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

Endotoxin (bacterial lipopolysaccharide, LPS) is paradoxically both inflammatory and antiinflammatory. A single intravenous injection of 100 micrograms Escherichia coli LPS markedly inhibits the inflammatory changes associated with cutaneous reversed passive Arthus (RPA) reactions in New Zealand white rabbits. Polymorphonuclear (PMN) leukocytes from LPS-treated rabbits exhibit diminished responsiveness in vitro to complement (C5) -derived peptides. Repeated injections of LPS render animals "tolerant", that is, refractory to the toxic and inflammatory effects of LPS. We examined whether tolerance would enhance the ability of LPS to inhibit inflammation not attributable to LPS. Surprisingly, as compared with rabbits receiving a single dose of LPS, tolerant rabbits demonstrated greater inflammatory changes (i.e., PMN exudation, vascular permeability) associated with RPA reactions. PMNs from LPS-tolerant rabbits responded in vitro to C5-derived peptides significantly more than PMNs from rabbits that received a single dose of LPS. We speculate that some antiinflammatory effects of LPS require the toxic or inflammatory effects of LPS itself. These observations might relate to the limited efficacy of fever therapy and the variable effects of gram-negative sepsis on functions of human PMNs.
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PMID:Endotoxin tolerance diminishes certain antiinflammatory effects of endotoxin. 293 63

Alterations in macrophage function may render the immunocompromised host more susceptible to infectious complications. Although allograft recipients are at increased risk of infection primarily because of pharmacologic immunosuppression, whether the process of allosensitization per se alters this risk is unknown. We therefore studied the effects of cloned allosensitized murine helper or cytotoxic T cells on both interleukin 1 (IL-1) and prostaglandin E2 (PGE2) production by syngeneic resident murine peritoneal macrophages. Endotoxin (lipopolysaccharide [LPS]) stimulated both IL-1 and PGE2 production in macrophages. Cloned T cells alone, with or without LPS pretreatment, produced neither IL-1 nor PGE2. After 48 hours of coculture with LPS-treated macrophages, cloned helper cells augmented IL-1 release by macrophages but inhibited PGE2 production. In contrast, cytotoxic T cells not only reduced IL-1 production by macrophages but also potentiated PGE2 release. These effects were not observed when macrophages were not first exposed to LPS. Thus, endotoxin renders macrophages more susceptible to allosensitized "help" (increases IL-1, decreases PGE2) or "suppression" (decreases IL-1, increases PGE2) by cytotoxic T cells. We hypothesize that, even in the absence of immunosuppression, the process of allosensitization itself may modulate the response to sepsis by altering host macrophage function.
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PMID:Allosensitized helper and cytotoxic T-lymphocyte clones differentially modulate endotoxin-stimulated macrophage function. 296 2

Tumor necrosis factor alpha (TNF), a monokine produced by mononuclear cells in response to bacterial endotoxin (LPS), creates a syndrome similar to septic shock in animal models. To study whether TNF could induce acute lung injury similar to that seen in gram-negative sepsis, we injected recombinant human TNF (rHuTNF alpha) into guinea pigs and monitored arterial blood gases, leukocyte counts, and left atrial (Pla), pulmonary artery (Ppa), and mean arterial pressures (MAP) serially for 8 h. Pulmonary histopathology was assessed microscopically, and cell counts and 125I-labeled albumin (125I-albumin) in bronchoalveolar lavage (BAL) fluid and lung wet/dry weight ratios were determined. Five groups of animals were studied; the 2 TNF groups received high (1.4 X 10(6) U/kg) or low (1.0 X 10(6) U/kg) doses of rHuTNF alpha, the sepsis group received 2 X 10(9) Escherichia coli/kg intravenously, and the control group received saline. An LPS control group receiving 40 ng/kg E. coli LPS was also included because the rHuTNF alpha contained a small amount of LPS as a contaminant. Pulmonary permeability was assessed by studying the Pla and the BAL fluid/plasma 125I-albumin ratio (permeability index). The permeability index was significantly increased in the high-dose TNF (0.0408 +/- 0.0041, p less than 0.05) and sepsis groups (0.0466 +/- 0.0068, p less than 0.01) relative to controls (0.0215 +/- 0.0028). The wet/dry lung weight ratios were also significantly increased in the high-dose TNF (6.07 +/- 0.29, p less than 0.05) and sepsis groups (6.22 +/- 0.30, p less than 0.05) relative to the control group (5.18 +/- 0.20).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor causes increased pulmonary permeability and edema. Comparison to septic acute lung injury. 305 59

Sixty-four infections due to Pseudomonas aeruginosa in patients of a respiratory intensive care unit were studied. The length of serologically latent period following the appearance of P. aeruginosa decreased with the growing severity of the infection, however, the longest latent period occurred in lethal cases. As the phase of development of peak anti-LPS antibody titres was constant in each group, in fatal infections the serological response developed too late when sepsis had already started. The duration of the persistence of peak titres was also stable. In consequence of a close negative correlation between these two latter parameters, the period from the onset of antibody increase till the beginning of decrease was especially constant, independent of the severity of infection, the duration of the antigenic stimulus and the intensity of the serological response. The rate of decrease was an another stable value. All these refer to an endogenous, time-dependent regulation which, despite existing clinical symptoms and the presence of P. aeruginosa, starts anti-LPS antibody level to decline. Pseudomonas carrier state in convalescence was observed in cases with prolonged persistence of peak titre and with a lower rate of titre decrease.
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PMID:Phases of the serological response in Pseudomonas aeruginosa infections. 312 15

Leukopenic, immunosuppressed recipients of solid organ allografts are at high risk for gram-negative bacterial sepsis, and mortality remains unacceptably high (greater than 30%). The purpose of this study was to determine whether murine monoclonal antibody (MAb) directed against lipopolysaccharide (LPS, endotoxin) would reduce lethality caused by a septic insult in immunosuppressed mice, and to determine if a specific antibody class would prove more efficacious in this setting. Two MAbs (3-H9, IgG3; 7-B5, IgM) were selected that reacted by ELISA, immunodot blot, and Western blot analysis against the O antigen polysaccharide portion of Escherichia coli 0111:B4 LPS. The 3-H9 MAb, 7B-5 MAb, or sterile saline was administered i.v. to normal or neutropenic Swiss-Webster mice immediately prior to an E coli 0111:B4 bacterial (i.v. or i.p. plus hemoglobin) or LPS (i.v.) challenge. In normal mice, administration of 3-H9 MAb or 7-B5 MAb i.v. immediately prior to a bacterial or endotoxin challenge resulted in a significant increase in the LD50. Neutropenia lowered the LD50 by nearly one log10 in both the bacteremia and peritonitis models. Both MAbs provided similar protection, raising the LD50 one log10 in neutropenic mice. Thus neutropenic animals receiving either MAb had a mortality nearly identical to that of normal animals receiving saline. No significant difference between the protective capacity of these MAbs was noted in any of the three models. These studies demonstrate that MAbs directed against LPS exert protection during gram-negative bacterial sepsis in either normal or neutropenic animals. In addition, the particular IgG and IgM MAbs examined provided similar protective capacity. Antibody directed against LPS may provide an additive form of therapy that may serve to decrease lethality during clinical gram-negative sepsis in immunosuppressed patients.
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PMID:Antibody immunotherapy of gram-negative bacterial sepsis in an immunosuppressed animal model. 327 38

Chronic sepsis was induced by administering endotoxin (lipopolysaccharide--LPS) at 12-hr intervals to sheep. The animals (n = 7) responded to the first dose of LPS with increased pulmonary arterial pressure (PAP), systemic vascular resistance, plasma and lymph thromboxane B2 (TxB2) concentrations, and lung lymph flow rate concurrent with a reduction in the cardiac index (CI). Subsequent doses of LPS produced an elevation of PAP and TxB2 which was progressively attenuated and eventually disappeared. With LPS the lung lymph flow was markedly elevated and CI increased. This latter was transient and associated with a reduction in systemic vascular resistance. Concomitant with the cardiopulmonary changes prekallikrein levels were not diminished, but there was a statistically significant reduction in C1-esterase inhibitor. The administration of LPS was discontinued after 5 days and the cardiopulmonary variables rapidly returned to baseline levels. Chronic endotoxemia appears to be associated with an elevated pulmonary microvascular permeability and a tendency toward a hyperdynamic circulation but with an appreciable degree of refractoriness associated with regional hemodynamics and eicosanoid biosynthesis.
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PMID:Cardiopulmonary changes with intermittent endotoxin administration in sheep. 329 76

Gram-negative bacterial sepsis continues to represent a significant cause of morbidity and mortality in hospitalized patients. Currently available medical therapy (antimicrobial agents, hemodynamic monitoring, aggressive fluid resuscitation, and nutritional support) for this disease process has reduced but not eliminated the severe consequences that may ensue. Recent investigations have demonstrated the ability of antibody directed against gram-negative bacterial lipopolysaccharide (LPS or endotoxin) to afford protection during experimental gram-negative bacillary sepsis. The core LPS-lipid A portion of endotoxin represents a determinant shared by many common gram-negative microorganisms that is luxuriantly expressed on the cell surface of rough mutants of Escherichia coli and Salmonella minnesota. These organisms or the outer membrane LPS isolated from them thus represent suitable immunogens for the development of cross-protective antibody preparations. Large quantities of highly cross-reactive antibody may potentially be obtained from several sources: murine or human monoclonal antibodies, immunization of large animals or humans with subsequent plasmapharesis and antibody isolation, affinity purification of large amounts of normal antibody, and pooling of prescreened lots of normal animal or human antibody that react to a particular bacterial antigen.
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PMID:Antibody immunotherapy of gram-negative bacterial sepsis. 329 99

Rabbits were injected intraperitoneally with sterile saline or Escherichia coli endotoxin (LPS; 50 or 500 micrograms/kg). Sixteen to 18 h later, the animals were anesthetized with ketamine and instrumented to permit measurement of mean arterial pressure, cardiac output (by thermodilution), and regional blood flow (using radioactive microspheres). The animals were allowed to waken fully in a plastic restraining cage prior to measuring systemic and regional hemodynamics. LPS had similar effects regardless of dose, and results from the two dosage groups have been combined. Compared to controls, administrations of LPS resulted in a 29.3% increase in cardiac output (P = .011) and a 22.8% decrease in systemic vascular resistance (P = .0009). Injection of LPS caused significant changes in blood flow to the heart (55.3% increase), small intestine (128.3% increase), portal vein (54.7% increase), and hepatic artery (65.0% decrease). The percentage of cardiac output perfusing the kidneys and hepatic artery was significantly decreased in the endotoxemic group (P = .037 and P = .002, respectively). Injecting LPS resulted in increased relative flow to the heart (P = .024), small intestine (P = .049), and portal vein (P = .041). We conclude that this model reproduces several of the systemic hemodynamic features of the sepsis syndrome in humans. In this model, the hyperdynamic state is associated with vasodilatation in mesenteric (small intestine and colon) and coronary beds and vasoconstriction in the hepatic artery.
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PMID:Systemic and regional hemodynamic changes after intraperitoneal endotoxin in rabbits: development of a new model of the clinical syndrome of hyperdynamic sepsis. 330 Oct 51

Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was associated with development of hypotension, focal hepatic necrosis, intravascular fibrin deposition and lethality. Based on (a) the peak levels of TNF observed in serum, 2.5 X 10(3) U/ml, (b) the specific activity of purified rabbit macrophage-derived TNF, 1 X 10(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t1/2 = 0.5 min, 11 min) we constructed a kinetic model showing that at least 130 micrograms of TNF (1.3 X 10(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock.
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PMID:Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. 338 55

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


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