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)

The most frequent cause of toxic shock in our area is meningococcal sepsis. It is currently assumed that endotoxin produce by this bacteria, a lipopolysaccharide with toxic properties, is able to trigger shock and DIC by stimulating both arachidonic acid pathways, among other actions. Previous studies in our laboratory demonstrated significant differences (p +/- 0.001) in the amounts of endotoxins released in vitro by strains from patients and healthy carriers and statistically related criteria of severity with mortality in 256 patients in our center over the last 10 years. In the present study we attempted to establish whether plasma levels of endotoxin were correlated with the severity of the disease. We studied 32 patients with meningococcal sepsis, dividing the subjects into two groups: those in whom six or more criteria of severity were present, and those in whom less than six criteria were found. Blood levels of endotoxin were determined upon admission and after the administration of antibiotics (penicillin and chloramphenicol) using the limulus test with a chromogenic substrate (Coatest, Endotoxin, Kabivitrum, Sweden). Levels of endotoxins were significantly higher in patients with more than six criteria of severity both upon admission (0.6 +/- 0.03) ng/ml) and 4 h. afterward (0.74 +/- 0.006 ng/ml) in comparison to children in whom the clinical picture was less serious (0.27 +/- 0.18 ng/ml and 0.27 +/- 0.18 ng/ml and 0.27 +/- 0.16 ng/ml7 t = 5.8 y t = 5.6 respectively. Endotoxin levels were highest in patients presenting shock, disseminated intravascular coagulation in the hypocoagulability phase and more than 8 criteria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Studying the levels of endotoxemia in meningococcal sepsis. Its relations to pregnancy and antibiotic treatment]. 188 9

Monoclonal antibodies (MAb) directed against bacterial lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF) provide partial protection in experimental models of septic shock. To determine if additional benefit accrues from a combination of anti-TNF and anti-LPS MAb in the treatment of septic shock, a neutropenic rat model was developed to study active infection with Pseudomonas aeruginosa 12.4.4. Animals were treated intravenously with an irrelevant MAb (group 1); anti-TNF MAb (group 2); MAb directed against P. aeruginosa 12.4.4 LPS (group 3); or a combination of anti-TNF and anti-LPS MAb (group 4). None of the control animals in group 1 survived the 7-d period of neutropenia (0/16). In contrast, the survival rate was 44% in group 2 (P less than 0.02); 37% in group 3 (P less than 0.05); and 75% in group 4 (P less than 0.0002). The combination of monoclonal antibodies provided greater protection than either MAb given alone (P less than 0.05). Serum TNF levels during infection were significantly greater in groups 1 and 3 (20.1 +/- 3.3 U, mean +/- SE) than in groups 2 and 4 (0.9 +/- 0.8 U, P less than 0.0001). These results indicate that a combination of monoclonal antibodies to LPS and TNF have additive benefit in experimental Pseudomonas aeruginosa sepsis. This immunotherapeutic approach may be of potential utility in the management of serious, gram-negative bacterial infection in neutropenic patients.
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PMID:Efficacy of antilipopolysaccharide and anti-tumor necrosis factor monoclonal antibodies in a neutropenic rat model of Pseudomonas sepsis. 188 75

This study examined lipopolysaccharide (LPS) induced in vitro secretion of interleukin-1 (IL-1) by peripheral blood monocytes from pre-term infants with and without sepsis. Thirteen pre-term babies were tested; eight were completely healthy and five suffered from six episodes of sepsis. The latter group was tested both in the acute septic phase and in the convalescent period. IL-1 secretion by monocytes derived from septic pre-term infants was lower, but not significantly different from healthy pre-term infants (7.1 +/- 1.0 U/ml versus 8.1 +/- 0.9 U/ml, respectively). IL-1 secretion by monocytes of eight control full-term babies was in the same range (8.4 +/- 0.6 U/ml). In the convalescent period IL-1 secretion by monocytes from septic pre-term babies increased (9.0 +/- 0.3 U/ml) and was significantly higher than values measured during acute infection (p less than 0.05). Septic premature babies were also found to have higher absolute blood neutrophil concentration (p less than 0.001), but their body temperature did not increase along the infectious stage. The decreased secretion of IL-1 by monocytes from pre-term babies in the acute phase of infection compared to the convalescent period may have contributed to their inability to mount appropriate immunological as well as inflammatory responses. Sepsis promoting IL-1 production in vivo may have limited the monocytes' capacity for LPS stimulated IL-1 synthesis in vitro.
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PMID:Interleukin-1 secretion by blood monocytes of septic premature infants. 188 67

Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.
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PMID:Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. 193 48

Despite the advent of aminoglycoside and beta-lactam antibiotics and early antimicrobial intervention, overall morbidity and mortality associated with gram-negative sepsis and bacteremia remain high. Complications of sepsis have been related to the release of endotoxin from the cell walls of gram-negative bacilli. Although antibiotics can effectively kill gram-negative bacteria, they have no effect on lipopolysaccharide lipopolysaccharide (LPS) and may, in fact, enhance its release when cell lysis occurs. Lipid A, the lipid portion of LPS, is composed of glucosamines, polar phosphate groups, and fatty acids. It represents the endotoxic component of gram-negative bacteria and is responsible for host responses to LPS, including fever, hypotension, and shock. E5 is a murine monoclonal immunoglobulin M antibody directed against the lipid A portion of the cell-wall endotoxin that is common to clinically important gram-negative bacilli. A clinical evaluation program of E5 included patients who were moderately to severely ill with clinical evidence of an infection usually caused by gram-negative bacteria. In pharmacokinetic and safety studies, laboratory tests revealed no evidence of antibody-mediated toxicity and serum antibody concentrations in the desired therapeutic range (greater than 5 microgramS/mL) were found as late as 72 hours after initial infusion of E5. In a Phase II study, mortality rates at seven days in patients with documented gram-negative infection were 22 percent in the placebo group compared with 7 percent in the E5-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:E5 monoclonal immunoglobulin M antibody for the treatment of gram-negative sepsis. 194 40

The study of the use of standard intravenous immunoglobulin (IVIG) preparations as adjunctive therapy for seriously ill patients is motivated by the need to restore immunoglobulin G depleted because of trauma or surgery and/or by the need to provide patients with specific antibodies to various microorganisms. Whereas no clinical studies have shown that standard IVIG has therapeutic efficacy, some data suggest that its prophylactic use is beneficial. Antisera or IVIG prepared from individuals who are hyperimmunized with the biologically active, highly conserved core portion of the endotoxin of gram-negative bacteria confer variable degrees of protection in animal models and clinical trials. Two clinical trials with use of monoclonal antibodies to core lipopolysaccharide have been completed. Only subsets of patients with gram-negative sepsis were protected by the monoclonal antibodies, but the results of the studies were discrepant in regard to the specific characteristics of patients who benefited from the administration of these antibodies. Further studies will be necessary to establish whether this therapy can be recommended for critically ill patients.
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PMID:Use of immunoglobulins in prevention and treatment of infection in critically ill patients: review and critique. 196 13

The role of tumor necrosis factor-alpha (TNF alpha) in the lethal consequences of intravascular lipopolysaccharide (LPS) or Escherichia coli sepsis was compared with that in bacterial peritonitis. Intravenous administration of E. coli LPS or E. coli (live or dead) resulted in large transient increases in serum TNF alpha levels, peaking at 90 min at 10,000-30,000 units/ml. In contrast, the serum TNF alpha response following the induction of bacterial peritonitis was substantially less, peaking at 200-500 units/ml. Sterile peritonitis (essentially nonlethal) and bacterial peritonitis (greater than 60% lethal) elevated TNF alpha levels to 1000-2000 units/lavage within the peritoneal cavity 2 h after challenge. Passive immunization with neutralizing goat anti-TNF alpha IgG improved survival from 8% to 75% in rats administered LPS intravenously but was completely ineffective in protecting rats from lethal E. coli peritonitis. Thus significant differences exist in the role TNF alpha plays in systemic intravascular models of sepsis and bacterial peritonitis.
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PMID:Divergent efficacy of antibody to tumor necrosis factor-alpha in intravascular and peritonitis models of sepsis. 198 80

Endotoxin (lipopolysaccharide [LPS]) and tumor necrosis factor (TNF-alpha) have been implicated in the pathogenesis of sepsis-induced adult respiratory distress syndrome. To evaluate the possible interaction of the hepatic-pulmonary macrophage axis in the adult respiratory distress syndrome, we compared the kinetics of immunosuppressive prostaglandin E2, TNF-alpha, and interleukin 6 production in LPS-stimulated Kupffer cells and alveolar macrophages (AMs). Interleukin 6 production by Kupffer cells was significantly higher than for equal numbers of AMs. Kupffer cell TNF-alpha levels peaked early before decreasing as regulatory prostaglandin E2 levels rose. In contrast, AM TNF-alpha levels rose sharply and remained significantly higher than for Kupffer cells throughout culture coincident with negligible prostaglandin E2 production. Kupffer cell sequestration of LPS may normally invoke a coordinated cytokine response able to locally induce acute-phase hepatocytes. In hepatic failure, however, LPS spillover to the lung may promote adult respiratory distress syndrome by inducing unregulated AM TNF-alpha production within the pulmonary microenvironment.
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PMID:Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis. 198 33

Diphosphoryl lipid A (DPLA) obtained from the nontoxic lipopolysaccharide (LPS) of Rhodopseudomonas sphaeroides ATCC 17023 did not induce interleukin-1 release by murine peritoneal macrophages. However, it blocked this induction by toxic deep-rough chemotype LPS (ReLPS) from Escherichia coli D31m4. Previously, we obtained similar results on the induction of tumor necrosis factor (TNF) by macrophages. These results showed that DPLA is able to block in vitro the induction of two important mediators of gram-negative bacterial sepsis. We then wanted to determine whether DPLA could also block the induction of TNF by LPS in animals. Mice were treated with 100 micrograms of R. sphaeroides DPLA and challenged 60 min later with 1.0 micrograms of ReLPS from E. coli. The serum TNF level was measured after 60 min. Treatment of mice with this DPLA blocked the rapid and transient rise of TNF caused by ReLPS. This result suggested that R. sphaeroides DPLA might be able to protect animals against endotoxin shock caused by gram-negative bacterial infection.
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PMID:Diphosphoryl lipid A obtained from the nontoxic lipopolysaccharide of Rhodopseudomonas sphaeroides is an endotoxin antagonist in mice. 198 57

While the production of tumor necrosis factor (TNF) and interleukin-6 (IL-6) in septic shock and other inflammatory states is well established, the role of interleukin-8 (IL-8), a recently described neutrophil chemoattractant and activator, has yet to be fully elucidated. Using lipopolysaccharide (LPS)-stimulated human whole blood as an ex vivo model of sepsis, the kinetics of messenger RNA (mRNA) up-regulation and protein release of these cytokines were examined. Two waves of cytokine gene activation were documented. TNF and IL-6 were induced in the first wave with mRNA levels peaking between 2-4 hours and then rapidly declining. TNF and IL-6 protein peaked at 4-6 hours and then stabilized. IL-8 mRNA and protein were induced in the first wave, reached a plateau between 6-12 hours, and rose again in a second wave which continued to escalate until the end of the 24 hour study. These data demonstrate the complex patterns of cytokine gene expression and suggest that production of early mediators may augment continued expression of IL-8 to recruit and retain neutrophils at a site of inflammation.
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PMID:Kinetics of TNF, IL-6, and IL-8 gene expression in LPS-stimulated human whole blood. 198 98


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