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)

There is increasing evidence that the hypercortisolemia in inflammatory diseases suppresses the elaboration of proinflammatory cytokines, thus protecting the host from its own defence reactions. In severe sepsis and septic shock cortisol levels are usually elevated, but some patients may have relative adrenal insufficiency. This may contribute to the overwhelming systemic inflammatory response syndrome. We evaluated the impact of low-dose hydrocortisone infusion (10 mg/h) on the course of the systemic inflammatory response syndrome. This dose corresponds to a maximum secretory rate of cortisol achieved in corticotropin-stimulated healthy humans. In a prospective observational study 57 surgical patients with severe sepsis or septic shock were studied, of which in addition to the conventional treatment 12 patients were infused with low-dose hydrocortisone, and 45 were treated without any corticosteroid. In the longitudinal analysis the systemic inflammatory response--as judged by body temperature, cardiovascular response, and kinetics of inflammatory mediators such as phospholipase A2, C-reactive protein, and neutrophil elastase--started to differ in favor of the hydrocortisone-treated patients after 2 days of treatment (P < 0.05, Mann-Whitney U test). The difference disappeared after withdrawal of exogenous cortisol. Shock reversal was achieved in all patients treated with low-dose hydrocortisone. The data provide evidence that low-dose hydrocortisone infusion attenuates the systemic inflammatory response in human septic shock. From an immunological point of view a relative cortisol deficiency may contribute to the amplified immune response in systemic inflammatory diseases. A randomized clinical trial must clarify the impact of low-dose hydrocortisone infusion on the clinical course and outcome of septic shock patients.
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PMID:Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group. 786 82

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

In a case-control study in 398 neonates the value of measuring the levels of neutrophil elastase-alpha 1 proteinase inhibitor (EPI) for early diagnosis of neonatal infection was studied in comparison to the commonly used parameters of leukocyte count, ratio of immature to total granulocytes and C-reactive protein levels. Investigations were performed on day 1 or day 6 of life. On the basis of the clinical findings patients were allocated to one of the three following groups: healthy neonates (group A), neonates with local infections such as pneumonia or skin infection (group B) or neonates with septicemia as demonstrated by a positive blood culture (group C). The median EPI levels (with range) measured on day 1 were: group A 40 (15-65) micrograms/l, group B 120 (80-260) micrograms/l, group C225 (140-355) micrograms/l. The levels on day 6 were: group A 27.5 (5-55) micrograms/l, group B 105 (65-370) micrograms/l, group C 182.5 (74-450) micrograms/l. EPI thus discriminated well between healthy neonates and neonates with infection, but not between neonates with infection and neonates with septicemia.
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PMID:Value of measurement of neutrophil elastase-alpha 1 proteinase inhibitor levels in the early diagnosis of neonatal infection. 840 19

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

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

Almost all respiratory diseases except benign lung tumors and lung dysplasia entail acute lung injury. The many clinical conditions associated with acute lung injury include aspiration pneumonia, bacterial pneumonia, and sepsis. The fundamental cause of acute lung injury is pulmonary vascular hyperpermeability. Pulmonary vascular hyperpermeability can be attenuated by nitric oxide and cyclic GMP, and potentiated by oxygen radicals and elastase released from neutrophils. Adhesion molecule inhibition could become an effective therapy against acute lung injury, because the adhesion molecules are very important in the pathogenesis of this condition. Adhesion molecules could also be useful markers of disease activity in various lung diseases. Neutrophil elastase inhibitors may become important as therapeutic agents against acute exacerbations of idiopathic interstitial pneumonia, because this pathological condition is a type of acute lung injury. Similarly, N-acetyl cysteine could also become a useful therapeutic agent against idiopathic interstitial pneumonia, because it is a precursor of glutathione, which is the major antioxidant in the fluid lining of the bronchial epithelium.
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PMID:[Pathophysiology of acute lung injury]. 921 75

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

Recently, we observed that D-dimers are degraded by human neutrophil elastase (HNE) into two D-like fragments, reacting with the monoclonal antibody in an ELISA D-dimer test but not reacting with the corresponding latex D-dimer test. To investigate this in more detail, we studied the degradation of cross-linked fibrin and fibrinogen by plasmin and HNE to see if this resulted in D-fragments or D-like fragments. Degradation of fibrinogen, both by plasmin and HNE, resulted in D- and D-like fragments, respectively, detected by the ELISA D-dimer test. Degradation of cross-linked fibrin by plasmin and HNE also resulted in D- and D-like fragments, which were detected by the ELISA method. Intact D-dimers detected by the latex D-dimer test were only observed after degradation of cross-linked fibrin with plasmin. We conclude that during lysis of cross-linked fibrin as well as fibrinogen by plasmin and HNE, D-fragments, and D-like fragments, detected by the ELISA D-dimer test, are formed. Only during degradation of cross-linked fibrin by plasmin, intact D-dimers, detected by latex D-dimer test, are formed. The ELISA D-dimer test may therefore be used to detect fibrin and fibrinogen degradation products generated by the combined action of plasmin and HNE in sepsis and other conditions with increased HNE activity, while the latex D-dimer test may be used to detect plasmin derived intact D-dimers.
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PMID:Degradation of fibrinogen and cross-linked fibrin by human neutrophil elastase generates D-like fragments detected by ELISA but not latex D-dimer test. 980 64

To investigate the possible role of lipopolysaccharide (LPS, endotoxin) in the pathogenesis of Kawasaki disease, neutrophils from 15 patients with the disease and 7 with sepsis (4 infected with gram-negative bacteria and 3 with gram-positive bacteria) were analyzed by flow cytometry using anti-LPS and anti-CD14 monoclonal antibodies. The number of LPS- and CD14-positive neutrophils was dramatically higher early after the onset of Kawasaki disease and gram-negative sepsis but not with gram-positive sepsis. An immunoprecipitation analysis revealed LPS was bound to CD14 in vivo on neutrophils from Kawasaki disease patients. The mean plasma level of neutrophil elastase was significantly higher in the acute phase of Kawasaki disease than in the acute phase of sepsis. These findings suggest that exposure to LPS occurs at the onset of Kawasaki disease when LPS-bound neutrophils secrete excess protease (implicated in neutrophil-mediated endothelial injury) into the circulation.
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PMID:The role of bacterial lipopolysaccharide-bound neutrophils in the pathogenesis of Kawasaki disease. 987 40


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