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)

Physiological inhibitors were tested for their in vitro interaction with neutrophil proteinase 3 (PR3). The major plasma proteinase inhibitor of PR3 is alpha 1AT. We have developed a radioimmunoassay (RIA) for quantitative detection of PR3-alpha 1AT complexes formed in vivo in inflammatory exudates such as synovial fluid and plasma from patients with sepsis. Levels of PR3-alpha 1AT complexes correlated significantly with levels of human neutrophil elastase (HNE)-alpha 1AT complexes. Thus, in vivo alpha 1AT not only protects against excessive HNE activity, but also against excessive PR3 activity.
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PMID:Determination of proteinase 3-alpha 1-antitrypsin complexes in inflammatory fluids. 145 41

Leukocyte activation is a property of systemic infection. Animal experiments indicate interleukin-1 (IL-1) as a possible modulator, while contradictory results have been reported from in-vitro stimulation of isolated leukocytes. The purpose of the present study was to investigate the activation of isolated polymorphonuclear (PMN) leukocytes in vitro by preparations of recombinant human IL-1 beta and IL-1 receptor antagonist, which in earlier studies could elicit and abrogate, respectively, a sepsis-like syndrome in rabbits. They have also been shown to influence acute phase protein synthesis in mice and rats, and release of leukocyte cathepsin G in vivo. It was found that recombinant human IL-1 beta elicited a dose-dependent luminol-enhanced chemiluminescence response in isolated human PMN leukocytes in the dose range 8.8 x 10(-11)-8.8 x 10(-8) M. The effect could be blocked by prior treatment with the IL-1 receptor antagonist, indicating a direct effect on the specific IL-1 receptor. Preincubation by IL-1 beta enhanced the effect of a secondary challenge with phorbol 12-myristate 13-acetate or formyl-Met-Leu-Phe by 30-40%. The priming effect of rhIL-1 beta could also be blocked by the specific receptor antagonist. In this study, incubation of PMN leukocytes with rhIL-1 beta failed to induce degranulation of both azurophil (neutrophil proteinase 4/proteinase 3) and specific (lactoferrin) granules. rhIL-1 beta has been shown to induce degranulation in vivo, which is thus indicated as an indirect effect. We conclude that IL-1 beta is a direct and specific, but probably weak stimulator of the PMN leukocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of human polymorphonuclear leukocytes by recombinant human interleukin-1 beta. 162 64

Whole-blood chemiluminescence and levels of leukocyte proteases and plasma protease inhibitors were studied in 43 patients with acute, generalized peritonitis. An almost three-fold increase in whole-blood chemiluminescence was found in acute peritonitis, which may indicate activation or "priming" of the leukocytes by blood-borne factors. High levels of leukocyte elastase and neutrophil proteinase 4(3) were found in plasma and peritoneal exudate. Patients with sepsis had higher plasma levels of both proteases than other patients. Large variations in the plasma levels among patients decreased their sensitivity as markers of infectious complications during the postoperative period. The plasma levels of the protease inhibitors followed three different patterns of reaction. The acute phase proteins alpha 1-proteinase inhibitor and C1-inactivator, increased during the first week of disease, to normalise later in its course. alpha 2-macroglobulin, antithrombin III and alpha 2-antiplasmin were all decreased from onset and normalised later in the course, while secretory leukocyte protease inhibitor showed a slow decrease throughout the course of disease. In peritonitis exudate, the levels of the main protease inhibitors, alpha 1-Proteinase Inhibitor and alpha 2-Macroglobulin, were decreased, probably due to complexation and subsequent elimination, as a part of the defense against liberated leukocyte proteases. The immunoreactive and especially functional levels of the protease inhibitors alpha 2-Antiplasmin, Antithrombin III and C1-Inactivator were also decreased in the exudate, indicating an increased turn-over of these proteins through activation of the cascade systems and/or break-down by leukocyte proteases. In contrast to the other inhibitors, secretory leukocyte protease inhibitor showed higher levels in exudate than in plasma, and unexpectedly high exudate/plasma-quotients were seen in cases with colonic perforations. Degradation of complement factor 3 (C3) and decreased "opsonic capacity" were found in exudate. The "opsonic capacity" could be correlated to the levels of leukocyte proteases in the exudate, which indicates that degradation of complement factor 3 may have been at least partly due to the action of leukocyte proteases. Further depletion of complement factors in exudates of long-standing peritonitis or abscesses may create a vicious circle of deficient opsonisation and clearance of bacteria, as earlier reported for chronic pleural exudates.
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PMID:Protease-antiprotease levels and whole-blood chemiluminescence in acute peritonitis. 822 20

Apart from the diagnostic value of anti-neutrophil cytoplasmic antibodies (ANCA), their detailed characterization and that of their corresponding antigens have opened new ways for the exploration of the pathogenesis of primary systemic vasculitis. ANCA are now thought to play an important functional role via activation of phagocytic cells (e.g. polymorphonuclear neutrophils (PMN)). In this study we examined the mechanisms by which ANCA could gain access to proteinase 3 (PR3) in intact PMN, at two levels: ex vivo by analysing the presence of PR3 on the plasma membrane of PMN from patients with ANCA-associated vasculitis, and in vitro by stimulation of PMN using different cytokines, including recombinant tumour necrosis factor-alpha (rhTNF-alpha) and two forms of IL-8 (produced by monocytic and endothelial cells). Using immunocytochemical staining techniques (FACS and immunoelectronmicroscopy) PR3 has been detected on the plasma membrane of PMN from patients with active ANCA-associated vasculitis. However, this phenomenon is also seen in patients with sepsis who do not have ANCA. In addition, TNF-alpha and both forms of IL-8 act synergistically and induce a translocation of PR3 from the intragranular loci to the cell surface of PMN. These results provide strong evidence for the hypothesis that ANCA are directly pathogenic by binding to PR3 which is expressed on the cell surface of primed/activated PMN.
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PMID:Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo. 830 99

Upon stimulation, polymorphonuclear leucocytes (PMNs) release potent serine proteases, i.e. elastase, cathepsin G and proteinase 3, which contribute to the degradation of tissue and plasma components. Here, we describe the development of a plasma test to assess PMN-mediated fibrinogenolysis as a biochemical marker for actual PMN-derived proteolysis in vivo, useful for monitoring therapeutic efficacy, i.e. of elastase inhibitors. We generated a monoclonal antibody (MAb), designated 1-1/B3, with a high affinity for elastase-degraded fibrinogen (EDF). The epitope for 1-1/B3 becomes exposed in a time-dependent manner during digestion of fibrinogen with purified PMN-derived serine proteases and with isolated PMNs in vitro. However, 1-1/B3 does not react with plasma fibrinogen or with fibrin(ogen) degradation products generated by plasmin or by other active proteases that may occur locally, i.e. metalloproteases and lysosomal cathepsins. On the basis of MAb 1-1/B3, we developed a plasma test for the assessment of PMN-mediated fibrin(ogen) degradation products (PMN-FDP). In a panel of control plasmas, we observed concentrations of PMN-FDP of 8.2 +/- 0.9 ng mL-1 (n = 18). These values were increased twofold in patients with alpha 1-proteinase inhibitor deficiency (18.6 +/- 3.3 ng mL-1; n = 12; P < 0.0001) and even more in patients with sepsis (365.7 +/- 97.7 ng mL-1; n = 16; P < 0.0001). Furthermore, synovial tissue extracts from patients with rheumatoid arthritis contained increased levels of PMN-FDP, compared with synovial tissue extracts (P < 0.005) from patients with osteoarthritis.
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PMID:An enzyme immunoassay for polymorphonuclear leucocyte-mediated fibrinogenolysis. 906 9

Antibodies to neutrophil cytoplasmic antigens (ANCA) targeted toward granule enzymes have been recognized as a valuable diagnostic tool in the detection of Wegener's granulomatosis and systemic vasculitides. However, the most commonly used method of detection, the indirect immunofluorescence assay, is prone to false-positive results due to antibodies of different pathological significance either targeted to, or cross-reacting with, similarly distributed epitopes. Using double immunofluorescence, the present study demonstrates that anticytokeratin antibodies are able to produce false-positive C-ANCA immunofluorescence assays. In addition, a case of natural appearance of cytokeratin-reactive antibodies causing a false-positive "pseudo-ANCA" staining pattern in a patient presenting with sepsis is reported. Since the expression of cytokeratins is almost exclusively confined to epithelial cells, the most plausible explanation for both phenomena is a crossreaction of anticytokeratin antibodies with granule associated epitopes. Due to the natural appearance of anticytokeratin antibodies in association with a variety of other pathologic entities, it is of crucial importance for the diagnostic significance of the C-ANCA immunofluorescence assay to exclude anticytokeratin caused false-positive results. It is shown that supplementary indirect immunofluorescence tests performed on cultured human epithelial cells readily distinguish anticytokeratin caused "pseudo-ANCA" from true C-ANCA.
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PMID:Anticytokeratins are a potential source of false-positive indirect immunofluorescence assays for C-ANCA. 948 70

Neutrophil elastase (NE) is a potent serine proteinase whose expression is limited to a narrow window during myeloid development. In neutrophils, NE is stored in azurophil granules along with other serine proteinases (cathepsin G, proteinase 3 and azurocidin) at concentrations exceeding 5 mM. As a result of its capacity to efficiently degrade extracellular matrix, NE has been implicated in a variety of destructive diseases. Indeed, while much interest has focused on the pathologic effects of this enzyme, little is known regarding its normal physiologic function(s). Because previous in vitro data have shown that NE exhibits antibacterial activity, we investigated the role of NE in host defense against bacteria. Generating strains of mice deficient in NE (NE-/-) by targeted mutagenesis, we show that NE-/- mice are more susceptible than their normal littermates to sepsis and death following intraperitoneal infection with Gram negative (Klebsiella pneumoniae and Escherichia coli) but not Gram positive (Staphylococcus aureus) bacteria. Our data indicate that neutrophils migrate normally to sites of infection in the absence of NE, but that NE is required for maximal intracellular killing of Gram negative bacteria by neutrophils.
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PMID:Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. 958 38

Wegener's granulomatosis (WG) is an inflammatory disorder characterized by granulomatous inflammation and vasculitis, and is strongly associated with antineutrophil cytoplasmic antibodies (ANCA). ANCA in patients with WG are directed against proteinase 3 (Pr3) in most of the cases. In vitro, upon neutrophil priming, ANCA antigens are expressed on the cell surface, thereby becoming available for interaction with ANCA. Subsequently, these neutrophils become activated. Since ANCA can only interact with leucocytes when the ANCA antigens are present on the cell surface, we questioned whether Pr3 is already expressed on the membranes of circulating granulocytes and monocytes of patients with WG, and whether Pr3 expression is related to disease activity, so explaining the systemic nature and severity of the disease. The expression of Pr3, and other ANCA antigens, i.e. myeloperoxidase (MPO) and human leucocyte elastase (HLE), was analysed on circulating granulocytes and monocytes by flow cytometry, using a non-activating whole-blood method. Disease activity was quantitated using the Birmingham Vasculitis Activity Score (BVAS). Seventeen patients with active WG and anti-Pr3 antibodies were included in this study. Nine of these patients were also analysed at the time of remission. Twelve patients with sepsis served as positive controls, and 10 healthy volunteers as negative controls for granulocyte/monocyte activation. Pr3 expression on neutrophils was increased in patients with active WG compared to patients with quiescent disease and healthy controls. On monocytes, no differences in Pr3 expression were found between those groups. Furthermore, the expression of MPO and HLE did not differ between patient groups and healthy controls. Upon follow-up, the expression of Pr3 on neutrophils from patients with active WG decreased when patients went into remission. Pr3 expression on neutrophils correlated with the BVAS score (r = 0.40, P < 0.05). In conclusion, circulating neutrophils from patients with active WG have increased expression of Pr3. In addition, the expression of Pr3 correlates with disease activity, suggesting that the availability of Pr3 for interaction with ANCA plays a central role in the disease process.
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PMID:Leucocyte membrane expression of proteinase 3 correlates with disease activity in patients with Wegener's granulomatosis. 973 83

The protein C anticoagulant pathway is critical for controlling microvascular thrombosis and is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. Protein C activation is augmented by an endothelial cell protein C receptor (EPCR). EPCR is shed from the vasculature by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves proteinase 3 and Mac-1 and appears to inhibit leukocyte extravasation. EPCR can undergo translocation from the plasma membrane to the nucleus where it re-directs gene expression. During translocation, EPCR can carry activated protein C (APC) to the nucleus, possibly accounting for the ability of APC to modulate inflammatory mediator responses in the endothelium. TNF-alpha and other inflammatory mediators can down-regulate EPCR and TM. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravasation in response to endotoxin and infusion of APC reverses these processes. In vitro, APC has been reported to inhibit TNF-alpha elaboration from monocytes and to block leukocyte adhesion to selectins. Since thrombin can elicit many inflammatory responses in microvascular endothelium, loss of control of microvascular thrombin generation due to impaired protein C pathway function probably contributes to microvascular dysfunction in sepsis.
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PMID:Coagulation and inflammation. 1283 62

Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Multiple mechanisms are at play including up regulation of tissue factor leading to the initiation of clotting, amplification of the clotting process by augmenting exposure of cellular coagulant phospholipids, inhibition of fibrinolysis by elevating plasminogen activator inhibitor 1 (PAI-1) and decreases in natural anticoagulant pathways, particularly targeted toward down regulation of the protein C anticoagulant pathway through multiple mechanisms. The decreased function of the natural anticoagulant pathways may be particularly problematic because these appear to play a role in dampening inflammatory responses. The protein C anticoagulant pathway provides a useful model for the impact of inflammation on coagulation. This pathway plays a major role in preventing microvascular thrombosis. The pathway is initiated when thrombin binds to thrombomodulin (TM) on the surface of the endothelium. An endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-TM complex more than 10-fold in vivo. EPCR is shed from the endothelium by inflammatory mediators and thrombin. EPCR binds to activated neutrophils in a process that involves proteinase 3 and Mac-1 and appears to inhibit leukocyte extravisation. EPCR can undergo translocation from the plasma membrane to the nucleus where it redirects gene expression. During translocation it can carry activated protein C (APC) to the nucleus, possibly accounting for the ability of APC to modulate inflammatory mediator responses in the endothelium. TNF alpha and other inflammatory mediators can down-regulate EPCR and TM and IL-6 can depress levels of protein S in experimental animals. Inhibition of protein C pathway function increases cytokine elaboration, endothelial cell injury and leukocyte extravisation in response to endotoxin, processes that are decreased by infusion of APC. In vitro, APC inhibits TNF alpha elaboration from monocytes and to block leukocyte adhesion to selectins. Since thrombin can elicit many inflammatory responses in microvascular endothelium, loss of control of microvascular thrombin generation due to impaired protein C pathway function probably contributes to microvascular dysfunction in sepsis.
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PMID:Crosstalk between inflammation and thrombosis. 1943 87


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