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)

Tissue factor (also known as tissue thromboplastin or CD142) is the protein that activates the blood clotting system by binding to, and activating, the plasma serine protease, factor VIIa, following vascular injury. Because of its essential role in hemostasis, tissue factor plays a role in pathology associated with hemostasis, triggering the coagulation system in many thrombotic diseases and the coagulopathies associated with sepsis and other forms of disseminated intravascular coagulation. Recent research has also implicated tissue factor in a variety of nonhemostatic roles, including cell signaling, inflammation, vasculogenesis, and tumor growth and metastasis. This review focuses on both the well-known roles of tissue factor in hemostasis and thrombosis and the newer concepts of tissue-factor biology including how it functions as a signaling receptor and the possible role of blood-borne tissue factor in thrombosis.
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PMID:Tissue factor: a key molecule in hemostatic and nonhemostatic systems. 1500 35

Human protein C is a serine protease that circulates in the blood as an inactive zymogen. It is converted to its active form by interaction with thrombomodulin on the endothelial wall. Activated protein C has a significant role in maintaining haemostasis, and is a major mechanism of controlling microvascular thrombosis. Recent reports describe the use of drotrecogin alfa (recombinant activated protein C) in severe sepsis, a condition relevant to emergency medicine. This review describes the physiology of the protein C pathway and its importance in sepsis. It will also focus on the use of drotrecogin alfa in sepsis, and its use in the ED.
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PMID:Drotrecogin alfa: a role in emergency department treatment of severe sepsis? 1579 37

Vibrio vulnificus is an opportunistic human pathogen causing septicemia, and the infection is characterized by formation of the edematous skin lesions on limbs. This pathogenic species secretes a thermolysin-like metalloprotease as a virulence determinant. The metalloprotease was confirmed to activate human factor XII-plasma kallikrein-kinin cascade that results in liberation of bradykinin, a chemical mediator enhancing the vascular permeability, from high-molecular weight kininogen. Namely, the metalloprotease showed to generate active fragments by cleavage of Arg-Ile, Arg-Val or Gly-Leu peptide bond in human zymogens (plasma prekallikrein and factor XII). In spite of induction of the sufficient vascular permeability-enhancing and edema-forming reaction in the guinea pig model, a serine protease from V. parahaemolyticus, a human pathogen causing primarily watery diarrhea, showed far less ability to activate and to cleave the human zymogens. These results in part may explain why only V. vulnificus often causes serious edematous skin damages in humans.
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PMID:Generation of active fragments from human zymogens in the bradykinin-generating cascade by extracellular proteases from Vibrio vulnificus and V. parahaemolyticus. 1553 Sep 71

Serotype III group B streptococci (GBS) are a common cause of neonatal sepsis and meningitis. Although deficiency in maternal capsular polysaccharide (CPS)-specific IgG correlates with susceptibility of neonates to the GBS infection, serum deficient in CPS-specific IgG mediates significant opsonophagocytosis. This IgG-independent opsonophagocytosis requires activation of the complement pathway, a process requiring the presence of both Ca(2+) and Mg(2+), and is significantly reduced by chelating Ca(2+) with EGTA. In these studies, we defined a role of L-ficolin/mannose-binding lectin-associated serine protease (MASP) complexes in Ca(2+)-dependent, Ab-independent opsonophagocytosis of serotype III GBS. Incubation of GBS with affinity-purified L-ficolin/MASP complexes and C1q-depleted serum deficient in CPS-specific Ab supported opsonophagocytic killing, and this killing was inhibited by fluid-phase N-acetylglucosamine, the ligand for L-ficolin. Binding of L-ficolin was proportional to the CPS content of individual strains, and opsonophagocytic killing and C4 activation were inhibited by fluid-phase CPS, suggesting that L-ficolin binds to CPS. Sialic acid is known to inhibit alternative complement pathway activation, and, as expected, the bactericidal index (percentage of bacteria killed) for individual strains was inversely proportional to the sialic acid content of the CPS, and L-ficolin-initiated opsonophagocytic killing was significantly increased by addition of CPS-specific IgG2, which increased activation of the alternative pathway. We conclude that binding of L-ficolin/MASP complexes to the CPS generates C3 convertase C4b2a, which deposits C3b on GBS. C3b deposited by this lectin pathway forms alternative pathway C3 convertase C3bBb whose activity is enhanced by CPS-specific IgG2, leading to increased opsonophagocytic killing by further deposition of C3b on the GBS.
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PMID:Role of L-ficolin/mannose-binding lectin-associated serine protease complexes in the opsonophagocytosis of type III group B streptococci. 1561 Dec 66

Increased endothelial cell (EC) permeability is central to the pathophysiology of inflammatory syndromes such as sepsis and acute lung injury (ALI). Activated protein C (APC), a serine protease critically involved in the regulation of coagulation and inflammatory processes, improves sepsis survival through an unknown mechanism. We hypothesized a direct effect of APC to both prevent increased EC permeability and to restore vascular integrity after edemagenic agonists. We measured changes in transendothelial electrical resistance (TER) and observed that APC produced concentration-dependent attenuation of TER reductions evoked by thrombin. We next explored known EC barrier-protective signaling pathways and observed dose-dependent APC-mediated increases in cortical myosin light chain (MLC) phosphorylation in concert with cortically distributed actin polymerization, findings highly suggestive of Rac GTPase involvement. We next determined that APC directly increases Rac1 activity, with inhibition of Rac1 activity significantly attenuating APC-mediated barrier protection to thrombin challenge. Finally, as these signaling events were similar to those evoked by the potent EC barrier-enhancing agonist, sphingosine 1-phosphate (S1P), we explored potential cross-talk between endothelial protein C receptor (EPCR) and S1P1, the receptors for APC and S1P, respectively. EPCR-blocking antibody (RCR-252) significantly attenuated both APC-mediated barrier protection and increased MLC phosphorylation. We next observed rapid, EPCR and PI 3-kinase-dependent, APC-mediated phosphorylation of S1P1 on threonine residues consistent with S1P1 receptor activation. Co-immunoprecipitation studies demonstrate an interaction between EPCR and S1P1 upon APC treatment. Targeted silencing of S1P1 expression using siRNA significantly reduced APC-mediated barrier protection against thrombin. These data suggest that novel EPCR ligation and S1P1 transactivation results in EC cytoskeletal rearrangement and barrier protection, components potentially critical to the improved survival of APC-treated patients with severe sepsis.
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PMID:Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. 1571 Jun 22

Sepsis is the leading cause of death in intensive care units and results from a deleterious systemic host response to infection. Although initially perceived as potentially deleterious, catalytic antibodies have been proposed to participate in removal of metabolic wastes and protection against infection. Here we show that the presence in plasma of IgG endowed with serine protease-like hydrolytic activity strongly correlates with survival from sepsis. Variances of catalytic rates of IgG were greater in the case of patients with severe sepsis than healthy donors (P < 0.001), indicating that sepsis is associated with alterations in plasma levels of hydrolytic IgG. The catalytic rates of IgG from patients who survived were significantly greater than those of IgG from deceased patients (P < 0.05). The cumulative rate of survival was higher among patients exhibiting high rates of IgG-mediated hydrolysis as compared with patients with low hydrolytic rates (P < 0.05). An inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients' IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies might play a role in recovery from a disease.
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PMID:High levels of catalytic antibodies correlate with favorable outcome in sepsis. 1574 15

Uropathogenic Escherichia coli is the most common cause of urinary tract infection (UTI). Cystitis in women is by far the most common UTI; pyelonephritis in both sexes and prostatitis in men are more severe but are less frequent complaints. The ability of E. coli to cause UTI is associated with specific virulence determinants, some of which are encoded on pathogenicity islands (PAI). One such PAI (PAI IICFT073), of the prototypical uropathogenic E. coli strain CFT073, contains 116 open reading frames, including iron-regulated genes, carbohydrate biosynthetic genes, the serine protease autotransporter picU, a two-partner secretion system, a type I secretion system, mobility genes, and a large number of hypothetical genes. To determine the association of PAI IICFT073 with UTI, PCR was used to examine the prevalence of the five virulence-associated loci among the ECOR collection and a collection of E. coli isolated from patients with cystitis, pyelonephritis, prostatitis, or septicemia. All PAI IICFT073 loci were found to be more prevalent among the B2 phylogenetic group than any other group within the ECOR collection and among invasive prostatitis strains than were cystitis or pyelonephritis strains. These data support the theory that clinical isolates causing prostatitis are more virulent than those producing cystitis or pyelonephritis in women.
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PMID:Prevalence of pathogenicity island IICFT073 genes among extraintestinal clinical isolates of Escherichia coli. 1587 76

Skeletal muscle atrophy in response to a number of muscle wasting conditions, including disuse, involves the induction of increased protein breakdown, decreased protein synthesis, and likely a variable component of apoptosis. The increased activation of specific proteases in the atrophy process presents a number of potential therapeutic targets to reduce muscle atrophy via protease inhibition. In this study, mice were provided with food supplemented with the Bowman-Birk inhibitor (BBI), a serine protease inhibitor known to reduce the proteolytic activity of a number of proteases, such as chymotrypsin, trypsin, elastase, cathepsin G, and chymase. Mice fed the BBI diet were suspended for 3-14 days, and the muscle mass and function were then compared with those of the suspended mice on a normal diet. The results indicate that dietary supplementation with BBI significantly attenuates the normal loss of muscle mass and strength following unloading. Furthermore, the data reveal the existence of yet uncharacterized serine proteases that are important contributors to the evolution of disuse atrophy, since BBI inhibited serine protease activity that was elevated following hindlimb unloading and also slowed the loss of muscle fiber size. These results demonstrate that targeted reduction of protein degradation can limit the severity of muscle mass loss following hindlimb unloading. Thus BBI is a candidate therapeutic agent to minimize skeletal muscle atrophy and loss of strength associated with disuse, cachexia, sepsis, weightlessness, or the combination of age and inactivity.
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PMID:Attenuation of skeletal muscle atrophy via protease inhibition. 1597 55

Urokinase-type plasminogen activator (uPA) is a serine protease that not only displays fibrinolytic function but also modulates innate and adaptive immune responses. In the present study, we assessed whether uPA acts as an endogenous antibiotic. It has been demonstrated that uPA inhibits growth of Staphylococcus aureus both in vivo and in vitro. Importantly, the bactericidal properties of uPA are associated with the serine protease domain of the molecule but are not dependent on its plasminogen-activation potential and cannot be inhibited by plasminogen activator inhibitor type 1 (PAI-1). In a murine infection model, uPA treatment alleviated staphylococcal sepsis by inhibiting bacterial growth. To further evaluate the changes in uPA levels during the course of staphylococcal infection, total uPA and active uPA levels were analyzed in plasma and in kidney homogenates. Expression of total uPA was constant, but PAI-1 levels were dramatically increased in plasma and in kidney homogenates during the course of staphylococcal infection. After infection with staphylococci, the level of metabolically active uPA was unaltered in plasma but was significantly decreased in kidney homogenates. Active uPA levels were inversely related to PAI-1 levels and to bacterial loads in kidney homogenates. In conclusion, we report that uPA acts as an endogenous antibacterial substance that might constitute the first line of host defense against staphylococcal infection. The decreased active uPA levels in infected organs might be due to the dramatically increased PAI-1 production during S. aureus infection.
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PMID:Urokinase-type plasminogen activator, an endogenous antibiotic. 1599 56

As a result of significant progress in reducing the risks of transfusion-transmitted viral infections, bacterial contamination of platelet components (1:2,000) and sepsis (1:50,000) are now the most frequent infectious complications of blood transfusions. Sepsis from bacterial contamination of red cell components is less frequent (1:500,000), because red blood cells, unlike platelet components, can be stored at refrigerated temperatures (1 degrees C-4 degrees C). Current risks for transfusion-transmitted viral diseases (per blood component transfused) are: human immunodeficiency virus, 1:2,135,000; hepatitis C virus, 1:1,935,000; hepatitis B virus, 1:205,000; and human T-lymphotropic viruses, 1:2,993,000. Transfusion-transmitted babesiosis has increased morbidity and mortality for splenectomized patients. Immunocompromised recipients are at increased risk of developing Chagas disease from blood contaminated by Trypanosoma cruzi. Reports of transfusion-related acute lunge injury and transfusion-associated graft-versus-host disease increase each year as physicians become increasingly aware of their varied clinical presentations. While strategies for preventing infections complications focus primarily on blood donor services, individual physicians can reduce risks to their patients by maintaining conservative "triggers" for transfusions, prescribing pharmacologic agents to reduce bleeding (antifibrinolytic drugs, serine protease inhibitors, fibrin sealants), and using epoetin alpha to reduce transfusion of red cells in selected patients.
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PMID:Risks of blood transfusion and their prevention. 1622 28


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