RESUMO
Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1-/- mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.
Assuntos
Coagulação Intravascular Disseminada , Inflamassomos , Staphylococcus aureus Resistente à Meticilina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sepse , Ubiquitinação , Animais , Humanos , Masculino , Camundongos , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/patologia , Coagulação Intravascular Disseminada/microbiologia , Células HEK293 , Inflamassomos/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sepse/microbiologia , Sepse/complicações , Sepse/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/metabolismoRESUMO
Septic shock is the archetypal clinical setting in which extensive crosstalk between inflammation and coagulation dysregulates the latter. The main anticoagulant systems are systematically impaired, depleted, and/or downregulated. Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that not only targets coagulation factors Xa and XIa but also acts as an acute phase reactant whose plasma concentration rises in inflammatory settings. The objective of the present study was to assess the plasma ZPI antigen level in a cohort of patients suffering from septic shock with or without overt-disseminated intravascular coagulation (DIC). The plasma ZPI antigen level was approximately 2.5-fold higher in the patient group (n = 100; 38 with DIC and 62 without) than in healthy controls (n = 31). The elevation's magnitude did not appear to depend on the presence/absence of DIC. Furthermore, Western blots revealed the presence of cleaved ZPI in plasma from patients with severe sepsis, independently of the DIC status. In vitro, ZPI was proteolytically inactivated by purified neutrophil elastase (NE) and by NE on the surface of neutrophil extracellular traps (NETs). The electrophoretic pattern of ZPI after NE-catalyzed proteolysis was very similar to that resulting from the clotting process-suggesting that the cleaved ZPI observed in severe sepsis plasma is devoid of anticoagulant activity. Taken as a whole, our results (1) suggest that NE is involved in ZPI inactivation during sepsis, and (2) reveal a novel putative mechanism for the procoagulant activity of NETs in immunothrombosis.
Assuntos
Coagulação Intravascular Disseminada , Armadilhas Extracelulares , Sepse , Serpinas , Choque Séptico , Anticoagulantes/farmacologia , Proteínas Sanguíneas , Coagulação Intravascular Disseminada/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Elastase de Leucócito/metabolismo , Inibidores de Proteases/metabolismo , Proteólise , Sepse/metabolismo , Serpinas/metabolismo , Choque Séptico/metabolismoRESUMO
BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17⯱â¯2 and 23⯱â¯2â¯days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer levelâ¯>â¯500⯵g/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.
Assuntos
Coagulação Sanguínea/fisiologia , COVID-19/complicações , Fibrinólise/fisiologia , Inflamação/etiologia , Inflamação/virologia , Adulto , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/metabolismo , Transtornos da Coagulação Sanguínea/patologia , Transtornos da Coagulação Sanguínea/virologia , COVID-19/metabolismo , COVID-19/patologia , China , Progressão da Doença , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/patologia , Coagulação Intravascular Disseminada/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Hemorragia/etiologia , Hemorragia/patologia , Hemorragia/virologia , Humanos , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , SARS-CoV-2/patogenicidadeRESUMO
Sepsis-induced disseminated intravascular coagulation (DIC) is a common life-threatening terminal-stage disease with high mortality. This study aimed to identify effective miRNAs as therapeutic targets for DIC. Bioinformatics and luciferase reporter gene analyses were performed to predict miR-19a-3p and validate that it targets tissue factor (TF). Quantitative real-time PCR was used to detect the expression of miR-19a-3p and TF, and TF procoagulant activity was determined using the chromogenic substrate method. Western blotting was used to detect the protein levels of TF, AKT serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK), nuclear factor kappa B (NF-κB) P65, NFKB inhibitor alpha (IκB-a) and their phosphorylated counterparts in cell experiments. Furthermore, a rat model was established to explore the potential of miR-19a-3p in DIC treatment. As a result, a human clinical study revealed that miR-19a-3p was downregulated and that TF was upregulated in neonates with sepsis-induced DIC compared with those in the control group. The luciferase reporter assay showed that TF was a direct target of miR-19a-3p. Cell experiments verified that the mRNA and protein levels of TF, and the p-AKT/AKT, p-Erk/Erk, p-P65/P65, p-IκB-a/IκB-a ratios, and TF procoagulant activity were significantly decreased in lipopolysaccharide (LPS) -induced human peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) inhibited by overexpression of miR-19a-3p, and that miR-19a-3p regulating TF was dependent on the NF-kB and AKT pathways. In vivo, miR-19a-3p injection into DIC rats suppressed the mRNA expression of TF; more importantly, significant improvements in coagulation function indicators and in histopathologies of lung and kidney were observed. In conclusion, miR-19a-3p may suppress DIC by targeting TF and might be a potential therapeutic target in treating sepsis-induced DIC.
Assuntos
Coagulação Intravascular Disseminada/metabolismo , Regulação para Baixo/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/biossíntese , Sepse/metabolismo , Tromboplastina/metabolismo , Animais , Células Cultivadas , Coagulação Intravascular Disseminada/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Recém-Nascido , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/induzido quimicamente , Tromboplastina/antagonistas & inibidoresRESUMO
During the current formidable COVID-19 pandemic, it is appealing to address ideas that may invoke therapeutic interventions. Clotting disorders are well recognized in patients infected with severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-CoV-2), which lead to severe complications that worsen the prognosis in these subjects. Increasing evidence implicate Heparan sulfate proteoglycans (HSPGs) and Heparanase in various diseases and pathologies, including hypercoagulability states. Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.
Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Coagulação Sanguínea , COVID-19/complicações , Glucuronidase/metabolismo , SARS-CoV-2/fisiologia , Animais , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/metabolismo , COVID-19/sangue , COVID-19/metabolismo , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/metabolismo , Proteoglicanas de Heparan Sulfato/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Internalização do VírusRESUMO
Septic shock and disseminated intravascular coagulation (DIC) are known to be characterized by an endothelial cell dysfunction. The molecular mechanisms underlying this relationship are, however, poorly understood. In this work, we aimed to investigate human circulating IFN-α in patients with septic shock-induced DIC and tested the potential role of endothelial Stat1 (signal transducer and activator of transcription 1) as a therapeutic target in a mouse model of sepsis. For this, circulating type I, type II, and type III IFNs and procoagulant microvesicles were quantified in a prospective cohort of patients with septic shock. Next, we used a septic shock model induced by cecal ligation and puncture in wild-type mice, in Ifnar1 (type I IFN receptor subunit 1)-knockout mice, and in Stat1 conditional knockout mice. In human samples, we observed higher concentrations of circulating IFN-α and IFN-α1 in patients with DIC compared with patients without DIC, whereas concentrations of IFN-ß, IFN-γ, IFN-λ1, IFN-λ2, and IFN-λ3 were not different. IFN-α concentration was positively correlated with CD105 microvesicle concentrations, reflecting endothelial injury. In Ifnar1-/- mice, cecal ligation and puncture did not induce septic shock and was characterized by lesser endothelial cell injury, with lower aortic inflammatory cytokine expression, endothelial inflammatory-related gene expression, and fibrinolysis. In mice in which Stat1 was specifically ablated in endothelial cells, a marked protection against sepsis was also observed, suggesting the relevance of an endothelium-targeted strategy. Our work highlights the key roles of type I IFNs as pathogenic players in septic shock-induced DIC and the potential pertinence of endothelial STAT1 as a therapeutic target.
Assuntos
Coagulação Intravascular Disseminada/metabolismo , Interferon-alfa/metabolismo , Fator de Transcrição STAT1/metabolismo , Choque Séptico/metabolismo , Transdução de Sinais , Idoso , Animais , Coagulação Intravascular Disseminada/genética , Feminino , Humanos , Interferon-alfa/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fator de Transcrição STAT1/genética , Choque Séptico/genética , Choque Séptico/terapiaRESUMO
Thrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated cofactor V (FVa), and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragment 1 (F1) and fragment 2 (F2) specifically to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa, which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin F1 + F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit patients with sepsis (n = 144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in factor VIII (FVIII)- and FIX-deficient plasma, as well as in FVIII-deficient mice. In summary, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation and correcting coagulation factor deficiency.
Assuntos
Coagulação Intravascular Disseminada/metabolismo , Fator V/metabolismo , Fator X/metabolismo , Fator Xa/metabolismo , Histonas/metabolismo , Animais , Coagulação Sanguínea , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Tromboplastina/metabolismoRESUMO
The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]), also known as COVID-19, is a single-stranded enveloped RNA virus that created a Public Health Emergency of International Concern in January 2020, with a global case burden of over 15 million in just 7 months. Infected patients develop a wide range of clinical manifestations-typically presenting with fever, cough, myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory distress syndrome, acute heart injuries, neurological manifestations, or complications due to secondary infections. These critically ill patients are also found to have disrupted coagulation function, predisposing them to consumptive coagulopathies, and both venous and thromboembolic complications. Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin degradation products, and fibrinogen, all of which have been associated with greater disease severity. Many cases of pulmonary embolism have been noted, along with deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism. The pathogenesis of coronavirus has not been completely elucidated, but the virus is known to cause excessive inflammation, endothelial injury, hypoxia, and disseminated intravascular coagulation, all of which contribute to thrombosis formation. These patients are also faced with prolonged immobilization while staying in the hospital or intensive care unit. It is important to have a high degree of suspicion for thrombotic complications as patients may rapidly deteriorate in severe cases. Evidence suggests that prophylaxis with anticoagulation may lead to a lower risk of mortality, although it does not eliminate the possibility. The risks and benefits of anticoagulation treatment should be considered in each case. Patients should be regularly evaluated for bleeding risks and thrombotic complications.
Assuntos
Transtornos da Coagulação Sanguínea/sangue , COVID-19/sangue , Embolia/sangue , Trombose/sangue , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/metabolismo , COVID-19/complicações , COVID-19/metabolismo , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/metabolismo , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/prevenção & controle , Embolia/etiologia , Embolia/metabolismo , Embolia/prevenção & controle , Endotélio Vascular/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Humanos , Hipóxia/sangue , Hipóxia/etiologia , Hipóxia/metabolismo , Imobilização , Inflamação/sangue , Inflamação/etiologia , Inflamação/metabolismo , AVC Isquêmico/sangue , AVC Isquêmico/etiologia , AVC Isquêmico/metabolismo , AVC Isquêmico/prevenção & controle , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Guias de Prática Clínica como Assunto , Embolia Pulmonar/sangue , Embolia Pulmonar/etiologia , Embolia Pulmonar/metabolismo , Embolia Pulmonar/prevenção & controle , Índice de Gravidade de Doença , Trombocitopenia/sangue , Trombocitopenia/etiologia , Trombose/etiologia , Trombose/metabolismo , Trombose/prevenção & controle , Trombose Venosa/sangue , Trombose Venosa/etiologia , Trombose Venosa/metabolismo , Trombose Venosa/prevenção & controleRESUMO
Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelial- and blood cell-derived damage-associated molecular patterns (DAMPs), and DAMP-mediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.
Assuntos
Coagulação Sanguínea , Coagulação Intravascular Disseminada/metabolismo , Endotélio Vascular/metabolismo , Inflamação/metabolismo , Trombomodulina/metabolismo , Trombose/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Plaquetas/metabolismo , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/imunologia , Endotélio Vascular/imunologia , Armadilhas Extracelulares/metabolismo , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Transdução de Sinais , Trombomodulina/uso terapêutico , Trombose/sangue , Trombose/imunologia , Lesões do Sistema Vascular/sangue , Lesões do Sistema Vascular/imunologiaRESUMO
Studies have shown that infection, excessive coagulation, cytokine storm, leukopenia, lymphopenia, hypoxemia and oxidative stress have also been observed in critically ill Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) patients in addition to the onset symptoms. There are still no approved drugs or vaccines. Dietary supplements could possibly improve the patient's recovery. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present an anti-inflammatory effect that could ameliorate some patients need for intensive care unit (ICU) admission. EPA and DHA replace arachidonic acid (ARA) in the phospholipid membranes. When oxidized by enzymes, EPA and DHA contribute to the synthesis of less inflammatory eicosanoids and specialized pro-resolving lipid mediators (SPMs), such as resolvins, maresins and protectins. This reduces inflammation. In contrast, some studies have reported that EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress. Although the inflammatory resolution improved by EPA and DHA could contribute to the recovery of patients infected with SARS-CoV-2, Omega-3 fatty acids supplementation cannot be recommended before randomized and controlled trials are carried out.
Assuntos
Infecções por Coronavirus/dietoterapia , Síndrome da Liberação de Citocina/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Leucopenia/dietoterapia , Pandemias , Pneumonia Viral/dietoterapia , Anti-Inflamatórios não Esteroides/administração & dosagem , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/dietoterapia , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/virologia , Humanos , Hipóxia/dietoterapia , Hipóxia/epidemiologia , Hipóxia/metabolismo , Hipóxia/virologia , Leucopenia/epidemiologia , Leucopenia/metabolismo , Leucopenia/virologia , Estresse Oxidativo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , SARS-CoV-2Assuntos
Transtornos da Coagulação Sanguínea/sangue , Infecções por Coronavirus/sangue , Pneumonia Viral/sangue , Microangiopatias Trombóticas/sangue , Tromboembolia Venosa/sangue , Anticoagulantes/uso terapêutico , Betacoronavirus , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/metabolismo , COVID-19 , Infecções por Coronavirus/metabolismo , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/metabolismo , Endotélio Vascular/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Metabolismo dos Lipídeos , Pandemias , Pneumonia Viral/metabolismo , Tempo de Protrombina , Embolia Pulmonar/sangue , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/metabolismo , SARS-CoV-2 , Trombocitopenia/sangue , Trombocitopenia/metabolismo , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/metabolismo , Triglicerídeos/metabolismo , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/metabolismoRESUMO
Sepsis is a heterogeneous clinical syndrome that is complicated commonly by acute kidney injury (sepsis-AKI). Currently, no approved pharmacologic therapies exist to either prevent sepsis-AKI or to treat sepsis-AKI once it occurs. A growing body of evidence supports a connection between red blood cell biology and sepsis-AKI. Increased levels of circulating cell-free hemoglobin (CFH) released from red blood cells during hemolysis are common during sepsis and can contribute to sepsis-AKI through several mechanisms including tubular obstruction, nitric oxide depletion, oxidative injury, and proinflammatory signaling. A number of potential pharmacologic therapies targeting CFH in sepsis have been identified including haptoglobin, hemopexin, and acetaminophen, and early phase clinical trials have suggested that acetaminophen may have beneficial effects on lipid peroxidation and kidney function in patients with sepsis. Bedside measurement of CFH levels may facilitate predictive enrichment for future clinical trials of CFH-targeted therapeutics. However, rapid and reliable bedside tests for plasma CFH will be required for such trials to move forward.
Assuntos
Injúria Renal Aguda/metabolismo , Hemoglobinas/metabolismo , Sepse/metabolismo , Acetaminofen/uso terapêutico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/prevenção & controle , Anemia Falciforme/metabolismo , Animais , Ponte de Artéria Coronária , Coagulação Intravascular Disseminada/metabolismo , Eriptose , Deformação Eritrocítica , Haptoglobinas/metabolismo , Haptoglobinas/uso terapêutico , Heme/metabolismo , Hemoglobinas/imunologia , Hemólise , Hemopexina/metabolismo , Hemopexina/uso terapêutico , Humanos , Túbulos Renais , Malária/metabolismo , Óxido Nítrico/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Sepse/imunologia , Reação Transfusional/metabolismoRESUMO
Lethal features of sepsis and acute respiratory distress syndrome (ARDS) relate to the health of small blood vessels. For example, alveolar infiltration with proteinaceous fluid is often driven by breach of the microvascular barrier. Spontaneous thrombus formation within inflamed microvessels exacerbates organ ischemia, and in its final stages, erupts into overt disseminated intravascular coagulation. Disruption of an endothelial signaling axis, the Angiopoietin-Tie2 pathway, may mediate the abrupt transition from microvascular integrity to pathologic disruption. This review summarizes preclinical and clinical results that implicate the Tie2 pathway as a promising target to restore microvascular health in sepsis and ARDS.
Assuntos
Injúria Renal Aguda/metabolismo , Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Estado Terminal , Coagulação Intravascular Disseminada/metabolismo , Receptor TIE-2/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Sepse/metabolismo , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/fisiopatologia , Animais , Coagulação Intravascular Disseminada/enzimologia , Coagulação Intravascular Disseminada/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Homeostase/fisiologia , Humanos , Síndrome do Desconforto Respiratório/enzimologia , Síndrome do Desconforto Respiratório/fisiopatologia , Sepse/enzimologia , Sepse/fisiopatologia , Transdução de SinaisAssuntos
Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/metabolismo , Mediadores da Inflamação/metabolismo , Sepse/metabolismo , Animais , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/metabolismo , Coagulação Intravascular Disseminada/diagnóstico , Humanos , Sepse/complicações , Sepse/diagnósticoRESUMO
Microparticle (MP)-associated tissue factor (TF) activity in plasma might play a role in human disseminated intravascular coagulation (DIC). The aim of this study was to compare MP-TF activity between non-DIC and DIC groups. Ten clinically healthy beagles and 26 diseased dogs were enrolled. The proportion of dogs with increased MP-TF activity was significantly higher in the DIC group than the non-DIC group (P=0.014). MP-TF activity in the DIC group was significantly higher than the non-DIC group (P=0.021). MP-TF activity positively correlated with plasma D-dimer concentration (r=0.42, P=0.034). Moreover, MP-TF activity was decreased by the time of recovery in some dogs with DIC. Larger prospective studies are warranted to assess its value as a diagnostic and prognostic biomarker in DIC.
Assuntos
Micropartículas Derivadas de Células/metabolismo , Coagulação Intravascular Disseminada/veterinária , Doenças do Cão/sangue , Tromboplastina/metabolismo , Animais , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/metabolismo , Doenças do Cão/metabolismo , Cães , Feminino , Masculino , Estudos RetrospectivosRESUMO
The phosphatidylserine (PS) molecule is present in cell membranes where it is actively kept on their inner leaflets but when cells are damaged it moves to the surface and become a signal for their removal, the platform upon which the coagulation cascade takes place and a ligand that activates a feedback cycle of inflammatory cytokine secretion and initiates the wakeup call for the innate immune response. These are physiologic responses to PS but the Ebola virus displays PS molecules on its membrane's surface and the huge numbers of viruses cause a pathologic inflammatory cytokine storm and a hemorrhagic consumptive coagulopathy. Annexin V is an innate molecule that can cloak membrane displayed PS and prevents its Th1 cell's inflammatory cytokine generation and cascade thrombin generation. The hypothesis presented is that its administration will cloak PS and prevent Ebola's consumptive coagulopathy and its cytokine storm.
Assuntos
Anexina A5/uso terapêutico , Citocinas/metabolismo , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/metabolismo , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/metabolismo , Fosfatidilserinas/metabolismo , Anexina A5/metabolismo , Coagulação Sanguínea , Membrana Celular/metabolismo , Síndrome da Liberação de Citocina/virologia , Humanos , Imunidade Inata , Inflamação , Células Th1/metabolismo , Trombina/metabolismoAssuntos
Alarminas/metabolismo , Proteína HMGB1/metabolismo , Estresse Psicológico/metabolismo , Adulto , Alarminas/imunologia , Animais , Isquemia Encefálica/metabolismo , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/metabolismo , Proteína HMGB1/antagonistas & inibidores , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Moléculas com Motivos Associados a Patógenos/metabolismo , Polineuropatias/tratamento farmacológico , Polineuropatias/metabolismo , Acidente Vascular Cerebral/metabolismo , Trombomodulina/uso terapêuticoRESUMO
This study aimed to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on disseminated intravascular coagulation (DIC) model rats and to further explore the underlying mechanism. A rat model of lipopolysaccharide (LPS)-induced DIC was successfully established, as indicated by impaired plasma hemostatic parameters and damaged organ functions in rats. Importantly, pre-treatment with rat allogeneic BMSCs before LPS injection significantly alleviated systemic intravascular coagulation, reduced plasma levels of organ dysfunction indicators and pro-inflammatory cytokines, suppressed fibrin microthrombi formation, ameliorated liver, heart, and renal injuries, and increased 24-hour survival rates in LPS-induced DIC rats. The protection of BMSCs against DIC was in a moderately dose-dependent manner. Further investigation revealed that BMSCs co-cultured with peripheral blood mononuclear cells (PBMCs) significantly inhibited the LPS-stimulated PBMCs proliferation and the release of pro-inflammatory cytokines from PBMCs. Of note, upregulation of immunosuppressive factors including indoleamine 2,3-dioxygenase and interleukin-10, which was induced by interferon-γ, contributed to BMSCs-mediated inhibition of LPS-stimulated PBMCs proliferation. These effects do not depend on the direct cell-cell contact. In conclusion, BMSCs pre-treatment ameliorates inflammation-related tissue destruction in LPS-induced DIC model rats. The protection of BMSCs may be attributed to their anti-inflammatory and immunomodulatory properties, which render BMSCs a promising source for stem cell-based therapeutic approaches in inflammation-related DIC.
Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura/métodos , Citocinas/metabolismo , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/patologia , Inflamação/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: The mortality rate from disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in non-lung cancer patients. Moreover, the prevalence of DIC varies among the pathologic types of lung cancer. This study analyzed the relationship between coagulation factors and the pathologic types of lung cancer. METHODS: Twenty-six patients with progressive, inoperable stage IIB or higher lung cancer (20 men, 6 women; mean age 71 years; 11 Adeno, 10 squamous cell carcinoma, and 5 small cell carcinoma) and five healthy volunteers without respiratory disease (3 men, 2 women; mean age 72 years) were enrolled in the study. Blood samples were collected at lung cancer diagnosis, before treatment. RESULTS: White blood cell count, platelet count, serum C-reactive protein, fibrin/fibrinogen degradation products, fibrinogen, thrombin-antithrombin complex, and D-dimer levels differed significantly between lung cancer patients and the control group, but not among the pathologic types of lung cancer. Thrombomodulin levels were significantly higher in patients with Adeno and squamous cell carcinoma than in those with small cell carcinoma (P < 0.05 and P < 0.01, respectively). Antithrombin levels were significantly lower in patients with squamous cell carcinoma than in those with Adeno (P < 0.05). CONCLUSION: Coagulation disorders may develop secondary to chronic inflammation in patients with progressive lung cancer. DIC in lung cancer may be attributed to changes in anticoagulation factors, such as thrombomodulin and antithrombin, but not in other coagulation factors.
Assuntos
Antitrombinas/sangue , Proteína C-Reativa/metabolismo , Coagulação Intravascular Disseminada/etiologia , Neoplasias Pulmonares/patologia , Trombomodulina/sangue , Idoso , Estudos de Casos e Controles , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/metabolismo , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/metabolismo , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Fatores de Risco , Regulação para CimaRESUMO
OBJECTIVE: High-density lipoprotein (HDL) has been epidemiologically shown to be associated with the outcome of sepsis. One potential mechanism is that HDL possesses pleiotropic effects, such as anti-apoptosis, some of which can be ascribed to sphingosine 1-phosphate (S1P) carried on HDL via apolipoprotein M (apoM). Therefore, the aim of this study was to elucidate the roles of apoM/S1P in the consequent lethal conditions of sepsis, such as multiple organ failure caused by severe inflammation and/or disseminated intravascular coagulation. METHODS AND RESULTS: In mice treated with lipopolysaccharide (LPS), both plasma apoM levels and the expression of apoM in the liver and kidney were suppressed. The overexpression of apoM improved the survival rate and ameliorated the elevated plasma alanine aminotransferase (ALT) and creatinine levels, while the knockout or knockdown of apoM deteriorated these parameters in mice treated with LPS. Treatment with VPC23019, an antagonist against S1P receptor 1 and 3, or LY294002, a PI3K inhibitor, partially reversed these protective properties arising from the overexpression of apoM. The overexpression of apoM inhibited the elevation of plasma plasminogen activator inhibitor-1, restored the phosphorylation of Akt, and induced anti-apoptotic changes in the liver, kidney and heart. CONCLUSION: These results suggest that apoM possesses protective properties against LPS-induced organ injuries and could potentially be introduced as a novel therapy for the severe conditions that are consequent to sepsis.