Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia-reperfusion (I/R) injury is associated with activation of coagulation and inflammation. Interestingly, various anticoagulants have been shown to reduce both coagulation and inflammation in animal models of kidney I/R injury. Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in the coagulation cascade. The aim of this study was to investigate the effect of fondaparinux in a lethal murine model of kidney I/R injury. A murine model of kidney I/R was established. In this model, we measured activation of the coagulation cascade and induction of inflammation. Administration of fondaparinux to I/R-injured mice reduced fibrin deposition in the kidney, reduced serum creatinine levels and increased survival from 0 to 44% compared with saline-treated control mice. Fondaparinux also reduced interleukin-6 and macrophage inflammatory protein-2 expression and decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced thioglycollate-induced recruitment of neutrophils into the peritoneum and inhibited the binding of U937 cells to P-selectin in vitro. Our data suggest that fondaparinux reduces kidney I/R injury primarily by inhibiting the recruitment of neutrophils.
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PMID:The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. 1574 44

Systemic inflammation and the activation of the coagulation system following cardiopulmonary bypass (CPB) may contribute to postoperative complications. In vitro studies have demonstrated that heparin possesses anti-inflammatory properties. To ascertain the relative benefits of high versus low heparin doses, we studied the impact of varying heparin doses on the inflammatory response and coagulation system during and following CPB. Forty patients scheduled for elective coronary artery bypass surgery requiring CPB were randomized to either a low dose (300 U/kg) (Group L) or a high dose of unfractionated heparin (600 U/kg) (Group H). To evaluate the inflammatory response, proinflammatory cytokines [tumor necrosis factor-alpha and interleukin-6 (IL-6)] were measured at four different times: before CPB (T0), 30 min after the institution of CPB (T1), 30 min after cross-clamp release (T2), and 4 h after the end of CPB (T3). Thrombin-antithrombin complex, platelet factor 4 and anti-activated factor X heparin concentrations were also measured. Patients in Group H received greater heparin (44.934 U versus 27.741 U, P<0.001) and protamine (P=0.003) doses. Postoperative blood loss and blood products transfusions were not significantly different in the groups. At T1, mean heparin plasma concentration was higher in Group H (P<0.001). IL-6 was significantly lower in Group H compared with Group L (P=0.01) only at T1. Using a mixed-effects statistical model, tumor necrosis factor-alpha and IL-6 levels were comparable regardless of the heparin dose. Thrombin-antithrombin complex levels were lower in Group H (P=0.04) and platelet factor 4 levels were significantly lower in Group H at T2 (P=0.04). Higher heparin doses were associated with higher heparin concentrations during CPB. A high heparin dose achieved a better preservation of the coagulation system with less thrombin formation and platelet activation. The heparin dose had small influence on proinflammatory cytokines release.
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PMID:The effects of high-dose heparin on inflammatory and coagulation parameters following cardiopulmonary bypass. 1597 Jul 15

Pentoxifylline (PTX, a methylxanthine derivative) has been found to interrupt early gene activation for tumour necrosis factor, interleukin-1, interleukin-6 and tissue factor production and to improve survival from experimental sepsis. During endotoxaemia, lipopolysaccharide (LPS, endotoxin) and proinflammatory cytokines trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. The present study was undertaken to determine whether pentoxifylline could prevent coagulation disturbances in LPS-treated rabbits. Endotoxaemia was induced with E. coli lipopolysaccharide in New Zealand White rabbits. Forty rabbits were used and divided into four equal groups. Group 1 served as a control group; Group 2: lipopolysaccharide was injected intravenously, Group 3: pentoxifylline was injected intraperitoneally, Group 4: lipopolysaccharide and pentoxifylline were injected simultaneously. Blood samples were collected 6 h after the treatments. In rabbits with endotoxin-induced DIC, platelet count, leukocyte count, percentage of differential leukocyte values, fibrinogen level, antithrombin III (AT-III) and protein C (PC) activity were decreased. Moreover, activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged when compared to the control group. In conclusion, haemostatic disturbances associated with endotoxin-induced DIC were moderately suppressed by the administration of PTX.
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PMID:Effect of pentoxifylline on endotoxin-induced haemostatic disturbances in rabbits. 1615 28

ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disintegrin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1balpha, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.
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PMID:Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. 1638 17

A 7-year-old female suddenly exhibited high fever and convulsions, and entered a semi-coma. She also had thrombocytopenia, elevated aminotransferase, prolonged prothrombin time and activated partial thromboplastin time, and hemophagocytes in the bone marrow. The brain magnetic resonance imaging revealed multiple low-intensity areas on the T1-weighted images, and high-intensity areas on the T2-weighted images bilaterally in the thalamus, the dorsal part of the pons, and the cerebellar white matter. The patient was diagnosed as having both acute necrotizing encephalopathy and hemophagocytic syndrome. Serum and cerebrospinal fluid interleukin-6 and tumor necrosis factor-alpha were elevated to the same high levels (serum:cerebrospinal fluid interleukin-6, 103:101 pg/mL; tumor necrosis factor-alpha 753:753 pg/mL). The clinical symptoms and the magnetic resonance imaging findings improved immediately after the administration of dexamethasone. These results suggest that the hypercytokinemia and the hyperpermeability of both the blood-brain barrier and the capillary walls of the central nervous system might be essential in the pathogenesis of acute necrotizing encephalopathy, and that early steroid therapy might be effective in these conditions.
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PMID:Acute necrotizing encephalopathy associated with hemophagocytic syndrome. 1663 10

Herein, we describe a confirmed case of Loxosceles spider bite that illustrates the critical complications seen in loxoscelism, including skin necrosis, rhabdomyolysis, hemolysis, coagulopathy, acute kidney failure, and electrolyte disorders. Upon initial assessment, laboratory studies revealed the following: the white blood cell count was 29,400 WBCs/mm(3), hemoglobin was 9.2g/dL, and the platelet count was 218,000 cells/mm(3). Coagulation studies revealed the following: international normalized ratio, 1.83; activated partial-thromboplastin time, 62 s; D-dimer, 600 ng/mL (normal range <500 ng/mL); free protein S, 37% (normal range=64-114%); protein C, negative; and antithrombin III, negative. Various serum levels were abnormal: urea, 110 mg/dL; creatinine, 3.1mg/dL; indirect bilirubin, 3.8 mg/dL; creatine kinase, 1631 U/L; lactate dehydrogenase, 6591 U/L; potassium 6.2 mmol/L. Urine tests were positive for hemoglobin and bilirubin. In addition, concentrations of interleukin-6 and tumor necrosis factor-alpha were notably elevated in the serum. In conclusion, physicians must be alert to the possibility of loxoscelism when a patient presents with the clinical and laboratory findings described above, especially if the patient resides in an endemic area. Advances in our understanding of multiple pathways and mediators that orchestrate the response to Loxosceles venom might reveal new possibilities for the management of loxoscelism.
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PMID:Loxosceles venom-induced cytokine activation, hemolysis, and acute kidney injury. 1792 22

Critically ill patients often have systemic activation of both inflammatory systems and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut off by proinflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa, and thrombin, can bind to protease-activated receptors on various cells, and the ensuing intracellular signaling leads to increased production of proinflammatory cytokines and chemokines. Activated protein C can bind to the protein C receptor on endothelial cells and mononuclear cells, thereby affecting NF-kappaB nuclear translocation and subsequently influencing inflammatory gene expression and inhibition of tissue factor expression on mononuclear cells. Observations in experimental models of targeted disruption of the protein C gene and restoration of the downregulated protein C pathway by administration of recombinant activated protein C support this notion.
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PMID:The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. 1895 86

HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV(+) patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.
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PMID:Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. 2007 68

Vascular intervention-induced neointimal formation is a major drawback for managing atherosclerotic cardiovascular diseases using invasive vascular procedures. Our previous studies demonstrated that hirulog-like peptide (HLP) reduced balloon catheter dilation-induced neointimal formation or restenosis in carotid arteries of rats or atherosclerotic rabbits with less interruption in coagulation or bleeding than heparin or hirulog-1. The present study examined the effect of HLP on balloon catheter injury-induced neointimal formation in femoral arteries of minipigs. Intravenous infusion of HLP (1.6 mg/kg/h for 4 h started 0.5 h before the intervention) or unfractured heparin (50 U/kg/h for 4 h) significantly reduced neointimal formation in femoral arteries 4 weeks after intervention compared with the vehicle. Heparin, but not HLP, significantly prolonged activated partial thromboplastin time. HLP or heparin significantly reduced vascular intervention-induced increases in C-reactive protein, P-selectin and interleukin-6 in serum. HLP, but not heparin, normalized vascular injury-induced increase in P-selectin in platelets. The results of the present study suggest that HLP is an effective agent for preventing balloon catheter injury-induced neointimal formation in femoral arteries of minipigs. The beneficial effects of HLP on vascular injury-induced neointimal formation may partially result from its inhibition on inflammatory mediators.
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PMID:Effect of hirulog-like peptide on balloon catheter injury-induced neointimal formation in femoral arteries of minipigs and relationship with inflammatory mediators. 1990 88

Critically ill patients often have systemic activation of both inflammation and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation not only leads to activation of coagulation, but coagulation also considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut-off by pro-inflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa and thrombin can bind to protease-activated receptors on various cells and the ensuing intracellular signaling leads to increased production of pro-inflammatory cytokines and chemokines. Physiological anticoagulants can modulate inflammatory activity as well. Increasing knowledge on the various mechanisms underlying activation of inflammation and coagulation may lead to better (adjunctive) management strategies in critically ill patients.
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PMID:The coagulant response in sepsis and inflammation. 2016 47


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