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)

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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
PMID:The role of bacterial lipopolysaccharide-bound neutrophils in the pathogenesis of Kawasaki disease. 987 40

Almost all of respiratory diseases except benign lung tumors and lung dysplasia entail acute lung injury (ALI). The many clinical conditions associated with acute lung injury include aspiration pneumonia, bacterial pneumonia and sepsis. Acute lung injury is the end results of common pathways initiated by a variety of local or systemic insults leading to diffuse damage to the pulmonary parenchyma. Despite the accumulation of abundant information regarding the physiological and cellular basis of lung injury and increasing sophisticated intensive care, an improvement in prognosis has lagged behind. It has become clear that there is not one mediator responsible for ALI, but rather a complex interplay exists between diverse proinflammatory (e.g., lipopolysaccharide, complement products, cytocains, chemocains, reactive oxygen species and arachidonic acid products) and anti-inflammatory (IL-10, IL-1-RA, PGI2) mediators. Early in the course of ALI, large numbers of neutrophils are sequestered in and emigrate from the pulmonary capillaries. The fundamental cause of ALI is pulmonary vascular hyperpermeability caused by the activated neutrophils which release oxygen radicals and proteases. In these processes several adhesion molecules play very important roles. Neutrophil elastase inhibitors become very useful therapeutic agents against acute exacerbation of idiopathic interstitial pneumonia (IIP), because this pathological conditions is a type of ALI. Similarly, N-acetyl cystein could also become a useful therapeutic agent against IIP, because it is a precursor of glutathione, which is the major antioxidant in the fluid lining of the bronchial epithelium.
 ...
PMID:[The 74th Annual Meeting President Lecture. Pathogenesis and therapy of acute lung injury]. 1053 83

In determining the mechanism of neutrophil elastase (NE)-mediated killing of Escherichia coli, we found that NE degraded outer membrane protein A (OmpA), localized on the surface of Gram-negative bacteria. NE killed wild-type, but not OmpA-deficient, E. coli. Also, whereas NE-deficient mice had impaired survival in response to E. coli sepsis, as compared to wild-type mice, the presence or absence of NE had no influence on survival in response to sepsis that had been induced with OmpA-deficient E. coli. These findings define a mechanism of nonoxidative bacterial killing by NE and point to OmpA as a bacterial target in host defense.
 ...
PMID:Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase. 1094 84

Acute respiratory distress syndrome (ARDS), is characterised by capillary permeability and pulmonary oedema formation and may complicate a variety of medical and surgical illnesses. As a self-perpetuating state of inflammatory derangement, acute lung injury (ALI)/ARDS is manifest clinically as rapid development of radiographic infiltrates, severe hypoxaemia and reduced lung compliance. Over the years, researchers have made significant progress in elucidating the pathophysiology of this complex syndrome. Therapies targeting specific pathophysiologic steps in the development or persistence of this syndrome are in various stages of laboratory and clinical testing. Results to date have shown nitric oxide (NO) to improve oxygenation in the majority of patients but fail to improve mortality. Surfactant replacement has had limited success in adults, but new formulations and delivery methods may prove beneficial. Several inflammatory mediator-targeted therapies have progressed successfully through early clinical evaluation. Among these, neutrophil elastase inhibitors have shown the most promise and are currently undergoing Phase III trials. Other mediator-targeted therapies, such as prostaglandin E1, IL-10 and platelet activating factor antagonists, have not been found efficacious in large clinical trials of ARDS. However, these therapies, along with coagulation modulators, may have a favourable impact on ARDS by improving outcomes in sepsis, the greatest risk factor for developing this condition. In the interim, supportive care through improvements in mechanical ventilation are beneficial, while specific fluid balance and nutrition strategies may prove advantageous.
 ...
PMID:Clinical developments for treating ARDS. 1177 19

We determined the concentration of umbilical cord blood neutrophil elastase (EN) in 143 neonates. The infants were divided into four groups: A - Term non-infected, B - Term infected, C - Preterm non-infected, D - Preterm infected. In the study a low concentration of cord blood elastase in premature children was found. It was significantly lower in preterm non-infected (p<0.001) and infected (p<0.05) neonates than in non-infected term children. In full-term infected neonates mean concentration of elastase was markedly (p<0.001) higher as compared to term healthy ones. 87% values of cord blood elastase measured in full-term infected neonates and 6% in preterm ones exceed the upper limit reference interval (209.3 ug/L) while 97% measurements in preterm neonates (all with and without clinical signs of infection) were within the reference range. We conclude that significant differences in elastase level in the cord blood depend on age of gestation at delivery. These age-dependent differences of elastase concentration can be taken into consideration and examination of cord blood elastase concentration may provide a valuable indicator in early diagnosis of sepsis in neonates. In full-term neonates cord blood neutrophil elastase is a good marker of infection.
 ...
PMID:[Neutrophil elastase level in cord blood and diagnosis of infection in mature and premature neonates]. 1217 9


<< Previous 1 2 3 4 5 6 7 Next >>