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)

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

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

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

Oxidant-mediated toxicity resulting from acute pulmonary inflammation has been demonstrated in acute lung injury. A potent biological oxidant, peroxynitrite, is formed by the near diffusion-limited reaction of nitric oxide with superoxide. In addition to having hydroxyl radical-like oxidative reactivity, peroxynitrite is capable of nitrating phenolic rings, including protein-associated tyrosine residues. Nitric oxide does not directly nitrate tyrosine residues, therefore, demonstration of tissue nitrotyrosine residues infers the action of peroxynitrite or related nitrogen-centered oxidants. Lung tissue was obtained from formalin-fixed, paraffin-embedded autopsy specimens, and specific polyclonal and monoclonal antibodies to nitrotyrosine were visualized by diaminobenzidene-peroxidase staining. Acute lung injury resulted in intense staining throughout the lung, including lung interstitium, alveolar epithelium, proteinaceous alveolar exudate, and inflammatory cells. In addition, staining of the vascular endothelium and subendothelial tissues was present in those patients with sepsis-induced acute lung injury. Antibody binding was blocked by coincubation with nitrotyrosine or nitrated bovine serum albumin but not by aminotyrosine, phosphotyrosine, or bovine serum albumin. Reduction of tissue nitrotyrosine to aminotyrosine by sodium hydrosulfite also blocked antibody binding. In control specimens with no overt pulmonary disease, there was only slight staining of the alveolar septum. These results demonstrate that nitrogen-derived oxidants are formed in human acute lung injury and suggest that peroxynitrite may be an important oxidant in inflammatory lung disease.
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PMID:Evidence for in vivo peroxynitrite production in human acute lung injury. 769 61

The ability of the vascular endothelium to elaborate cytokines in response to gram-positive sepsis has received limited attention. This study examined cytokine expression by human umbilical vein endothelial cells (EC) following infection with a gram-positive bacterial pathogen, Staphylococcus aureus. S. aureus infection of EC resulted in the production of interleukin-6 (IL-6) and IL-1 beta. For IL-6, message was detected at 3 h after infection, protein was present at 24 h, and both message and protein persisted for 72 h. IL-1 beta message was detected at 12 h, IL-1 beta protein was detected at 24 h, and both persisted for 72 h. Message for colony-stimulating factor 1 remained unaltered. UV-killed S. aureus also elicited IL-1 beta and IL-6 message and protein expression at 24 and 48 h. Twenty-one clinical isolates of S. aureus were tested, and all induced IL-6 release by 48 h. However, the laboratory strain 8325-4 did not induce cytokine expression at any time point and was internalized by EC 1,000-fold less than other strains were. Internalization of latex beads by EC did not induce IL-6 gene expression. Furthermore, cytochalasin D treatment of the EC prevented IL-1 and IL-6 induction by S. aureus but not by tumor necrosis factor alpha or lipopolysaccharide. These results indicate that S. aureus is a potent inducer of IL-1 and IL-6 in EC and that internalization of S. aureus by EC is necessary for their cytokine expression. Thus, our data suggest that the vascular endothelium may play an important role in the pathogenesis of septicemia caused by gram-positive organisms.
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PMID:Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression. 772 92

Adhesion molecules play a critical role in the interaction of circulating neutrophils with vascular endothelium during inflammation. Increased quantities of soluble, circulating intercellular adhesion molecule-1 (cICAM-1) are present in various inflammatory conditions. The purpose of this investigation was to measure cICAM-1 levels in septic adults, as well as to examine the relationship between this potential marker of endothelial-cell activation and the consequences of sepsis (i.e., multiple organ failure and death). Using a sandwich-type enzyme-linked immunosorbent assay (ELISA), we measured cICAM-1 in blood samples obtained within 12 h of admission to an intensive care unit (ICU) for sepsis and other conditions. We found cICAM-1 levels to be increased in 25 septic patients (1,259 +/- 159 ng/ml, mean +/- SEM) as compared with 12 healthy volunteers (355 +/- 41 ng/ml, p < 0.0001) and four ICU patients without systemic inflammatory response syndrome (SIRS) (585 +/- 76 ng/ml, p < 0.001). Twenty-five patients with SIRS but no evidence of causative infection also had elevated levels of cICAM-1 (937 +/- 144 ng/ml, p = 0.12 versus sepsis). Serial measurements over the first week of sepsis demonstrated persistent elevation in most patients. Day 1 cICAM-1 levels were higher (p = 0.017, ANOVA) in 16 patients with septic shock than in seven with severe sepsis and two with sepsis but without hypotension or hypoperfusion. There was a positive correlation (r = 0.50, p = 0.009) between Day-1 cICAM-1 measurements and severity of shock as determined by the presence of hypotension and vasopressor use.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Circulating ICAM-1 is increased in septic shock. 773 95


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