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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding of the causes of pulmonary oedema must be based on knowledge of the mechanism responsible for fluid exchange between the several compartments of the normal lung. Recent physiological studies have clarified the main features of these mechanisms. However in three areas knowledge is still incomplete--the magnitude of the hydrostatic and oncotic forces responsible for fluid movement within the lung, the means by which protein leaks across the wall of small pulmonary vessels and the routes by which fluid and protein pass between the interstitial tissues of the lung and the alveolar space. Further work is needed in these areas. On the basis of this physiological knowledge the mode of development of hydrostatic oedema, the role of lymphatics in pulmonary oedema, and the several stages of pulmonary oedema development that may culminate in alveolar flooding are now clearly understood. Knowledge is less complete about oedema due to increased vascular permeability. In some experimental models, such as alloxan, leakage is due to irreversible injury to the alveolar wall; in other models, including ANTU, oedema formation has been shown to depend upon minor and reversible changes in pulmonary vascular endothelium similar to those that cause exudate formation in areas of acute inflammation. In no instance is detailed information available of both the rate and magnitude of protein leakage and of the morphological basis of increased vascular permeability. Further work is required in this area. Present knowledge allows an adequate explanation of the changes that occur in many clinically important types of pulmonary oedema, including cardiac failure and neurogenic pulmonary oedema. Other types of oedema, notably that which may complicate traumatic shock or extrapulmonary sepsis and high altitude pulmonary oedema, are more complex and the details of their pathogenesis are still obscure.
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PMID:Current views on the mechanisms of pulmonary oedema. 36 92

The processes that underlie the coagulopathy observed in severe infection are not fully understood, but seem to be due to an imbalance in the antithrombotic, and prothrombotic properties of the vascular endothelium. Sulphated glycosaminoglycans (GAGs) present on the vessel wall represent an important component of the non-thrombogenic nature of the endothelium. We have modified an amidolytic assay to study the functional ability of GAGs on human umbilical vein endothelial cells (HUVECS), and investigate the effect of E. coli endotoxin and neutrophils on HUVEC surface anticoagulant activity (SAA). Neither endotoxin alone, nor separated neutrophils at lower concentrations (less than 10(6) neutrophils per ml), had major effects on endothelial SAA. When activated neutrophils were incubated with HUVECS pre-stimulated with endotoxin, a significant decrease in SAA was seen using either plasma (mean percentage of control 67.8% +/- sem 7.8; p < 0.02) or purified ATIII (mean percentage of control 69% +/- sem 4.6; p < 0.001). We suggest that alterations in endothelial surface GAGs may occur during sepsis and inflammation, and that this may have important consequences for vascular function. This system will allow the further study of the role of GAGs in the intravascular thrombosis of severe sepsis, and other inflammatory diseases.
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PMID:Reduction of the anticoagulant activity of glycosaminoglycans on the surface of the vascular endothelium by endotoxin and neutrophils: evaluation by an amidolytic assay. 144 May 32

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.
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PMID:Fibrinolytic response to tumor necrosis factor in healthy subjects. 171 36

Respiratory tract infections are major causes of excessive morbidity and mortality in hospitalized patients. Persons with systemic sepsis have an especially high risk of acquiring these infections, which indicates that their lung antibacterial defenses are compromised. To evaluate the effects of sepsis on pulmonary antibacterial defenses, we injected either saline or 5 mg/kg of Escherichia coli lipopolysaccharide intravenously into Sprague-Dawley rats. Two hours later, the animals were challenged by aerosol inhalation with either Staphylococcus aureus or Pseudomonas aeruginosa. It is known that phagocytic defenses against aerosolized S. aureus challenges are provided solely by the alveolar macrophage; in normal animals challenged with P. aeruginosa, however, an intrapulmonary inflammatory response is elicited. Animals pretreated with endotoxin showed a significant decrease in pulmonary bactericidal activity against S. aureus with 31 +/- 3% bacteria remaining viable at 4 hr compared with 20 +/- 2% in the controls, which indicates a defect in alveolar macrophage antimicrobial activity. After P. aeruginosa challenge, saline-injected control animals developed a marked intrapulmonary inflammatory response and killed greater than 85% of their initial inoculum by 4 hr. By contrast, endotoxin-treated animals failed to recruit neutrophils into the alveoli in response to P. aeruginosa, resulting in a proliferation of this pathogen within the lung (212 +/- 6% bacteria remaining viable at 4 hr). Endotoxin is known to be a potent stimulus for the production of tumor necrosis factor (TNF) by the host. TNF is a potent inflammatory mediator and promotes neutrophil adhesion to the vascular endothelium. In these experiments, serum TNF peaked at 28,390 +/- 7,766 Units/ml. 90 min after intravenous endotoxin. Histopathology of the lungs in these animals showed considerable sequestration of the neutrophils within the pulmonary vasculature. These data show that systemic endotoxin significantly impairs lung host defenses against intrapulmonary bacterial challenges and suggest that TNF-mediated events may play a central role.
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PMID:Endotoxin-induced suppression of lung host defenses. 212 Mar 77

We have investigated the effects of recombinant human tumor necrosis factor-alpha (rhTNF alpha) on polymorphonuclear leukocytes (PMNs), concentrating on the mechanisms involved in the alterations of PMN-directed migration and adherence by this cytokine. RhTNF alpha profoundly suppressed PMN chemotaxis toward FMLP by 80%. At similar concentrations, it enhanced adhesion to gelatin-coated plastic dishes by more than tenfold and increased the expression of the CD11b antigen to 182% of the control. The monoclonal antibody 60.1, which is directed against the alpha chain of the CD11b/CD18 complex, completely blocked rhTNF alpha, induced inhibition of the chemotactic response to FMLP, and rhTNF alpha induced hyperadherence, suggesting that these effects were related to rhTNF alpha's effects on CD11b antigen expression. The fluid state of the PMN membrane was also decreased by rhTNF alpha. N-butanol, a known membrane fluidizer, partially inhibited the effect of rhTNF alpha on membrane fluidity and chemotaxis and completely reversed its effects on adherence and the expression of the CD11b antigen. Pentoxifylline, an agent that has previously been studied for its ability to prevent some effects of rhTNF alpha on PMNs, completely prevented the effect of rhTNF alpha on chemotaxis, the expression of the CD11b antigen, and membrane fluidity. Pentoxifylline partially prevented changes in adherence caused by this cytokine. Increased CD11b antigen expression caused by rhTNF alpha may result in enhanced PMN adhesion and suppression of migration. These events may, in turn, lead to the accumulation of PMNs on the vascular endothelium, resulting in the extensive vascular and tissue damage that is seen in gram-negative sepsis.
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PMID:Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration. 218 25

Coculture of endothelial and smooth muscle cells was used to study effects of endotoxin on depolarization-induced Ca2+ transients in fura-2-loaded individual smooth muscle cells. Although endotoxin did not modify the response of cultured smooth muscle cells to depolarization, endotoxin resulted in an attenuation of cytosolic Ca2+ (Cai2+) transients in response to K+ depolarization and failure of KCl-induced contractions in smooth muscle cells when they were cocultured with endothelial cells. The observed endothelial modulation of smooth muscle responses was not accomplished via gap junctions. The possible role of free radical species secreted by endothelial cells in conditioning of smooth muscle responses to depolarization was supported by the results of three sets of experiments: 1) endothelial cells did respond to endotoxin with oxidative burst, 2) pretreatment of cocultured cells with catalase prevented endotoxin-induced downregulation of Ca2+ transients, and 3) in isolated smooth muscle cells, the addition of hydrogen peroxide virtually abolished depolarization-induced Ca2+ transients. Hence vascular endothelium stimulated by endotoxin generates reduced oxygen intermediates, which in turn downregulate depolarization-induced Cai2+ transients in smooth muscle cells. This phenomenon may contribute to the development of hypotension in septicemia.
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PMID:Role of endothelium in endotoxin blockade of voltage-sensitive Ca2+ channels in smooth muscle cells. 255 35

Escherichia coli strains that cause sepsis and meningitis in neonatal infants carry S fimbriae that bind to sialyl galactoside units of cell surface glycoproteins. To investigate the possible role of S fimbriae in determining the tissue tropism of neonatal meningitis, we have studied the presence of binding sites for S fimbriae in different tissues of the neonatal rat which is susceptible to meningitis caused by S-fimbriated E. coli. Purified S fimbriae were incubated on cryostat sections of different rat organs and their binding was assessed by indirect immunofluorescence. In the brain of the neonatal rat, S fimbriae specifically bound to the luminal surfaces of the vascular endothelium and of the epithelium lining the choroid plexuses and brain ventricles. The binding was completely inhibited by the trisaccharide NeuAc alpha 2-3Gal beta 1-4Glc, a receptor analogue of S fimbriae, and by a preceding neuraminidase treatment of the sections. A recombinant E. coli strain expressing S fimbriae adhered in large numbers to the same tissue sites in the neonatal brain sections as did the purified fimbriae, whereas the non-fimbriated host strain and a recombinant strain expressing P fimbriae did not adhere to brain tissues. The results suggest that adhesion of S-fimbriated bacteria to the binding sites observed in the neonatal brain has a pathogenetic role during bacterial invasion from circulation into the cerebrospinal fluid.
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PMID:Binding sites in the rat brain for Escherichia coli S fimbriae associated with neonatal meningitis. 289 10

von Willebrand factor (vWF), a large adhesive glycoprotein, is synthesized by vascular endothelial cells (EC). Plasma levels of vWF manifest a broad normal range, and are elevated during sepsis and in inflammatory states. Since the inflammatory mediator, interleukin 1 (IL1) and bacterial endotoxin (LPS) both initiate procoagulant changes in vascular endothelium, we investigated the effect of these substances on endothelial cell release and residual endothelial cell content of vWF-antigen (vWFAg). Cultured human EC exposed to either IL1 or LPS released greater amounts of vWFAg compared to control EC. The augmented release could be detected within 1-2 h after exposure to IL1 or LPS and was not inhibited by cycloheximide, suggesting that de novo protein synthesis was not required for release to occur. Residual cellular vWFAg was reciprocally lower in IL1- or LPS-treated EC at 24 and 48 h, indicating that compensatory increase in synthesis of vWFAg did not occur during this time interval. Released vWF contained the higher molecular weight multimers observed in normal endothelial cells, and it possessed ristocetin cofactor activity. We propose that release of functional vWF from EC exposed to inflammatory mediators may be at a mechanism for localization of platelets and enhanced thrombogenicity at inflammatory foci.
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PMID:Interleukin 1 or endotoxin increases the release of von Willebrand factor from human endothelial cells. 349 29

In this study, we compared responses to norepinephrine (NE) by thoracic aortic rings isolated from rats made septic by cecal ligation with puncture, and aortic tissue from sham-operated control rats. We also examined the responses of septic and sham-operated rat aortas after removal of the vascular endothelium. Acetylcholine caused relaxation of NE-induced contractions in septic and sham tissue with an intact endothelium but had no effect on tissue with the endothelium removed experimentally. In preparations with intact endothelium, septic tissue manifests a significantly diminished maximal contractile response to NE (424 +/- 62 (SE) mg tension/mg tissue) in comparison to sham tissue (747 + 30). Tissues with the endothelium removed show no significant maximal contractile difference between septic (688 +/- 23) and sham (669 +/- 32) preparations, or the equivalent sham tissue with an intact endothelium. No difference in the log ED50 for sham tissue (-7.33 +/- 0.12 M) and septic tissue (-7.53 +/- 0.15) with intact endothelium existed. Removal of the endothelium from both septic and sham tissue shifted the dose response curves to the left, disclosing a significant difference in the ED50 between sham (-8.88 +/- 0.14) and septic (-8.18 +/- 0.20) tissue. In conclusion, a significant impairment of vascular contractility in response to NE, with no change in ED50, persists in septic vascular tissue in vitro, and the sepsis-induced defect in contractility is mediated, at least in part, by vascular endothelium, since removal of the endothelium partially restores the NE-stimulated contraction to normal.
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PMID:Vascular endothelium contributes to decreased aortic contractility in experimental sepsis. 373 2

Severe infections and particularly infectious shock are frequently accompanied by a varying degrees of disseminated intra-vascular coagulation (DIC). The mechanism at work is complex, involving endotoxin or bacterial lipopolysaccharide constituents that damage vascular endothelium and activate intrinsic coagulation, platelet function and the release of leucocyte coagulation-promoting compounds. The activation of coagulation in turn activates prekallikrein and complement and plays a part in shock. The laboratory plays an essential role in diagnosing DIC, determining its repercussions on the parameters of haemostasis and in monitoring its course under antibiotics, which in some cases may be combined with carefully controlled heparin treatment. Sensitive and specific tests are the assays for fibrinogen-fibrin degradation products (FDP) and soluble complexes (SC) using the haemagglutination test or the ethanol test. The platelet count should be combined with measurement of the bleeding time. A varying degree of thrombopenia is frequent but non specific. In cases of septicemia, it is an early warning sign. A selective fall in proaccelerin is an indirect early sign. A fall in antithrombin III (AT III) is considered a good sign of DIC but it does not occur in every case, and is most liable to be present in liver failure. From the FDP and fibrinogen results, it should be clear whether one is dealing with compensated, decompensated or even over-compensated DIC. Diagnosis should be complemented by a careful search for the clinical signs of coagulation and haemorrhage. It is indispensable for investigations to be repeated every 6-12 hours, for the sake both of treatment strategy, which can be extremely difficult, and DIC monitoring.
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PMID:[Diagnosis of defibrination syndromes in infectious pathology]. 673 53


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