Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In sepsis, several cell types (e.g., lymphocytes) undergo apoptosis and have the potential to harm the host if not cleared by professional phagocytes. Apoptotic cells display "eat me" signals such as phosphatidylserine that can be readily recognized by phagocytes. For full engulfment of these cells, binding to integrin alpha(v)beta(3), mediated by the bridging protein, milk fat globule epidermal growth factor-factor VIII (MFG-E8), is necessary. We hypothesized that, in sepsis, phagocytosis of apoptotic cells is impaired due to decreased MFG-E8 expression and that adoptive transfer of exosomes containing MFG-E8 is beneficial. Sepsis was induced in rats by cecal ligation and puncture (CLP) and MFG-E8 expression assessed by Western blot 20 h later. Dendritic cells were generated from bone marrow cells, and secreted exosomes were collected and injected into CLP animals. Plasma cytokines (enzyme-linked immunosorbent assay) and thymocyte apoptosis (TC-Ao, annexin V) were assessed. The ability of peritoneal macrophages from septic animals to engulf apoptotic cells was determined in an ex vivo phagocytosis assay. A 10-day survival study was conducted. Cecal ligation and puncture reduced MFG-E8 protein levels in the spleen and liver by 48% and 70%, respectively, and increased TC-Ao by 1.6-fold. Injection of MFG-E8-containing exosomes, however, led to a 33% reduced detection of TC-Ao, without directly inhibiting apoptosis. In fact, peritoneal macrophages from exosome-treated rats displayed a 2.8-fold increased ability to phagocytose apoptotic thymocytes. Inhibition of MFG-E8 before injection of exosomes completely abrogated the enhanced phagocytosis. Treatment with bone marrow dendritic cell-derived exosomes also reduced plasma tumor necrosis factor alpha and interleukin (IL)-6 levels and improved survival from 44% to 81%. We conclude that, by providing the indispensable factor MFG-E8 for complete engulfment of apoptotic cells, these exosomes lead to an attenuation of the systemic inflammatory response and overall beneficial effect in sepsis.
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PMID:Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. 1672 Dec 66

Haemostatic changes in septic patients are complex, with both procoagulant and anticoagulant changes. Thirty-eight patients with severe sepsis and 32 controls were investigated by coagulation screens, individual factor assays, calibrated automated thrombography (CAT), whole blood low-dose-tissue factor activated (LD-TFA) Rotem and LD-TFA waveform analysis. Thirty-six of 38 patients had an abnormal coagulation screen. The mean levels of factors II, V (P < 0.05), VII, X, XI and XII, antithrombin and protein C (P < 0.01) was decreased in sepsis compared with controls. The mean factor VIII and fibrinogen level (P < 0.001) was increased. CAT in platelet rich and poor plasma showed a prolonged lag time (P < 0.02), decreased peak thrombin (P < 0.02) and delayed time to peak thrombin (P < 0.001) in sepsis patients, however, the endogenous thrombin potential was equivalent in sepsis and controls. In LD-TFA Rotem, septic patients had delayed clot times (P = 0.04) but an increased maximum velocity of clot formation (P < 0.01) and area under the clot elasticity curve (P < 0.01). LD-TFA waveform analysis showed a delayed onset time but an increased rate of clot formation (P < 0.005). In conclusion, global tests of haemostasis suggest that in this patient group, activation of haemostasis is delayed but once initiated thrombin generation and clot formation are normal or enhanced.
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PMID:Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. 1701 48

Bleeding diatheses are frequent alterations during sepsis and surgical-anesthetic aggression. Generally, the bleeding is related with platelet dysfunction, inadequate surgical hemostasis, vitamin K deficit, etc. We present the case of a patient with no background of coagulopathy who, after two surgical interventions, developed abdominal sepsis and peritoneal hematoma after puncture for drainage of abdominal collection, due to an autoimmune origin factor VIII acquired deficit. The hematoma caused a picture of hypovolemic shock that required transfusion of several units of red blood cells, expansion and drug support. Finally, the bleeding was controlled by treatment with immunosuppressants, recombinant activated factor VII (RFVIIa) and polyvalent gammaglobulin. The peritoneal hematoma was drained surgically and the patient evolved towards improvement until being discharged from the intensive therapy unit.
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PMID:[Peritoneal bleeding due to acquired hemophilia during an abdominal sepsis clinical picture]. 1706 8

Enoxaparin, a low-molecular-weight heparin used to treat and prevent deep venous thrombosis, has been evaluated in several clinical trials. Thrombosis induced by enoxaparin with no evidence of heparin-induced thrombocytopenia (HIT) is seldom described. We report a rare case in which an 89-year-old African-American female developed large, multiple, painful lesions induced by enoxaparin administration. Laboratory investigations for HIT, disseminated intravascular coagulation, protein C, protein S, factor V, factor VIII, antithrombin III, and homocysteine deficiency were negative. Unfortunately, despite aggressive management for 2 weeks, the patient developed severe sepsis and died.
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PMID:Enoxaparin-induced skin necrosis: a fatal outcome. 1766 18

Clearance of apoptotic cells is crucial to maintain cellular function under normal and pathological conditions. We have recently shown that administration of immature dendritic cell-derived exosomes to septic animals promotes phagocytosis of apoptotic cells and improves survival by providing milk fat globule epidermal growth factor-factor VIII (MFG-E8). MFG-E8 acts as an opsonin for apoptotic cells to be engulfed by phagocytosis. In the present study we investigated whether the CX(3)C-chemokine fractalkine (CX(3)CL1) promotes apoptotic cell clearance through the induction of MFG-E8 in peritoneal macrophages. Cultured rat peritoneal macrophages (pMphi) and RAW264.7 macrophages were stimulated with LPS and CX(3)CL1. MFG-E8 expression was assessed by Western blot, cytokine secretion was assessed by ELISA, and phagocytosis of apoptotic thymocytes was determined by microscopy. For in vivo studies, cecal ligation and puncture (CLP) was used to induce sepsis in rats and mice. LPS significantly decreased MFG-E8 levels and phagocytosis of apoptotic cells, whereas CX(3)CL1 induced MFG-E8 expression in both nonstimulated and LPS-stimulated pMphi, without affecting TNF-alpha and IL-6 release. Anti-MFG-E8 blocking antibodies completely abrogated the prophagocytic effect of CX(3)CL1. Twenty hours after the induction of sepsis in rats via CLP, plasma CX(3)CL1 levels as well as MFG-E8 production in peritoneal macrophages decreased by 21% and 56%, respectively. Administration of CX(3)CL1 on the other hand induced MFG-E8 and prevented tissue injury. We conclude that CX(3)CL1 induces MFG-E8 in vitro and in vivo and enhances clearance of apoptotic cells in an MFG-E8-dependent manner. These findings suggest a possible novel treatment for patients in sepsis.
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PMID:Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. 1767 41

The activated partial thromboplastin time (APTT) is the most common coagulation test procedure performed in routine laboratories, apart from the prothrombin time. The test is traditionally used for identifying quantitative and qualitative abnormalities in the intrinsic and common pathways of coagulation, monitoring anticoagulant therapy with unfractionated heparin, and detecting inhibitors of blood coagulation, the most common of which is the lupus anticoagulant. Whereas short APTT values have been mostly overlooked in the past, recent evidence suggests that these might be associated with hypercoagulability. Although clinical relevance is yet to be clearly defined, hypercoagulability detected by a shortened APTT appears to be significantly associated with a major risk of venous thromboembolism independently from other variables such as blood group, the presence of inherited thrombophilia, and factor VIII levels. This novel finding suggests that this traditional, simple, and inexpensive test might have renewed utility along with traditional thrombophilic tests in the evaluation of venous thromboembolic risk. In addition, APTT waveform analysis is also providing mounting evidence of added utility, in particular for identifying sepsis and disseminated intravascular coagulation in critically ill patients (particularly where this might worsen the prognosis), for monitoring therapy in patients with inhibitors, and as a diagnostic aid to identify patients with antiphospholipid antibodies. In total, such emerging evidence suggests that the APTT is either an old dogma displaying new tricks or else might describe a new dogma for an old laboratory trick.
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PMID:Activated partial thromboplastin time: new tricks for an old dogma. 1908 61

Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule epidermal growth factor (EGF)-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Because endotoxin is elevated in polymicrobial sepsis, we hypothesized that down-regulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14(-/-)), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by i.p. injection of LPS. LPS was also neutralized by pretreating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity, and apoptosis were assessed 5 and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49 and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the down-regulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14(-/-) and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14(-/-) mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14(-/-) mice. Thus, MFG-E8 production is down-regulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
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PMID:Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway. 1910 91

Sepsis, a highly lethal systemic inflammatory syndrome, is associated with increases of proinflammatory cytokines (e.g., TNF-alpha, HMGB1) and the accumulation of apoptotic cells that have the potential to be detrimental. Depending on the timing and tissue, prevention of apoptosis in sepsis is beneficial; however, thwarting the development of secondary necrosis through the active removal of apoptotic cells by phagocytosis may offer a novel anti-sepsis therapy. Immature dendritic cells (IDCs) release exosomes that contain milk fat globule EGF factor VIII (MFGE8), a protein required to opsonize apoptotic cells for phagocytosis. In an experimental sepsis model using cecal ligation and puncture, we found that MFGE8 levels decreased in the spleen and blood, which was associated with impaired apoptotic cell clearance. Administration of IDC-derived exosomes promoted phagocytosis of apoptotic cells and significantly reduced mortality. Treatment with recombinant MFGE8 was equally protective, whereas MFGE8-deficient mice suffered from increased mortality. IDC exosomes also attenuated the release of proinflammatory cytokines in septic rats. Liberation of HMGB1, a nuclear protein that contributes to inflammation upon release from unengulfed apoptotic cells, was prevented by MFGE8-mediated phagocytosis in vitro. We conclude that IDC-derived exosomes attenuate the acute systemic inflammatory response in sepsis by enhancing apoptotic cell clearance via MFGE8.
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PMID:Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor-factor VIII [corrected]. 1981 88

Multiple organ failure is a common feature of pediatric meningococcal sepsis and is associated with an imbalance of coagulation and fibrinolysis. This is partly due to an increased secretion of prothrombotic ultra-large von Willebrand factor (VWF) as the result of vascular endothelial damage. Another factor that may contribute is ADAMTS13, which converts VWF into smaller, less active, VWF multimers and thus influences VWF activity in plasma. We investigated the role of ADAMTS13 and VWF in the severity and outcome of sepsis. In 58 children with severe meningococcal sepsis we measured ADAMTS13 activity and antigen, VWF collagen binding activity (VWF:CB) and antigen levels (VWF:Ag), VWF propeptide and factor VIII at different time points during their stay in the paediatric intensive care unit. In the acute phase, both ADAMTS13 activity and antigen were decreased (median 23.4% and 33.7% of normal, respectively) and VWF:CB and VWF:Ag levels were strongly increased (325% and 348%, respectively.) ADAMTS13 antigen (23.9% vs. 34.6%; p=0.06) and VWF:CB (240% and 340% p<0.001) were lower in non-survivors than in survivors. ADAMTS13 activity and VWF:CB were both correlated with the severity of the disease, as indicated by the Pediatric Risk of Mortality score (R(s)= -0.38 and R(s)= -0.50, p=0.01, respectively, p<0.001). In the acute phase of severe sepsis decreased levels of ADAMTS13 and increased levels of VWF are observed, and the changes are related to severity of disease and outcome. This may contribute to the formation of microthrombi and the severity of thrombotic sequelae of sepsis.
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PMID:Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome. 2039 Feb 23

Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.
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PMID:Milk fat globule-EGF factor VIII in sepsis and ischemia-reperfusion injury. 2088 59


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