Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitronectin, also known as serum-spreading factor or S-protein, mediates cell adhesion and inhibits formation of the membrane-lytic complex of complement and the rapid inactivation of thrombin by antithrombin III in the presence of heparin. Vitronectin is normally present in plasma at a concentration of approximately 300 micrograms/mL. The investigators quantified plasma vitronectin with an enzyme-linked immunosorbent assay and visualized reduced and nonreduced vitronectin by immunoblotting after separation of plasma or serum by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The concentration of plasma vitronectin was markedly reduced in some patients with disseminated intravascular coagulation, especially in those with liver failure; it was near normal in patients with metastatic cancer and acute leukemia. Patients with vitronectin levels less than 40% normal invariably had low fibrinogen and antithrombin III and a prolonged prothrombin time. In both normal and patient plasmas there was heterogeneity in the ratio of the 75,000- and 65,000-mol wt polypeptides of reduced vitronectin: 18% had mostly the 75,000-mol wt polypeptide, 59% had roughly equal amounts of the two polypeptides, and 22% had mostly the 65,000-mol wt polypeptide. This polymorphism is inherited and appears to be due to two alleles that are present with approximately equal frequency. The blotting patterns of vitronectin in reduced and nonreduced plasmas were largely unaltered in plasma of patients with defibrination syndrome, fibrinolysis, liver failure, sepsis, metastatic cancer, and acute leukemia. There was no evidence of fragmentation of vitronectin or formation of the disulfide-bonded complex of vitronectin and thrombin-antithrombin III that is found when blood is clotted. Thus these results corroborate in vitro observations that the liver is the major source of plasma vitronectin, suggest that vitronectin may become depleted during disseminated intravascular coagulation, and define a genetic polymorphism of vitronectin.
 ...
PMID:Plasma vitronectin polymorphism in normal subjects and patients with disseminated intravascular coagulation. 245 67

Radiolabeled antithrombin III (ATIII) was incubated at 37 degrees C with purified vitronectin (VN) or fibrinogen-deficient plasma before thrombin was added to initiate complex formation. Incorporation of radiolabeled ATIII was detected using polyacrylamide gel electrophoresis (PAGE) and autoradiography. The PAGE conditions appeared to be crucial for the detection of VN.TAT complexes. In the absence of SDS, ternary complexes formed instantaneously, whereas in the presence of SDS, only 50% of the TAT was associated with VN after a 60-min incubation. Formation of ternary complexes could be confirmed by gel filtration of the plasma to which thrombin was added. Furthermore, TAT in patient plasmas (disseminated intravascular coagulation and sepsis) was found to bind to heparin-Sepharose, indicating that this endogenously formed TAT was also associated with VN. The amino-terminal region of VN and the thrombin moiety of the TAT complex were found to be responsible for their interaction, which was stabilized by disulfide bridges. These results indicate that in normal plasma all TAT is complexed with VN. This association alters the conformational state of plasma VN, which appears to be responsible for the clearance of thrombin complexes from the circulation.
 ...
PMID:Ternary vitronectin-thrombin-antithrombin III complexes in human plasma. Detection and mode of association. 767 52

Native complement factors and complement activation products were measured in healthy neonates (n = 72) and in a group of infants with premature prolonged rupture of the membranes (PPROM) without sepsis (n = 10). Vitronectin concentration in normal cord blood was not correlated with gestational age, and the median value was 86.0% of adult values. This was markedly higher than other native complement factors studied (factor B: 35.9%, C4: 45.1%, C3: 56.2%). The concentration of C9 showed a positive correlation with gestational age and was very low, 10.8% of normal adult values in cord blood and 8.3% in the patients. Fifteen percent of the neonates had C9 levels lower than 2% of adult values. The complement activation products Bb and SC5 b-9 were significantly elevated in the patients (159% and 130% of control values, respectively), indicating alternative and terminal pathway activation. In contrast, C4 bc and C3 bc levels were not increased. The maximum amount of SC5 b-9 which could be generated in the neonatal sera by cobra venom factor was highly correlated with C9 concentration (rs = 0.86, p = 0.0001) The profound C9 deficiency found in neonates is correlated with gestational age, limits the capacity to form bacteriolytic C5 b-9 (m) and may predispose for severe invasive bacterial infection. The plasma level of SC5 b-9 under normal conditions was very low, only 0.3% (0.1%-3.0%) of the values obtained after CVF activation of the same samples. Therefore, we suggest that the analysis of SC5 b-9 is applicable also in neonates, in spite of their extremely low C9 levels.
 ...
PMID:The analysis of the complement activation product SC5 b-9 is applicable in neonates in spite of their profound C9 deficiency. 1076 13

The goals of this chapter are to provide a brief review of the biology of the protein C pathway and some of the features of the pathway that make it uniquely positioned to control microvascular coagulation and control the acute inflammatory response. Activated protein C works as an antithrombotic agent by inactivating factors Va and VIIIa. It is particularly effective at preventing microvascular thrombosis. Platelets may provide a margin of safety for activated protein C as an antithrombotic. Approximately 25% of the factor V/Va in plasma is contained within the platelet and hence resistant to time dependent inactivation by activated protein C. In addition, factor Va bound to the platelet surface is relatively resistant to inactivation by activated protein C. Activated protein C also facilitates clot lysis by inhibiting plasminogen activator inhibitor 1, a process that is accelerated markedly by vitronectin. Inflammatory cytokines like tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) downregulate two key components of the protein C activation complex, thrombomodulin and the endothelial cell protein C receptor resulting in decreased protein C activation. Activated protein C in turn has been shown in several animal models and in vitro to inhibit TNF elaboration in response to endotoxin. This inhibition appears to be due to diminished nuclear factor kappaB (NF kappaB) expression and nuclear translocation. Activated protein C has been shown to reduce the rate of death due to severe sepsis. This reduction may be due to both the anticoagulant effects as demonstrated by a reduction in D-dimer and inflammatory effects as demonstrated by a reduction in interleukin 6.
 ...
PMID:Protein C pathway in sepsis. 1255

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
 ...
PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

Staphylococci can cause a wide spectrum of infections, including endocarditis, osteomyelitis, and sepsis, which is reflected by the numerous virulence factors they produce, among them a recently identified new class of adhesins, namely, the multifunctional autolysins/adhesins. Here we report the identification and molecular characterization of Aaa, a novel autolysin/adhesin from Staphylococcus aureus. The gene encoding Aaa was cloned from the clinical isolate Staphylococcus aureus 4074. DNA sequence analysis revealed that aaa encodes a deduced protein of 334 amino acids with a predicted molecular mass of 35.8 kDa. Aaa contains three N-terminal repetitive sequences that comprise features of a peptidoglycan-binding domain, the LysM domain. The expression of aaa by Escherichia coli and its subsequent characterization revealed that Aaa possesses bacteriolytic activity as well as adhesive properties, such as binding to extracellular matrix proteins. Real-time biomolecular interaction analysis demonstrated that the interaction of Aaa with fibrinogen, fibronectin, and vitronectin is dose dependent and saturable and occurs with a high affinity. Furthermore, we demonstrate that Aaa binds to the Aalpha and Bbeta chains of fragment D of fibrinogen. Immunofluorescence microscopy revealed that Aaa is located at the cell surface. Finally, an aaa knockout mutant showed reduced adherence to surface-adsorbed fibrinogen and fibronectin, strongly suggesting a role for Aaa in the colonization of host factor-coated polymer surfaces and/or host tissue.
 ...
PMID:The multifunctional Staphylococcus aureus autolysin aaa mediates adherence to immobilized fibrinogen and fibronectin. 1604 Sep 92

We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury.
 ...
PMID:Role of phosphatidylinositol 3-kinase-gamma in mediating lung neutrophil sequestration and vascular injury induced by E. coli sepsis. 1618 69

Angiostatin, integrin alphavbeta3, and vitronectin play important roles in inflammation. However, there is very little information on expression of these molecules in the lungs of humans with sepsis. Therefore, as a first step to eventually study the function of these molecules, the authors conducted an immunohistochemical study to evaluate their expression in lungs of normal (N = 8) and sepsis patients (N = 8). In normal lungs, angiostatin expression was minimal in the alveolar septa and alveolar macrophages, and absent in large blood vessels, bronchioles, and interstitium. In sepsis patients, the staining was intense in the septa, neutrophils, alveolar macrophages, and large blood vessels. Integrin alphavbeta3 staining was observed in occasional bronchiolar epithelial cells and a few alveolar macrophages in the normal lungs. The integrin was expressed extensively and intensely in bronchiolar epithelium and alveolar macrophages, and with lesser intensity in large blood vessels in inflamed lungs. Compared to the normal lung, vitronectin expression was increased in alveolar macrophages and in vascular smooth muscles in inflamed lungs. These data show cell-specific increase in the expression of integrin alphavbeta3, angiostatin, and vitronectin in inflamed lungs of sepsis patients. Because all these molecules can have significant influence on inflammation, the data reported in this manuscript create a need for further investigation.
 ...
PMID:Expression of angiostatin, integrin alphavbeta3, and vitronectin in human lungs in sepsis. 1636 51

High molecular weight kininogen (HK) is a plasma protein that is cleaved by plasma kallikrein in the clinical settings of sepsis and chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. This proteolytic event results in a nonapeptide, bradykinin (BK), and a kinin-free derivative of HK, namely HKa. BK promotes angiogenesis by upregulation of bFGF through the B1 receptor or by stimulation of VEGF formation via the B2 receptor. Kininogen-deficient rats show diminished angiogenesis when neovascularization is stimulated. The formation of HKa results in exposure of domain 5 (D5). HKa or D5 inhibit endothelial cell migration and proliferation, both of which are needed for angiogenesis. In the chicken chorioallantoic membrane assay when neovascularization is stimulated by bFGF or VEGF, HKa or D5 inhibit angiogenesis. Monoclonal antibody C11C1, which prevents binding of HK to endothelial cells, also limits its conversion to BK thus downregulating angiogenesis. In vivo, mAb C11C1 inhibits tumor angiogenesis in mice as well as in experimental inflammatory arthritis and inflammatory bowel disease in Lewis rats. In vitro HKa or D5 inhibits endothelial cell adhesion to vitronectin and fibrinogen, resulting in anokis and apoptosis. The HKa receptor, uPAR, forms a signaling complex containing the integrin alphavbeta3 or alpha5beta1, caveolin, Src kinase Yes, focal adhesion kinase and paxcillin. HKa physically disrupts the complex by interfering with the binding of vitronectin to uPAR. Both mAb C11C1 and D5 have potential applications for controlling unwanted angiogenesis in inflammation and cancer.
 ...
PMID:Regulation of angiogenesis by the kallikrein-kinin system. 1684 60

The aim of the present study was to analyze the importance of nontypeable Haemophilus influenzae (NTHi) isolated from patients with sepsis (invasive isolates) compared to nasopharyngeal isolates from patients with upper respiratory tract infection for resistance to complement-mediated attack in human serum and to correlate this result with disease severity. We studied and characterized cases of invasive NTHi disease in detail. All patients with invasive NTHi isolates were adults, and 35% had a clinical presentation of severe sepsis according to the ACCP/SCCM classification of sepsis grading. Moreover, 41% of the patients had evidence of immune deficiency. The different isolates were analyzed for survival in human serum and for binding of 125I-labeled, purified human complement inhibitors C4b-binding protein (C4BP), factor H, and vitronectin, in addition to binding of regulators directly from serum. No significant differences were found when blood-derived and nasopharyngeal isolates were compared, suggesting that interactions with the complement system are equally important for NTHi strains, irrespective of isolation site. Interestingly, a correlation between serum resistance and invasive disease severity was found. The ability to resist the attack of the complement system seems to be important for NTHi strains infecting the respiratory tract as well as the bloodstream.
 ...
PMID:Binding of complement regulators to invasive nontypeable Haemophilus influenzae isolates is not increased compared to nasopharyngeal isolates, but serum resistance is linked to disease severity. 2008 57


1 2 Next >>