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

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

Much effort has been directed toward elucidating the host response to sepsis and inflammation, resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8, a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines, appears in the circulation of primates in vivo during septic shock, sublethal endotoxemia, and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult, and levels of IL-8 peak relatively late, after those of TNF-alpha and IL-1 beta, and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils, and we demonstrate that after LPS or IL-1 alpha infusion, circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal, supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and, as such, may play a significant role in host defense and disease.
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PMID:IL-8 in septic shock, endotoxemia, and after IL-1 administration. 202 76

Human recombinant interleukin-1 alpha (IL-1) has a diverse range of physiological activities which may be beneficial or deleterious to the host. Pretreatment with doses of IL-1 has been shown to protect mice against a subsequent lethal bacterial injection; however, the protective effects of a single intravenous (iv) dose of IL-1 have not been well characterized. The current experiments were performed to determine the best dose, timing, and duration of action of a single iv dose of IL-1 against a subsequent lethal challenge with intraperitoneal endotoxin (LPS) or experimental sepsis induced by cecal ligation and puncture (CLP). Female C57B1/6 mice treated with iv IL-1 24 hr prior to 30 mg/kg LPS ip had improved survival compared to saline-treated controls (P less than 0.01). IL-1 was also protective when given 6 to 72 hr, but not 2 or 96 hr, prior to LPS. IL-1 protection against LPS lethality was similar to protection seen with an iv dose of tumor necrosis factor (TNF). After CLP, survival was improved with IL-1 versus saline pretreatment (P = 0.02). Unlike previous work with TNF, no toxicity or lethality was observed at any dose of IL-1 administered. A single iv dose of IL-1 protects against the lethality of LPS and CLP in mice. IL-1 may be a useful treatment strategy in patients at risk for the development of life-threatening sepsis.
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PMID:Human recombinant interleukin-1 alpha protection against the lethality of endotoxin and experimental sepsis in mice. 203 79

We tested the hypothesis that substitution of omega-3 fat for dietary omega-6 fat would reduce mortality and decrease Kupffer cell prostaglandin E2 (PGE2) production in a rat model of chronic sepsis. Rats were fed via gastrostomy for 12 days with isonitrogenous, isocaloric diets containing 15% of calories as either safflower oil (omega-6) or a 10:1 mixture of menhaden oil (omega-3) and safflower oil. After five days of feeding, animals received an intra-abdominal abscess of defined bacterial content. Survivors were killed on post-laparotomy day 6 in conjunction with liver perfusion and protease liver digestion for Kupffer cell isolation. Kupffer cell PGE2 production was measured by radioimmunoassay after 18 hours of cell culture and again after stimulation with 0 LPS, 10 ng/ml LPS, and 10 micrograms/LPS. Mortality was decreased in menhaden oil-fed animals compared with safflower oil-fed animals (16% vs. 35%). Kupffer cell PGE2 production was decreased in menhaden oil-fed animals at 18 hours (354 +/- 54 vs. 570 +/- 95 pg/0.1 ml; p = 0.09) and after stimulation with 10 micrograms/ml LPS (140 +/- 41 vs. 288 +/- 45 pg/0.1 ml; p = 0.03) compared with safflower oil-fed animals.
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PMID:Dietary omega-3 fatty acids decrease mortality and Kupffer cell prostaglandin E2 production in a rat model of chronic sepsis. 205 40

Endotoxin induces alterations in the neonatal red cell membrane that result in decreased deformability and an increase in whole blood viscosity. These rheologic alterations are detrimental to flow in the microcirculation. Pentoxifylline (PTX), a methyl xanthine derivation, increases red cell deformability presumably through its effect on intracellular adenosine 5-triphosphate. The purpose of this study was to evaluate the effect of PTX on endotoxin-induced alterations in the neonatal red blood cell. Anticoagulated whole blood specimens obtained from the cord of 12 neonates at birth were used to study the effects of Escherichia coli endotoxin (LPS) with and without PTX (50 micrograms/mL) on red cell deformability and whole blood viscosity. LPS resulted in a significant (P less than .001) decrease in deformability compared with controls. PTX reversed these endotoxin-induced alterations (P less than .01), normalizing deformability to control values (P = NS). LPS resulted in a significant increase (P less than .005) in blood viscosity that was reversed by PTX (P = NS). Pentoxifylline reverses the detrimental rheologic effect of endotoxin in the neonate. This activity may be helpful in sustaining normal microcirculation in neonatal sepsis.
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PMID:The role of pentoxifylline in endotoxin-induced alterations of red cell deformability and whole blood viscosity in the neonate. 206 13

The mortality of sepsis/septic shock continues to be high in newborns. However, there is no established method in its treatment. Although calcium channel blockers ameliorate the hemodynamic deterioration of adult circulatory shock, their effects on newborn endotoxic shock have not been elucidated. This study was performed in newborn dogs to investigate the effects of diltiazem on newborn endotoxic shock. Endotoxic shock was induced in newborn dogs (2-10 days old, 300-800 g) by an intravenous injection of E. coli lipopolysaccharide (LPS; 1.5 mg/kg), and diltiazem (DZ) at the dose of 300, 600 or 1200 micrograms/kg was administered intravenously 20 min prior to LPS injection. Hemodynamic changes were serially observed until 120 min after LPS injection. The heart rate, mean arterial pressure and cardiac output decreased after LPS injection, and systemic vascular resistance decreased. DZ at the dose of 600 micrograms/kg attenuated the decreases of MAP and cardiac output, but 300 and 1200 micrograms/kg of DZ exacerbated them. DZ at the dose of 1200 micrograms/kg decreased the heart rate, and DZ at all three doses attenuated the increase of systemic vascular resistance. Therefore, 600 micrograms/kg of DZ is beneficial in the treatment of endotoxic shock in newborn dogs.
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PMID:Diltiazem treatment in newborn canine endotoxic shock. 208 81

It is likely that dynamic interactions between hepatocytes and Kupffer cells contribute to the responses of these cell types both under normal conditions and during sepsis. In this study, we examined the influences of hepatocytes on the concentration of the inflammatory mediator PGE2 in Kupffer cell cultures. Evidence to suggest that cultured rat hepatocytes both metabolize PGE2 and produce a substance that promotes LPS-stimulated Kupffer cell PGE2 biosynthesis include the following: 1) PGE2 levels in Kupffer cell: hepatocyte coculture were lower than the levels in Kupffer cell cultures early after LPS stimulation; 2) 36 h after LPS, coculture PGE2 levels exceeded the levels in Kupffer cell cultures despite the demonstrated capacity for hepatocytes to metabolize PGE2; 3) a transferable, non-dialyzable, and heat-unstable factor in hepatocyte supernatant promoted PGE2 production when added to Kupffer cells with LPS or after LPS; 4) there was no increased PGE2 synthesis when the hepatocyte supernatant was added without LPS or if hepatocyte supernatant was preincubated with the Kupffer cells for 6 or 18 h before LPS administration; 5) there was an inability of the hepatocyte factor to promote PGE2 production in response to other macrophage-activating agents, including calcium ionophore A23187 or phorphol myristate acetate; and 6) there was no increased cell replication or protein synthesis in the Kupffer cell cultures following hepatocyte supernatant incubation. The increased Kupffer cell PGE2 production by the hepatocyte supernatant was not due to contamination of the hepatocyte supernatant by endotoxin or PGE2. These in vitro results raise the possibility that hepatocytes have the capacity to modulate local PGE2 levels by two distinct mechanisms. Hepatocytes can metabolize PGE2 as well as release factor(s) which promote LPS-induced PGE2 production by Kupffer cells.
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PMID:Hepatocyte modulation of Kupffer cell prostaglandin E2 production in vitro. 210 27

The present experiments were undertaken to elucidate the effect of either the hepatocyte (HC) or hepatocyte supernatant on prelabeled endotoxin (LPS)-stimulated Kupffer cell (KC) arachidonic acid utilization. HC, KC, or their coculture were incubated for 18 hours with labeled 1-14C- arachidonic acid followed by a 24 hour incubation with 10 micrograms/ml LPS. LPS had no effect on the percent distribution of labeled arachidonate into the HC phospholipid or neutral lipid. KC showed a decreased percent neutral lipid labeled arachidonic acid distribution with generally no effect on the phospholipid. However, KC:HC cocultures or the addition of HC supernatant to KC exposed to LPS dramatically reversed the labeled arachidonate distribution into the KC with an increased incorporation into neutral lipid. Labeled PGE2 and PGD2 were increased in the KC following incubation with HC supernatant while only labeled PGE2 levels were elevated in the cocultures. The changes in the distribution of cell's labeled arachidonate required the addition of LPS. These results suggest that the HC can promote changes in the lipid fraction during sepsis by elaborating a substance that can modulate labeled arachidonate distribution in the KC lipids as well as stimulate prostaglandin production.
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PMID:Kupffer cell-hepatocyte interactions and the changes in 1-14C-arachidonate incorporation in response to endotoxin in vitro. 211 70

Despite significant advances in intensive care unit technology and mechanical ventilatory support, mortality due to adult respiratory distress syndrome (ARDS) or multiorgan failure (MOF) has not changed significantly within the past two decades. The key to improving survival requires understanding and modifying (or eliminating) factors that may initiate (or modulate) these syndromes. Infection, and the host responses to infection, are major etiological factors responsible for the induction and perpetuation of the injury to the lung and microvasculature in ARDS and MOF, and contribute to late mortality. While the pathogenesis of ARDS and MOF-complicating sepsis remains to be elucidated, bacterially derived (eg, endotoxin or lipopolysaccharides [LPS]) and host-derived humoral and cellular mediators are of importance in both disease states. In fact, the host response to infection (or injurious stimuli) may be a more critical determinant of the outcome of sepsis and ARDS than the original inciting stimulus. The pleiotropic effects of LPS are largely indirect, and are orchestrated via its ability to trigger the release of an array of host-derived mediators of inflammation. Several potential mechanisms of injury in ARDS, sepsis, and MOF have been suggested and include a variety of inflammatory cells (neutrophils, mononuclear phagocytes, platelets), activated complement and coagulation components, vasoactive mediators (kinins, arachidonic acid metabolites, lipids, peptides), reactive oxygen radicals, and diverse cytokines. Interactions between these humoral and cellular mediators appear to set in motion an amplified cascade of events culminating in cellular and tissue injury. In this article, several of these putative inflammatory mediators are discussed in detail, and the importance of cytokine networking and the possible role of nonimmune cells in the orchestration of the inflammatory response associated with ARDS and MOF are explained. Finally, future therapeutic strategies aimed at blocking or suppressing the release or effects of endogenous mediators may be the key to improving the outcome of these disorders.
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PMID:Host responses in mediating sepsis and adult respiratory distress syndrome. 212 91

International Antigen Typing Schema (IATS) serotypes 1, 2, 5, 6, 8 and 11 comprise approximately 80% of Pseudomonas aeruginosa strains isolated from blood, wounds and respiratory specimens. Five human immunoglobulin M (IgM) monoclonal antibodies (MAbs) reactive with lipopolysaccharide O antigens of these IATS serotypes were studied in an opsonophagocytic assay. The assay employed human polymorphonuclear leukocytes, 2% guinea pig serum as the complement source and MAb. Each MAb promoted killing of inoculum of the homologous LPS serotype. The opsonic activity of each MAb was complement-dependent. In a murine model of Pseudomonas burn wound sepsis the LD50 of five strains of P. aeruginosa was increased greater than or equal to 22-fold by MAb-treatment (1.0 mg/kg). The mean effective dose of the five MAbs in mice challenged with approximately 10 LD50 of the homologous LPS serotype ranged from less than 0.01 mg/kg to 1.00 mg/kg.
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PMID:Opsonic and protective activity of five human IgM monoclonal antibodies reactive with lipopolysaccharide antigen of Pseudomonas aeruginosa. 212 68


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