Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The effect of supernatant from phorbol myristate acetate (PMA) stimulated human polymorphonuclear granulocytes (PMN) on human factor VII was studied in vitro. The supernatant caused a rapid loss in factor VII coagulant activity by the action of human leukocyte elastase (HLE) and cathepsin G in the supernatant, as demonstrated by the use of specific inhibitors of the two serine proteases, respectively. Preincubation of the supernatant with the elastase inhibitor and the cathepsin G inhibitor preserved 80% and 25% of the clotting activity, respectively. Calcium protected factor VII completely from the supernatant mediated inactivation. Cathepsin G and HLE purified from PMN each destroyed the coagulant activity of factor VII when added to a non-plasma system. There were, however, no effect on factor VII activity when cathepsin G was added to plasma. Polyacrylamide gel electrophoresis in the presence of SDS indicated that HLE and cathepsin G cleaved the zymogen in the same manner, producing (a) peptide(s) of low molecular mass and a single large product of 48 kDa. Preincubation of factor VII with calcium ions inhibited the proteolytic action of HLE and cathepsin G. It is suggested that HLE and cathepsin G from activated granulocytes may be partly responsible for the loss in factor VII activity that is observed during sepsis.
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PMID:Human leukocyte elastase and cathepsin G inactivate factor VII by limited proteolysis. 805 78

1. We investigated the relationship between circulating tumour necrosis factor-alpha concentrations, resting energy expenditure, cachexia and altered intermediary metabolism in patients with cystic fibrosis and chronic pulmonary infection. 2. Twenty adult patients with cystic fibrosis and chronic bronchial sepsis covering a spectrum of severity of lung disease (forced expiratory volume in 1 s 30-100% of predicted) were compared with 10 age matched, healthy, non-cystic fibrosis subjects. 3. Circulating tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex concentrations were determined simultaneously with glycerol, non-esterified fatty acids, catecholamines, anthropometric indices and resting energy expenditure (ventilated hood method). 4. Weight, body mass index and arm muscle mass were reduced in patients with cystic fibrosis compared with healthy control subjects (P < 0.01), whereas mean resting energy expenditure was increased [121 versus 101% predicted, mean difference 19.2% (95% confidence interval 11.0-27.4%), P < 0.001]. Circulating concentrations of glycerol (P < 0.01), non-esterified fatty acids (P < 0.01), adrenaline (P < 0.05), tumour necrosis factor-alpha, C-reactive protein and neutrophil elastase-alpha 1-antiproteinase complex (P < 0.01) were increased in patients compared with control subjects [tumour necrosis factor-alpha 96.9 versus 24.7 pg/ml, mean difference 72.2 pg/ml [95% confidence interval 27.7-116.7 pg/ml), P < 0.001]. Resting energy expenditure was significantly related to tumour necrosis factor-alpha levels and forced expiratory volume in 1 s. 5. In patients with cystic fibrosis and chronic pulmonary sepsis changes in resting energy expenditure, body composition and intermediary metabolism are consistent with the systemic effects of the host inflammatory response, which may be responsible for cachexia in adult patients. In particular these changes are consistent with the action of tumour necrosis factor-alpha, which was detected in the circulation during a period of apparent clinical stability.
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PMID:Tumour necrosis factor-alpha, resting energy expenditure and cachexia in cystic fibrosis. 828 44

A brief explanation of the molecular markers of coagulation, fibrinolysis and endothelial cell activation was done. The clinical significance of markers, such as, soluble fibrin monomer complex, FDP D-dimer, prothrombin fragment 1 + 2, thrombin-antithrombin III complex, plasmin-alpha 2 plasmin inhibitor complex and plasma thrombomodulin in our patients with disseminated intravascular coagulation (DIC) due to abdominal sepsis and malignancy is discussed. The coagulopathy in the DIC patients due to abdominal sepsis had a different aspect from that in the DIC patients due to malignancy. Activation of the coagulation and fibrinolytic systems in sepsis was milder than that in malignancy, despite the decrease of antithrombin III activity in the patients with sepsis. In the patients with sepsis, granulocyte elastase was increased. It was proposed that the coagulopathy was caused not only thrombin formation but also by granulocyte proteinase. It could be expected that the pathophysiology of disseminated intravascular coagulation should be clarified, because of the high sensitivity.
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PMID:[Advancement in the diagnosis of disseminated intravascular coagulation for the surgeon]. 838 85

Adult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dansyl Glu Gly Arg chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase. Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.
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PMID:Recombinant human soluble thrombomodulin reduces endotoxin-induced pulmonary vascular injury via protein C activation in rats. 860 7

With limited resources and the current concerns about using animals for research purposes, the needs must be clear when setting up trauma and sepsis experiments for pharmacologic interventions. Such interventions are performed typically for four reasons: (1) to study the pathophysiologic role of certain mediators (which can be influenced by pharmacologic agents); (2) to study the therapeutic efficacy of treatment strategies; (3) to study the overall safety of new drugs under trauma/sepsis conditions, which are adjunct studies to standard toxicology; (4) to test new diagnostic procedures in a defined trauma or sepsis setting. Intervention in the inflammatory response may be performed at several levels: (1) at the primary induction site (e.g., by antilipopolysaccharide or by preventing complement activation); (2) at the intermediate mediator level (e.g., by antitumor necrosis factor); (3) at the final mediator level (e.g. , by block of polymorphonuclear neutrophil elastase, and (4) at the target (e.g., by membrane stabilization or enhanced antioxidant defense).
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PMID:Animal models as the basis of pharmacologic intervention in trauma and sepsis patients. 866 40

Multiple organ dysfunction syndrome (MODS) is a critical condition developing in the patients under overwhelming surgical insults such as a major surgery, severe trauma, extensive burn, and systemic sepsis. The host response to those surgical insults is the main pathogenetic factor contributing to the development of shock and MODS seen in surgical patients. The proinflammatory cytokines, TNF-alpha (TNF) and interleukin-1 beta (IL-1), are known to play a pivotal role in the pathogenetic mechanisms of MODS. In response to surgical insults, macrophages produce and release TNF and IL-1 which subsequently induce the production of other cytokines (IL-6, IL-8, etc.) and other endogenous chemical mediators (growth factors, adhesion molecules, complement cleavage products, thrombin, eicosanoids, PAF, nitric oxides, oxygen-free radicals, granulocyte elastase, etc.) The resultant systemic inflammation may develop into shock and MODS when the primary insults are overwhelming (early MODS) or a second inflammatory insult such as sepsis triggers an exaggerated inflammation. In the patients suffering from MODS, a systemic release of various cytokines is not properly regulated, and the high blood levels of the proinflammatory cytokines induce an autodestructive generalized inflammatory reaction. This condition is termed "Cytokine Storm" by the author. In the cytokine storm, not only proinflammatory cytokines but also anti-inflammatory cytokines are elevated in the blood stream. With the recent understanding of the biological and pathological roles of cytokines and other mediators, a new therapeutic strategy has been developed. In addition to the reduction of the surgical insults, a variety of anti-cytokine therapy and anti-mediator therapy has been tested in an attempt to prevent or treat the life-threatening MODS.
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PMID:[Cytokine storm in the pathogenesis of multiple organ dysfunction syndrome associated with surgical insults]. 894 Jun 90

Cytokine levels during infection and sepsis have been extensively studied in the past. In contrast to the excellent data on tumour necrosis factor alpha (TNF-alpha), interleukin 8 (IL-8), and polymorphonuclear (PMN) granulocyte elastase (PMN-E) concentrations in blood, little is known about cytokine and PMN-E levels in tissue or local fluids like abdominal exudate in secondary, purulent peritonitis of man. Therefore, the authors studied perioperative intra-abdominal levels of TNF-alpha, IL-8 and PMN-E in 21 patients with severe purulent peritonitis. The average pre-operative levels of TNF-alpha were 694 +/- 239 pg/ml in exudate and 26 +/- 6 pg/ml in plasma, for IL-8 100 +/- 34 ng/ml and 0.7 +/- 0.5 ng/ml, and for PMN-E 68 +/- 14 microg/ml and 0.7 +/- 0.1 microg/ml, respectively. Standard surgical procedures reduced the intra-abdominal concentrations of cytokines and PMN-E to as low as one tenth of the pre-operative levels. Postoperatively, TNF-alpha and IL-8 levels recovered rapidly and pre-operative levels of IL-8 were reached again after 1 h and for TNF-alpha after 8 h. PMN-E concentration remained below the initial baseline within 8 h of observation. TNF-alpha concentration, but not IL-8 or PMN-E, depended on the microbiological load of the abdominal exudate (< or > 10(3) cfu/ml). There were no significant differences in the intra-abdominal or plasma levels of cytokines or PMN-E between survivors and non-survivors at any observation time.
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PMID:Perioperative pattern of peritoneal interleukin 8, tumour necrosis factor-alpha, and granulocyte elastase release in human secondary peritonitis. 911 38

Extravascular fibrin formation and dissolution is a pivotal event in numerous inflammatory and malignant diseases. In inflammatory cells such as monocytes/macrophages, neutrophil granulocytes appear to interact intimately with hemostasis and regulate the activity of the cascade systems of coagulation and fibrinolysis. Proteases such as neutrophil elastase are thought to influence components of hemostasis, and furthermore provide an alternative pathway of fibrinolysis. Histological, experimental, and clinical data suggest that extravascular fibrinolysis, mediated both by the plasmin system and by proteases like neutrophil elastase, is a prominent finding in various diseases such as lung cancer, chronic inflammatory bowel disease, vasculitis and connective tissue disease, bacterial sepsis, and septic shock.
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PMID:The role of inflammatory cells and their proteases in extravascular fibrinolysis. 912 14

We have recently shown that D-dimers are degraded by human neutrophil elastase (HNE) in vitro, causing rapid decrease in the D-dimer levels measured by a Latex test, but not with an ELISA test employing the same monoclonal antibody against D-dimer. To see if such discrepant D-dimer concentrations occurred in patients with high HNE concentration, we examined 80 plasma samples from 8 patients with sepsis with a Latex and an ELISA test and calculated the ratio between the D-dimer values obtained with the two tests. Twenty healthy pregnant and twenty pre-eclamptic patients, who are known to have raised D-dimer but low HNE concentrations, were chosen as controls. HNE levels were estimated by determining the HNE-alpha 1-proteinase inhibitor complex (HNE-A1PI) concentration. HNE-A1PI concentration was increased in sepsis patients compared with pre-eclamptic patients (p < 0.0005) and healthy pregnant women (p < 0.0005). In sepsis patients, the D-dimer results were skewed towards lower ratios between Latex and ELISA values compared to pre-eclamptic patients (p = 0.008) and healthy pregnant women (p = 0.0001). In plasma samples from patients with the largest discrepancy between Latex and ELISA D-dimer values, Western blotting with immunostaining indicated degradation of D-dimers to D-like fragments similar to those observed following degradation of cross-linked fibrin by HNE in vitro. We conclude that in sepsis patients there is a marked discrepancy between Latex and ELISA D-dimer values that may be caused by HNE. In such patients Latex D-dimer assays may cause severe underestimation of fibrinolysis.
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PMID:Discrepancy between latex and ELISA D-dimer values in sepsis may be caused by human neutrophil elastase. 917 35


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