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)

Factor VII-activating protease (FSAP) is a serine protease in plasma that has a role in coagulation and fibrinolysis. FVII could be activated by purified FSAP in a tissue factor independent manner and pro-urokinase has been demonstrated to be a substrate for purified FSAP in-vitro. However, the physiological role of FSAP in haemostasis remains unclear. More recently FSAP is suggested to be involved in inflammation. It modulates vascular permeability directly and indirectly by the generation of bradykinin. Furthermore, FSAP is activated by dead cells induced by the inflammatory response and subsequently removes nucleosomes from apoptotic cells. FSAP activation can be detected in sepsis patients as well. However, whether FSAP activation upon inflammation is beneficial or detrimental remains an open question. In this review the structure, activation mechanisms and the possible role of FSAP in inflammation are discussed.
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PMID:FSAP, a new player in inflammation? 2225 69

Disseminated intravascular coagulation (DIC) is a heterogeneous group of disorders, which manifest as a spectrum of haemorrhage and thrombosis complicating many primary conditions including sepsis, trauma and malignancies. The pathophysiology of this condition is complex. In the recent years there is growing evidence that damage associated molecular patterns (DAMPs) play a crucial role in the pathogenesis of DIC. Upon cell-death and/or cell activation of hematopoietic and parenchymal cells extracellular cell-free DNA as well as DNA binding proteins (e.g. histones and high mobility group box 1 protein [HMGB1]) are released into circulation. This release is a highly regulated process mediated among others by serine proteases, such as factor VII-activating protease (FSAP) and DNase1. Circulating cell-free DNA has been demonstrated to influence primary and secondary hemostasis by inducing platelet aggregation, promoting coagulation activation, inhibition of fibrinolysis and directly interfering with clot stability. In this respect cell-free DNA in tissue as well as released into the circulation after neutrophil activation in the form of neutrophil extracellular traps (NETs) has been shown to be cytotoxic and highly procoagulant. DNA-binding proteins such as histones and HMGB1 are also strongly procoagulant and are involved in the pathogenesis of DIC. The present review gives an overview on how extracellular DNA is released into circulation and the structure of circulating DNA. In addition it summarizes the effect of extracellular DNA and DNA-binding proteins on platelet activation, plasmatic coagulation as well as fibrinolysis.
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PMID:DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. 2677 4

Factor VII (FVII)-activating protease (FSAP) is a serine protease in plasma, which was initially described to play a role in coagulation by activation of FVII, independent of tissue factor, and in fibrinolysis by cleavage of single-chain urokinase. Recent studies, however, suggest that FSAP-mediated FVII cleavage is negligible and that FSAP may exert procoagulant functions via cleavage of tissue factor pathway inhibitor. Meanwhile, many substrates of FSAP have been identified, such as platelet-derived growth factor, basic fibroblast growth factor/epidermal growth factor, histones, and high-molecular-weight kininogen. FSAP has also shown to induce DNA released from dead cells. Given its propensity for autoproteolysis and degradation, studies on the activation and regulation of FSAP are difficult to perform. Recent animal studies suggest a role of FSAP in the pathogenesis of arteriosclerosis, vascular integrity and probably also in the regulation of coagulation initiation. This review will focus on the biochemical properties of FSAP, regulation of FSAP activation, and finally its role in vascular disease and acute systemic inflammatory diseases, such as sepsis.
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PMID:Factor VII-Activating Protease: Hemostatic Protein or Immune Regulator? 2917 15

Circulating histones have been implicated as major mediators of inflammatory disease because of their strong cytotoxic effects. Histones form the protein core of nucleosomes; however, it is unclear whether histones and nucleosomes are equally cytotoxic. Several plasma proteins that neutralize histones are present in plasma. Importantly, factor VII-activating protease (FSAP) is activated upon contact with histones and subsequently proteolyzes histones. We aimed to determine the effect of FSAP on the cytotoxicity of both histones and nucleosomes. Indeed, FSAP protected against histone-induced cytotoxicity of cultured cells in vitro. Upon incubation of serum with histones, endogenous FSAP was activated and degraded histones, which also prevented cytotoxicity. Notably, histones as part of nucleosome complexes were not cytotoxic, whereas DNA digestion restored cytotoxicity. Histones in nucleosomes were inefficiently cleaved by FSAP, which resulted in limited cleavage of histone H3 and removal of the N-terminal tail. The specific isolation of either circulating nucleosomes or free histones from sera of Escherichia coli challenged baboons or patients with meningococcal sepsis revealed that histone H3 was present in the form of nucleosomes, whereas free histone H3 was not detected. All samples showed signs of FSAP activation. Markedly, we observed that all histone H3 in nucleosomes from the patients with sepsis, and most histone H3 from the baboons, was N-terminally truncated, giving rise to a similarly sized protein fragment as through cleavage by FSAP. Taken together, our results suggest that DNA and FSAP jointly limit histone cytotoxicity and that free histone H3 does not circulate in appreciable concentrations in sepsis.
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PMID:DNA and factor VII-activating protease protect against the cytotoxicity of histones. 2929