Estudios de Casos y Controles , Femenino , Genotipo , Glomeruloesclerosis Focal y Segmentaria/epidemiología , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Rechazo de Injerto/epidemiología , Rechazo de Injerto/genética , Rechazo de Injerto/patología , Supervivencia de Injerto/genética , Humanos , Incidencia , Riñón/patología , Masculino , Persona de Mediana Edad , Pronóstico , Donantes de Tejidos , Trasplante Homólogo/efectos adversosRESUMEN
Sickle cell disease (SCD) is a life-threatening chronic condition primarily caused by genetic mutation. The disease is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Acute complications in patients with SCD are difficult to manage due to the pathophysiological nature of the disease. Transfusion therapy is the cornerstone of management of acute complications and significantly reduces SCD morbidity and mortality. Red cell exchange (RCE), which is characterized by low iron accumulation and volume overload, has been widely used for transfusion therapy in recent years.
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Anemia de Células Falciformes/terapia , Transfusión de Eritrocitos/métodos , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/genética , HumanosRESUMEN
We developed a microfluidics-based model to quantify cell-level processes modulating the pathophysiology of sickle cell disease (SCD). This in vitro model enabled quantitative investigations of the kinetics of cell sickling, unsickling, and cell rheology. We created short-term and long-term hypoxic conditions to simulate normal and retarded transit scenarios in microvasculature. Using blood samples from 25 SCD patients with sickle hemoglobin (HbS) levels varying from 64 to 90.1%, we investigated how cell biophysical alterations during blood flow correlated with hematological parameters, HbS level, and hydroxyurea (HU) therapy. From these measurements, we identified two severe cases of SCD that were also independently validated as severe from a genotype-based disease severity classification. These results point to the potential of this method as a diagnostic indicator of disease severity. In addition, we investigated the role of cell density in the kinetics of cell sickling. We observed an effect of HU therapy mainly in relatively dense cell populations, and that the sickled fraction increased with cell density. These results lend support to the possibility that the microfluidic platform developed here offers a unique and quantitative approach to assess the kinetic, rheological, and hematological factors involved in vasoocclusive events associated with SCD and to develop alternative diagnostic tools for disease severity to supplement other methods. Such insights may also lead to a better understanding of the pathogenic basis and mechanism of drug response in SCD.
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Anemia de Células Falciformes/fisiopatología , Eritrocitos Anormales/fisiología , Reología , Anemia de Células Falciformes/genética , Genotipo , Humanos , CinéticaRESUMEN
Our goal was to develop a model of the microvasculature that would allow us to quantify changes in the rheology of sickle blood as it traverses the varying vessel sizes and oxygen tensions in the microcirculation. We designed and implemented a microfluidic model of the microcirculation that comprises a branching microvascular network and physiologic oxygen gradients. We used computational modeling to determine the parameters necessary to generate stable, linear gradients in our devices. Sickle blood from six unique patients was perfused through the microvascular network and subjected to varying oxygen gradients while we observed and quantified blood flow. We found that all sickle blood samples fully occluded the microvascular network when deoxygenated, and we observed that sickle blood could cause vaso-occlusions under physiologic oxygen gradients during the microvascular transit time. The number of occlusions observed under five unique oxygen gradients varied among the patient samples, but we generally observed that the number of occlusions decreased with increasing inlet oxygen tension. The model system we have developed is a valuable tool to address fundamental questions about where in the circulation sickle-cell vaso-occlusions are most likely to occur and to test new therapies.