RESUMO
Red blood cells (RBCs) have been hypothesized to support hemostasis by facilitating platelet margination and releasing platelet-activating factors such as adenosine diphosphate (ADP). Significant knowledge gaps remain regarding how RBCs influence platelet function, especially in (patho)physiologically relevant hemodynamic conditions. Here we present results showing how RBCs affect platelet function and hemostasis in conditions of anemia, thrombocytopenia, and pancytopenia, and how the biochemical and biophysical properties of RBCs regulate platelet function at the blood-vessel wall interface and in the fluid phase under flow conditions. We found that RBCs promoted platelet deposition to collagen under flow conditions in moderate (50 ï´ 103/ïL) but not severe (10 ï´ 103/ïL) thrombocytopenia in vitro. Reduction in hematocrit by 45% led to increased bleeding in mice with hemolytic anemia. In contrast, bleeding diathesis was observed in mice with a 90% but not with a 60% reduction in platelet counts. RBC transfusion improved hemostasis by enhancing fibrin clot formation at the site of vascular injury in mice with severe pancytopenia induced by total body irradiation. Altering membrane deformability changed the ability of RBCs to promote platelet aggregation. RBC-derived ADP contributed to platelet activation and aggregation in vitro under pathologically high shear stresses, as observed in patients supported by left ventricular assist devices. These findings demonstrate that RBCs support platelet function and hemostasis through multiple mechanisms, both at the blood-vessel wall interface and in the fluidic phase of circulation.
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Allogeneic haematopoietic stem cell transplantation (allo-HSCT) can potentially cure malignant blood disorders and benign conditions such as haemoglobinopathies and immunologic diseases. However, allo-HSCT is associated with significant complications. The most common and debilitating among them is graft-versus-host disease (GVHD). In GVHD, donor-derived T cells mount an alloimmune response against the recipient. The alloimmune response involves several steps, including recognition of recipient antigens, activation and proliferation of T cells in secondary lymphoid organs, and homing into GVHD-targeted organs. Adhesion molecules on T cells and endothelial cells mediate homing of T cells into lymphoid and non-lymphoid tissues. In this study, we showed that Von Willebrand factor (VWF), an adhesion molecule secreted by activated endothelial cells, plays an important role in mouse models of GVHD. We investigated the effect of the VWF-cleaving protease ADAMTS13 on GVHD. We found that ADAMTS13 reduced the severity of GVHD after bone marrow transplantation from C57BL6 donor to BALB/C recipient mice. A recombinant VWF-A2 domain peptide also reduced GVHD in mice. We showed that ADAMTS13 and recombinant VWF-A2 reduced the binding of T cells to endothelial cells and VWF in vitro, and reduced the number of T cells in lymph nodes, Peyer's patches and GVHD-targeted organs in vivo. We identified LFA-1 (αLß2) as the binding site of VWF on T cells. Our results showed that blocking T-cell homing by ADAMTS13 or VWF-A2 peptide reduced the severity of the GVHD after allo-HSCT, a potentially novel method for treating and preventing GVHD.
Assuntos
Proteína ADAMTS13 , Doença Enxerto-Hospedeiro , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T , Fator de von Willebrand , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Animais , Proteína ADAMTS13/metabolismo , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de von Willebrand/metabolismo , Humanos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Modelos Animais de Doenças , Transplante de Medula Óssea , Células Endoteliais/metabolismoRESUMO
Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI in mouse models combined with in vitro experiments. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V (ANV) with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. The phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared with EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.
Assuntos
Anexina A5/uso terapêutico , Anticoagulantes/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Vesículas Extracelulares/efeitos dos fármacos , Fosfolipídeos/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Trombofilia/tratamento farmacológico , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Masculino , Camundongos Endogâmicos C57BL , Trombofilia/etiologia , Trombofilia/metabolismo , Trombofilia/patologiaRESUMO
Traumatic brain injury-induced coagulopathy (TBI-IC) causes life-threatening secondary intracranial bleeding. Its pathogenesis differs mechanistically from that of coagulopathy arising from extracranial injuries and hemorrhagic shock, but it remains poorly understood. We report results of a study designed to test the hypothesis that von Willebrand factor (VWF) released during acute TBI is intrinsically hyperadhesive because its platelet-binding A1-domain is exposed and contributes to TBI-induced vascular leakage and consumptive coagulopathy. This hyperadhesive VWF can be selectively blocked by a VWF A2-domain protein to prevent TBI-IC and to improve neurological function with a minimal risk of bleeding. We demonstrated that A2 given through intraperitoneal injection or IV infusion reduced TBI-induced death by >50% and significantly improved the neurological function of C57BL/6J male mice subjected to severe lateral fluid percussion injury. A2 protected the endothelium from extracellular vesicle-induced injury, reducing TBI-induced platelet activation and microvesiculation, and preventing a TBI-induced hypercoagulable state. A2 achieved this therapeutic efficacy by specifically blocking the A1 domain exposed on the hyperadhesive VWF released during acute TBI. These results suggest that VWF plays a causal role in the development of TBI-IC and is a therapeutic target for this life-threatening complication of TBI.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Fator de von Willebrand/antagonistas & inibidores , Reação de Fase Aguda , Animais , Plaquetas/metabolismo , Lesões Encefálicas Traumáticas/complicações , Síndrome de Vazamento Capilar/etiologia , Síndrome de Vazamento Capilar/prevenção & controle , Estudos de Casos e Controles , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/prevenção & controle , Circulação Cerebrovascular , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Vesículas Extracelulares , Humanos , Infusões Intravenosas , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos/efeitos dos fármacos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de von Willebrand/química , Fator de von Willebrand/fisiologia , Fator de von Willebrand/uso terapêuticoRESUMO
Traumatic brain injury (TBI) is a leading cause of injury-related disability and death around the world, but the clinical stratification, diagnosis, and treatment of complex TBI are limited. Due to their unique properties, extracellular vesicles (EVs) are emerging candidates for being biomarkers of traumatic brain injury as well as serving as potential therapeutic targets. However, the effects of different extracellular vesicle subtypes on the pathophysiology of traumatic brain injury are very different, or potentially even opposite. Before extracellular vesicles can be used as targets for TBI therapy, it is necessary to classify different extracellular vesicle subtypes according to their functions to clarify different strategies for EV-based TBI therapy. The purpose of this review is to discuss contradictory effects of different EV subtypes on TBI, and to propose treatment ideas based on different EV subtypes to maximize their benefits for the recovery of TBI patients. Video Abstract.
Assuntos
Lesões Encefálicas Traumáticas , Vesículas Extracelulares , Humanos , Lesões Encefálicas Traumáticas/terapiaRESUMO
RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.
Assuntos
AVC Embólico/tratamento farmacológico , Fibrinolíticos/toxicidade , Infarto da Artéria Cerebral Média/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , AVC Isquêmico/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/toxicidade , Animais , Anexina A2/metabolismo , Linhagem Celular , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , AVC Embólico/sangue , AVC Embólico/imunologia , Feminino , Fibrinolíticos/administração & dosagem , Humanos , Infarto da Artéria Cerebral Média/sangue , Infarto da Artéria Cerebral Média/imunologia , Infusões Intravenosas , Hemorragias Intracranianas/sangue , Hemorragias Intracranianas/imunologia , AVC Isquêmico/sangue , AVC Isquêmico/imunologia , Masculino , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ratos Wistar , Receptores de Esfingosina-1-Fosfato/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
Endothelial dysfunction is a key proponent of pathophysiological process of traumatic brain injury (TBI). We previously demonstrated that extracellular vesicles (EVs) released from injured brains led to endothelial barrier disruption and vascular leakage. However, the molecular mechanisms of this EV-induced endothelial dysfunction (endotheliopathy) remain unclear. Here, we enriched plasma EVs from TBI patients (TEVs), and detected high mobility group box 1 (HMGB1) exposure to 50.33 ± 10.17% of TEVs and the number of HMGB1+TEVs correlated with injury severity. We then investigated for the first time the impact of TEVs on endothelial function using adoptive transfer models. We found that TEVs induced dysfunction of cultured human umbilical vein endothelial cells and mediated endothelial dysfunction in both normal and TBI mice, which were propagated through the HMGB1-activated receptor for advanced glycation end products (RAGE)/Cathepsin B signaling, and the resultant NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and canonical caspase-1/gasdermin D (GSDMD)-dependent pyroptosis. Finally, von Willebrand factor (VWF) was detected on the surface of 77.01 ± 7.51% of HMGB1+TEVs. The TEV-mediated endotheliopathy was reversed by a polyclonal VWF antibody, indicating that VWF might serve a coupling factor that tethered TEVs to ECs, thus facilitating HMGB1-induced endotheliopathy. These results suggest that circulating EVs isolated from patients with TBI alone are sufficient to induce endothelial dysfunction and contribute to secondary brain injury that are dependent on immunologically active HMGB1 exposed on their surface. This finding provided new insight for the development of potential therapeutic targets and diagnostic biomarkers for TBI.
Assuntos
Lesões Encefálicas Traumáticas , Vesículas Extracelulares , Proteína HMGB1 , Doenças Vasculares , Humanos , Camundongos , Animais , Fator de von Willebrand , Lesões Encefálicas Traumáticas/complicações , Células Endoteliais da Veia Umbilical HumanaRESUMO
When stimulated by proinflammatory mediators, endothelial cells release ultra-large von Willebrand factor (ULVWF) multimers that are hyperactive in activating and aggregating platelets. These ULVWF multimers can accumulate in the circulation and on the inflamed endothelium because they are insufficiently cleaved by the metalloprotease ADAMTS-13, which becomes moderately deficient under conditions of systemic inflammation. This moderate ADAMTS-13 deficiency may lead to thrombotic complications that contribute to ischemic tissue injury and organ failure that are associated with severe infections. To test this hypothesis, we investigated whether recombinant ADAMTS-13 improves the pathological course of endotoxemia in lipopolysaccharide (LPS)-treated mice. C57BL/J6 mice received a bolus infusion of either 5 µg/mouse of ADAMTS-13 or vehicle control 30 min after LPS challenge and were monitored for seven-day survival. During the monitoring period, platelet counts, VWF antigen, and ADAMTS-13 activity were measured. Thrombosis was also examined by the immunohistochemistry in the liver. We found that ADAMTS-13 reduced mortality from 66% to 34.9%. The improved survival was associated with a greater recovery from thrombocytopenia, higher plasma ADAMTS-13 activity, and less thrombotic vascular occlusion. These results suggest that systemic inflammation could result in deficient ULVWF proteolysis by ADAMTS-13 and that ADAMTS-13 improves the outcomes of endotoxemia-induced inflammation.
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Proteínas ADAM , Endotoxemia , Animais , Camundongos , Células Endoteliais , Proteína ADAMTS13 , Endotoxemia/tratamento farmacológico , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Fator de von WillebrandRESUMO
PURPOSE OF REVIEW: Preeclampsia is a common complication of pregnancy and contributes significantly to maternal and fetal morbidity and mortality. A protective hypercoagulable state is often developed during late pregnancy and can evolve into a prothrombotic state in patients with preeclampsia. The underlying mechanism of this prothrombotic transition remains poorly understood. We discuss recent progress in understanding the pathophysiology of preeclampsia and associated prothrombotic state. RECENT FINDINGS: The hypercoagulable state developed during pregnancy is initiated by placental factors and progresses into the prothrombotic state in preeclampsia when the placenta is subjected ischemic and oxidative injuries. The cause of the preeclampsia-induced prothrombotic state is multifactorial, involving not only placental factors but also maternal conditions, which include genetic predisposition, preexisting medical conditions, and conditions acquired during pregnancy. Endotheliopathy is the primary pathology of preeclampsia and contributes to the prothrombotic state by inducing the dysregulation of coagulation, platelets, and adhesive ligands. SUMMARY: Patients with preeclampsia often develop a severe prothrombotic state that predisposes them to life-threatening thrombosis and thromboembolism during and after pregnancy. Early recognition and treatment of this prothrombotic state can improve maternal and infant outcomes of preeclampsia patients.
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Predisposição Genética para Doença , Pré-Eclâmpsia , Trombose , Plaquetas/metabolismo , Feminino , Humanos , Placenta/metabolismo , Adesividade Plaquetária , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/genética , Gravidez , Proteínas da Gravidez/sangue , Proteínas da Gravidez/genética , Trombose/sangue , Trombose/genéticaRESUMO
Traumatic brain injury (TBI) induced coagulopathy remains a significant clinical challenge, with unmet needs for standardizing diagnosis and optimizing treatments. TBI-induced coagulopathy is closely associated with poor outcomes in affected patients. Recent studies have demonstrated that TBI induces coagulopathy, which is mechanistically distinct from the deficient and dilutional coagulopathy found in patients with injuries to the body/limbs and hemorrhagic shock. Multiple causal and disseminating factors have been identified to cause TBI-induced coagulopathy. Among these are extracellular mitochondria (exMTs) released from injured cerebral cells, endothelial cells, and platelets. These circulating exMTs not only express potent procoagulant activity but also promote inflammation, and could remain metabolically active to become a major source of oxidative stress. They activate platelets and endothelial cells to propagate TBI-induced coagulopathy and secondary tissue injury after primary traumatic impact. In this review, we discuss recent advances in our understanding of the role of exMTs in the development of TBI-induced coagulopathy.
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Transtornos da Coagulação Sanguínea/fisiopatologia , Lesões Encefálicas Traumáticas/fisiopatologia , Mitocôndrias/metabolismo , HumanosRESUMO
Traumatic brain injury (TBI)-induced coagulopathy is a common and well-recognized risk for poor clinical outcomes, but its pathogenesis remains poorly understood, and treatment options are limited and ineffective. We discuss the recent progress and knowledge gaps in understanding this lethal complication of TBI. We focus on (1) the disruption of the brain-blood barrier to disseminate brain injury systemically by releasing brain-derived molecules into the circulation and (2) TBI-induced hypercoagulable and hyperfibrinolytic states that result in persistent and delayed intracranial hemorrhage and systemic bleeding.
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Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Lesões Encefálicas Traumáticas/complicações , Coagulação Sanguínea , Transtornos da Coagulação Sanguínea/mortalidade , Testes de Coagulação Sanguínea , Plaquetas/metabolismo , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/metabolismo , Endotélio/metabolismo , Fibrinólise , Humanos , Fenótipo , Avaliação de SintomasRESUMO
Coagulopathy is common in patients with traumatic brain injury (TBI) and predicts poor clinical outcomes. We have shown that brain-derived extracellular microvesicles, including extracellular mitochondria, play a key role in the development of TBI-induced coagulopathy. Here, we further show in mouse models that the apoptotic cell-scavenging factor lactadherin, given at a single dose of 400 µg/kg 30 minutes before (preconditioning) or 30 minutes after cerebral fluid percussion injury, prevented coagulopathy as defined by clotting time, fibrinolysis, intravascular fibrin deposition, and microvascular bleeding of the lungs. Lactadherin also reduced cerebral edema, improved neurological function, and increased survival. It achieved these protective effects by enhancing the clearance of circulating microvesicles through phosphatidylserine-mediated phagocytosis. Together, these results identify the scavenging system for apoptotic cells as a potential therapeutic target to prevent TBI-induced coagulopathy and improve the outcome of TBI.
Assuntos
Antígenos de Superfície/uso terapêutico , Transtornos da Coagulação Sanguínea/prevenção & controle , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/genética , Micropartículas Derivadas de Células/efeitos dos fármacos , Proteínas do Leite/uso terapêutico , Fagocitose/efeitos dos fármacos , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/farmacologia , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/mortalidade , Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/patologia , Micropartículas Derivadas de Células/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Leite/genética , Proteínas do Leite/farmacologia , Fagocitose/genética , Sobrevida , Índices de Gravidade do TraumaRESUMO
von Willebrand factor (VWF) is an adhesive ligand, and its activity is proteolytically regulated by the metalloprotease ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat 13). An elevated level of plasma VWF has been widely considered a marker for endothelial cell activation in trauma and inflammation, but its causal role in these pathological conditions remains poorly defined. Using a fluid percussion injury mouse model, we demonstrated that VWF released during acute traumatic brain injury (TBI) was activated and became microvesicle-bound. The VWF-bound microvesicles promoted vascular leakage and systemic coagulation. Recombinant ADAMTS-13 given either before or after TBI reduced the VWF reactivity with minimal influence on VWF secretion. rADAMTS-13 protected the integrity of endothelial cell barriers and prevented TBI-induced coagulopathy by enhancing VWF cleavage without impairing basal hemostasis. Promoting microvesicle clearance by lactadherin had efficacy similar to that of rADAMTS-13. This study uncovers a novel synergistic action between VWF and cellular microvesicles in TBI-induced vascular leakage and coagulopathy and demonstrates protective effects of rADAMTS-13.
Assuntos
Transtornos da Coagulação Sanguínea/metabolismo , Lesões Encefálicas/metabolismo , Células Endoteliais/metabolismo , Microvasos/metabolismo , Fator de von Willebrand/metabolismo , Animais , Transtornos da Coagulação Sanguínea/genética , Transtornos da Coagulação Sanguínea/patologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Modelos Animais de Doenças , Células Endoteliais/patologia , Masculino , Camundongos , Camundongos Knockout , Microvasos/patologia , Fator de von Willebrand/genéticaRESUMO
Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.2% of these microvesicles, leading to the hypothesis that these extracellular mitochondria are metabolically active and serve as a source of oxidative stress that activates platelets and renders them procoagulant. In testing this hypothesis experimentally, we found that the extracellular mitochondria purified from brain trauma mice and those released from brains subjected to freeze-thaw injury remained metabolically active and produced reactive oxygen species. These extracellular mitochondria bound platelets through the phospholipid-CD36 interaction and induced α-granule secretion, microvesiculation, and procoagulant activity in an oxidant-dependent manner, but failed to induce aggregation. These results define an extracellular mitochondria-induced and redox-dependent intermediate phenotype of platelets that contribute to the pathogenesis of traumatic brain injury-induced coagulopathy and inflammation.
Assuntos
Transtornos da Coagulação Sanguínea , Micropartículas Derivadas de Células , Animais , Plaquetas , Camundongos , Mitocôndrias , Agregação Plaquetária , Espécies Reativas de OxigênioRESUMO
Preeclampsia is a pregnancy-induced condition that impairs the mother's health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesicles (pcEV) in the circulation have been consistently associated with preeclampsia, but whether these vesicles induce preeclampsia or are the product of preeclampsia is not known. Guided by a small cohort study of preeclamptic patients, we examined the impact of pcEV on the pathogenesis of preeclampsia in mouse models. We detected pcEV in pregnant C56BL/6J mice with a peak level of 3.8±0.9×107/mL at 17-18 days post-coitum. However, these pregnant mice developed hypertension and proteinuria only after being infused with vesicles purified from injured placenta. These extracellular vesicles released from injured placenta disrupted endothelial integrity and induced vasoconstriction. Enhancing the clearance of extracellular vesicles prevented the development of the extracellular vesicle-induced preeclampsia in mice. Our results demonstrate a causal role of pcEV in preeclampsia and identify microvesicle clearance as a new therapeutic strategy for the treatment of this pregnancy-associated complication.
Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , Animais , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Placenta , GravidezRESUMO
A novel seven-core fiber (SCF)-based sensor capable of simultaneous measurement of temperature and strain was proposed and experimentally demonstrated. The sensor consists of a fiber Bragg grating (FBG) and a SCF-based Mach-Zehnder interferometer (MZI). The MZI is formed by splicing a short section of SCF between two single-mode fibers (SMFs), and in the meantime, two fiber tapers that act as light splitter and coupler are formed at both ends of the SCF by the fusion splicing method. In addition, the FBG with a central wavelength of 1547.98 nm is cascaded at the end of one fiber taper, and thus simultaneous measurement of temperature and strain can be realized. The experiment result shows that the SCF-based MZI is only sensitive to temperature and has the higher temperature sensitivity of 93.11 pm/°C, while the FBG is sensitive to temperature and strain with sensitivities of 11.46 pm/°C and 0.627pm/µÎµ, respectively. The corresponding temperature and strain resolutions of the sensor are 0.21°C and 27.95µÎµ, respectively. The proposed sensor has the advantages of simple fabrication and high repeatability and has potential applications in many fields such as engineering machinery and building structure health monitoring.
RESUMO
Transplant-associated thrombotic microangiopathy (TA-TMA) after allogeneic hematopoietic cell transplantation (HCT) has not been well characterized in large population studies with clinically adjudicated cases. We performed a retrospective cohort study of adults who underwent allogeneic HCT between 2006 and 2015 to determine the incidence of and risk factors for TA-TMA and to describe its natural history and response to immunosuppressant withdrawal management. Among 2145 patients in this study, 192 developed TA-TMA with a cumulative incidence of 7.6% by 100days post-transplant. Independent pretransplant risk factors included the receipt of a second (or third) allogeneic HCT, HLA-mismatched donor, and myeloablative conditioning with or without total body irradiation; post-transplant risk factors included the antecedent development of acute graft-versus-host disease, diffuse alveolar hemorrhage, bacteremia, invasive aspergillosis, BK viremia, and higher sirolimus trough level. Among TA-TMA patients 27% achieved hematologic resolution and 57% remained alive as of 90days after diagnosis. Antecedent risk factors stratified patients into different survival groups, and immunosuppressant withdrawal alone did not improve patient outcomes. In conclusion, TA-TMA is a heterogenous disease that occurs after allogeneic transplantation. Management with immunosuppressant withdrawal does not impact patient outcomes. Until further evidence becomes available, the management of TA-TMA should focus on the treatment of underlying diseases.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Microangiopatias Trombóticas/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Imunossupressores , Masculino , Estudos Retrospectivos , Fatores de Risco , Microangiopatias Trombóticas/terapia , Transplante Homólogo/efeitos adversosRESUMO
Severe brain injury significantly influences immune responses; however, the levels at which this influence occurs and which neurogenic pathways are involved are not well defined. Here, we used MRI to measure spleen volume and tissue diffusion changes in patients with intracerebral hemorrhage (ICH). We observed increased capillary exchange and spleen shrinkage by d 3 post-ICH, with recovery by d 14. The extent of spleen shrinkage was associated with brain hematoma size, and a reduced progression of perihematomal edema was observed in the presence of severe spleen shrinkage. At the cellular level, lymphopenia was present in patients with ICH at admission and persisted up to 14 d. Lymphopenia did not parallel the observed spleen alteration. In addition, patients with ICH with infection had significant deficiencies of T and NK cells and poor functional outcomes. Finally, in mouse models of ICH, spleen shrinkage could be related to innervations from adrenergic input and the hypothalamus-pituitary-adrenal (HPA) axis. In sum, the profound impact of ICH on the immune system involves the coordinated actions of sympathetic innervation and the HPA axis, which modulate spleen shrinkage and cellular immunity.-Zhang, J., Shi, K., Li, Z., Li, M., Han, Y., Wang, L., Zhang, Z., Yu, C., Zhang, F., Song, L., Dong, J.-F., La Cava, A., Sheth, K. N., Shi, F.-D. Organ- and cell-specific immune responses are associated with the outcomes of intracerebral hemorrhage.
Assuntos
Hemorragia Cerebral/imunologia , Idoso , Animais , Edema Encefálico/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Modelos Animais de Doenças , Progressão da Doença , Feminino , Hematoma/diagnóstico por imagem , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Imunidade Celular , Células Matadoras Naturais/imunologia , Linfopenia/imunologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neuroimunomodulação , Sistema Hipófise-Suprarrenal/imunologia , Baço/diagnóstico por imagem , Baço/imunologia , Linfócitos T/imunologiaRESUMO
Traumatic brain injury (TBI)-induced coagulopathy has long been recognized as a significant risk for poor outcomes in patients with TBI, but its pathogenesis remains poorly understood. As a result, current treatment options for the condition are limited and ineffective. The lack of information is most significant for the impact of blood transfusions on patients with isolated TBI and in the absence of confounding influences from trauma to the body and limbs and the resultant hemorrhagic shock. Here we discuss recent progress in understanding the pathogenesis of TBI-induced coagulopathy and the current state of blood transfusions for patients with TBI and associated coagulopathy.
Assuntos
Transtornos da Coagulação Sanguínea , Transfusão de Sangue , Lesões Encefálicas Traumáticas , Choque Hemorrágico , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/terapia , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/terapia , Humanos , Choque Hemorrágico/sangue , Choque Hemorrágico/complicações , Choque Hemorrágico/terapiaRESUMO
BACKGROUND AND PURPOSE: Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. METHODS: Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. RESULTS: By coupling transfer of labeled MOG35-55-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG91-108 and MOG103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. CONCLUSIONS: Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.