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)

The effect of a serine protease (ASP) secreted from Aeromonas sobria on plasma coagulation was investigated. Proteolytically active ASP promoted human plasma coagulation in a dose-dependent manner. Consistent with the preference for a factor Xa-specific oligo-peptide substrate, ASP produced enzymatic activity from human prothrombin but not from factors IX and X. ASP cleaved prothrombin to produce enzymatically active 37 kDa-fragment displaying the same molecular mass as alpha-thrombin. ASP is the first bacterial serine protease that produces alpha-thrombin, through which ASP may contribute to the induction of thrombotic tendency in disseminated intravascular coagulation complicated with sepsis caused by A. sobria infections.
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PMID:Activation of prothrombin by ASP, a serine protease released from Aeromonas sobria. 1806 62

Vibrio vulnificus is a causative agent of septicemia or wound infection in human and eel; however, the genetic variation between human and eel isolates has been reported. In the present study, the difference in the vvp gene encoding a tissue-damaging metalloprotease was investigated. The gene of strain E86 from a diseased eel (type B vvp) was 95.2% identical with that of strain L-180 from human blood (type A vvp). PCR using oligonucleotide primers designed to differentiate two types of the gene showed that eel avirulent strains (9 isolates) commonly carry type A vvp, whereas eel virulent strains (18 isolates) revealed significant genetic variation. The vvp genes from 12 strains including strain E86 were placed on type B while those from 3 strains were on type A. Other strains were found to be vvp-negative, but PAGE and amino acid sequencing analysis showed that they secreted a serine protease (VVA0302) instead of the metalloprotease. This protease is an orthologue of a toxic protease from Vibrio parahaemolyticus, a human pathogen causing wound infection as well as gastroenteritis. These findings suggest that, in addition to metalloprotease, the extracellular serine protease may contribute to pathogenicity of V. vulnificus.
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PMID:Variation of extracellular proteases produced by Vibrio vulnificus clinical isolates: genetic diversity of the metalloprotease gene (vvp), and serine protease secretion by vvp-negative strains. 1826 48

Aeromonas sobria infection often advances to sepsis, in which interaction of bacterial components with plasma proteins possibly causes various disorders. This bacterium releases a serine protease (ASP), a putative virulence factor, and binds to fibrinogen. To study the ASP effect on fibrinogen, we incubated fibrinogen or plasma with ASP and investigated their clotting elicited by thrombin, which converts fibrinogen to a fibrin clot. Enzymatically active ASP retarded plasma clotting in a dose-dependent manner starting at an ASP concentration of 10 nM. ASP also retarded fibrinogen clotting at 3 nM and above, which appeared to correspond to ASP cleavage of fibrinogen at the A alpha-chain. Consistent with containing serine protease activity for an ASP-specific substrate, the culture supernatant of an ASP gene-introduced strain retarded plasma and fibrinogen clotting more than that of the wild-type strain. The culture supernatant of an ASP gene-disrupted strain that releases negligible serine protease activity for the ASP-specific substrate did not affect plasma clotting. These results indicate that ASP is the main fibrinogenolytic protease released from A. sobria. Impaired plasma clottability induction through fibrinogen degradation is a new virulence activity of ASP and may contribute to hemorrhagic tendencies in sepsis caused by infection with this bacterium.
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PMID:Impaired plasma clottability induction through fibrinogen degradation by ASP, a serine protease released from Aeromonas sobria. 1846 93

Activated protein C (APC) is a serine protease, an effector enzyme of the natural anticoagulant pathway. APC is approved for treatment of severe sepsis characterized by the increased concentrations of H(2)O(2) and hypochlorite. We found that treatment of APC with these oxidants markedly inhibits the cleavage of the APC-specific chromogenic substrate, suggesting that oxidants can induce changes in the structure of the active site of APC. Resistance of oxidant-treated APC to chemical digestion with cyanogen bromide (CNBr) implies that methionine oxidation can at least in part be responsible for inhibition of APC. Since methionine residues, the main targets of oxidants in APC, are not included in the active site, we hypothesize that oxidation induces allosteric changes in the architecture of the catalytic triad of APC. Using molecular dynamics (MD) simulations we found that methionine oxidation alters the distance between cSer195Ogamma and cHis57Nepsilon2 atoms placing them in positions unfavorable for the catalysis. At the same time, neither distances between Calpha atoms of the catalytic triad cAsp102-cHis57-cSer195, nor the overall structure of APC changed significantly after oxidation of the methionine residues. Disruption of the H-bond between Ndelta1 of cHis57 and carboxyl group of cAsp102, which can take place during the hypochlorite-induced modification of cHis57, dramatically changed the architecture of the catalytic triad in oxidized APC. This mechanism could contribute to APC inactivation by hypochlorite concurrently with methionine oxidation. These are novel findings, which describe potentially pathophysiologically relevant changes in the functional stability of APC exposed to the oxidative stress.
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PMID:Possible mechanisms contributing to oxidative inactivation of activated protein C: molecular dynamics study. 1861 33

The protective effect of recombinant activated protein C therapy in patients with severe sepsis likely reflects the ability of recombinant activated protein C to modulate multiple pathways implicated in sepsis pathophysiology. In this study, we examined the effects of recombinant activated protein C on the anti-inflammatory cytokine IL-10 and on the procoagulant molecule tissue factor (TF) in LPS-challenged blood monocytes. Treatment of LPS-stimulated monocytes with recombinant activated protein C resulted in an up-regulation of IL-10 protein production and mRNA synthesis. The up-regulation of IL-10 required the serine protease activity of recombinant activated protein C and was dependent on protease-activated receptor-1, but was independent of the endothelial protein C receptor. At the intracellular level, p38 MAPK activation was required for recombinant activated protein C-mediated up-regulation of IL-10. We further observed that incubation of LPS-stimulated monocytes with recombinant activated protein C down-regulated TF Ag and activity levels. This anticoagulant effect of recombinant activated protein C was dependent on IL-10 since neutralization of endogenously produced IL-10 abrogated the effect. In patients with severe sepsis, plasma IL-10 levels were markedly higher in those treated with recombinant activated protein C than in those who did not receive recombinant activated protein C. This study reveals novel regulatory functions of recombinant activated protein C, specifically the up-regulation of IL-10 and the inhibition of TF activity in monocytes. Our data further suggest that these activities of recombinant activated protein C are directly linked: the recombinant activated protein C-mediated up-regulation of IL-10 reduces TF in circulating monocytes.
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PMID:Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes. 1864 55

This is a review of the management of septic shock that suggests an approach to treatment (ABCDEF: Airway, Breathing, Circulation, Drugs, Evaluate the source of sepsis, Fix the source of sepsis) for clinicians. The incidence of septic shock is increasing and mortality ranges from 30% to 70%. The commonest sources of infection are lung (25%), abdomen (25%), and other sources. Septic shock occurs because of highly complex interactions between the infecting microorganism(s) and the responses of the human host. The innate immune response is rapidly followed by the more specific adaptive immune response. Septic shock is characterized by alterations in the coagulant/anticoagulant balance such that there is a more pro-coagulant phenotype. Lung protective ventilation (which means the use of relatively low tidal volumes of 4 -6 mL/kg ideal body weight) is recommended for treatment of patients who have septic shock. Rivers early goal-directed therapy is recommended because it showed a significant increase in survival. Surviving Sepsis guidelines recommend resuscitation of septic shock with either crystalloid or colloid. Patients who have septic shock should be treated with intravenous broad-spectrum antibiotics as rapidly as possible and certainly within one hour. Activated protein C (APC) is a vitamin K dependent serine protease that is an anticoagulant and is also cytoprotective and anti-inflammatory. APC (24 mg/kg/hour infusion for 96 hours) decreased mortality (APC 25% vs placebo 31%, relative risk 0.81P=0.005) and improved organ dysfunction in patients at high risk of death (e.g. APACHE II >25 [APC 31% vs placebo 44%]). APC is not recommended to treat surgical patients who have one organ system dysfunction. In 2006, the European regulatory authority indicated that there must be another randomized placebo-controlled trial of APC to further establish efficacy as assessed by mortality reduction. Vasopressin is a key stress hormone in response to hypotension. The VASST study was a randomized trial of vasopressin versus norepinephrine in septic shock. There was no difference in mortality between vasopressin versus norepinephrine-treated patients (35% versus 39% respectively). In patients who had less severe septic shock, patients treated with vasopressin may have lowered mortality compared with norepinephrine (26% vs 36%). Annane et al. found that hydrocortisone plus fludrocortisone (compared to placebo) was associated with lower mortality in patients who had an inadequate response to corticotropin stimulation test (mortality 53% vs 63% respectively). Sprung et al. did a randomized controlled trial of hydrocortisone (50 mg intravenously every 6 hours) compared to placebo (CORTICUS) to address lingering questions regarding the Annane trial. There was no difference in mortality (39.2% hydrocortisone vs 36.1%) or organ dysfunction. Several randomized controlled trials of intensive insulin versus conventional insulin in the critically ill have yielded conflicting results and do not support the routine use of intensive insulin in the ancillary management of septic shock. A recent randomized controlled trial of intensive versus less intensive renal support in patients who had acute kidney injury found no difference in mortality (53.6% vs 51.5% respectively), duration of renal support, or rates of recovery of renal and non-renal organ dysfunction.
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PMID:The current management of septic shock. 1897 11

The anaerobic bacterium Aeromonas sobria is known to cause potentially lethal septic shock. We recently proposed that A. sobria serine protease (ASP) is a sepsis-related factor that induces vascular leakage, reductions in blood pressure via kinin release, and clotting via activation of prothrombin. ASP preferentially cleaves peptide bonds that follow dibasic amino acid residues, as do Kex2 (Saccharomyces cerevisiae serine protease) and furin, which are representative kexin family proteases. Here, we revealed the crystal structure of ASP at 1.65 A resolution using the multiple isomorphous replacement method with anomalous scattering. Although the overall structure of ASP resembles that of Kex2, it has a unique extra occluding region close to its active site. Moreover, we found that a nicked ASP variant is cleaved within the occluding region. Nicked ASP shows a greater ability to cleave small peptide substrates than the native enzyme. On the other hand, the cleavage pattern for prekallikrein differs from that of ASP, suggesting the occluding region is important for substrate recognition. The extra occluding region of ASP is unique and could serve as a useful target to facilitate development of novel antisepsis drugs.
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PMID:Structural basis for the kexin-like serine protease from Aeromonas sobria as sepsis-causing factor. 1965 32

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.
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PMID:Activated protein C and acute kidney injury: Selective targeting of PAR-1. 1971 37

The risk of mortality is high in burn patients and correlates with age, burn area extent, and sepsis. Immunosuppression has been reported to occur after severe burn. Cytotoxic cells possess specialized granules containing perforin and a group of serine proteases (granzymes). Granzyme A is a serine protease constitutively expressed by gammadelta and NK cells, in agreement with their functional cytolytic potential. In vitro studies have shown that GrA may be released extracellularly during cytotoxic cell degranulation, indicating the activation of cytotoxic cells. The aim of our study was to determine plasma GrA activity in burned patients and to verify if decreased GrA levels were associated with poor prognosis. Specific GrA activity was tested in the plasma of burned and healthy subjects by esterase assay. Plasma GrA was significantly decreased in septic rather than in nonseptic burn patients and in healthy subjects (p < 0.05 and p < 0.001, respectively). At day 3 plasma GrA was significantly lower in nonsurvivor than in survivor septic patients (p < 0.05). The value of 91 mOD showed a sensitivity of 100% and a specificity of 84% in differentiating survivor from nonsurvivor septic patients. Because this is a retrospective study, Granzyme A is not a confirmed predictor of septic outcome after burn, but its determination could give useful information about the development and severity of sepsis.
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PMID:Reduction of plasma granzyme A correlates with severity of sepsis in burn patients. 2036 98

Protein C is a vitamin K-dependent anticoagulant serine protease zymogen in plasma which upon activation by the thrombin-thrombomodulin complex down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, activated protein C (APC) also binds to endothelial protein C receptor (EPCR) in lipid-rafts/caveolar compartments to activate protease- activated receptor 1 (PAR-1) thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells. These properties have led to FDA approval of recombinant APC as a therapeutic drug for severe sepsis. The mechanism by which APC selects its substrates in the anticoagulant and antiinflammatory pathways is not well understood. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as 39-loop (Lys-37, Lys-38, and Lys-39), 60-loop (Lys-62, Lys- 63, and Arg-67), and 70-80-loop (Arg-74, Arg-75, and Lys-78) (chymotrypsin numbering) constitute an anion binding exosite in APC that interacts with the procoagulant cofactors Va and VIIIa in the anticoagulant pathway. Furthermore, two negatively charged residues on the opposite side of the active-site of APC on a helical structure have been demonstrated to determine the specificity of the PAR-1 recognition in the cytoprotective pathway. This article will review the mechanism by which APC exerts its proteolytic function in two physiologically inter-related pathways and how the structure- function insights into determinants of the specificity of APC interaction with its substrates in two pathways can be utilized to tinker with the structure of the molecule to obtain APC derivatives with potentially improved therapeutic profiles.
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PMID:Regulation of the protein C anticoagulant and antiinflammatory pathways. 2042 10


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