UMLS:C0243026 - FACTA Search

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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemorrhagic shock suppresses the ability of Kupffer cells (KC) to present antigen and express the major histocompatibility complex class II (Ia) antigen. These alterations are concomitant with an enhanced release of cytokines (tumor necrosis factor [TNF], interleukin-1 [IL-1], IL-6) and prostaglandin E2 (PGE2) by KC after hemorrhagic shock. The aim of this study was to determine whether chloroquine (CQ) administration in vivo before or after hemorrhage affects the altered cytokine and PGE2 release by KC as well as the capacity of KC to present antigen and express Ia. To study this, C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 mm Hg for 60 minutes, followed by fluid resuscitation. Chloroquine (10 mg/kg body weight) was injected intramuscularly 2 hours before or during resuscitation following shock. The administration of CQ led to a significant reduction in the hemorrhage-induced elevation of TNF, IL-6, and PGE2 release by KC; however, IL-1 secretion was not affected by CQ. In addition, CQ treatment abolished the hemorrhage-induced increase in circulating TNF and IL-6. These changes in cytokine and PGE2 release following CQ administration correlated with a significant enhancement of the antigen-presenting capacity of KC. No differences were observed between pretreatment and posttreatment with CQ. Our data indicate that CQ selectively inhibits the release of TNF, IL-6, and PGE2 by KC, while IL-1 secretion was unaffected. Because the reduction of these inflammatory mediators was concomitant with a significant improvement of KC capacity to present antigen and express Ia, we propose that TNF, IL-6, and PGE2 play a pivotal role in the induction of posthemorrhage immunosuppression. Furthermore, the data suggest that the suppression of KC functions occurs during or after resuscitation, because posttreatment with CQ was as effective as pretreatment. Additional studies indicated that the survival of animals after hemorrhage and sepsis was significantly increased by posttreatment of hemorrhaged mice with CQ. Thus, CQ, because of its unique ability to selectively inhibit the release of inflammatory cytokines and prostaglandins, represents a potent immunomodulating agent in the treatment of conditions associated with increased cytokine release and for decreasing the mortality from sepsis after hemorrhage.
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PMID:Chloroquine attenuates hemorrhagic shock-induced suppression of Kupffer cell antigen presentation and major histocompatibility complex class II antigen expression through blockade of tumor necrosis factor and prostaglandin release. 191 65

A traditional view has been that bacterial products, such as endotoxins from gram negative bacteria, have a direct deleterious effect on the host, resulting in fever, hypermetabolism, anorexia, and tissue damage. In recent years, however, it has been shown that endogenous products of the host, secreted by macrophages and other cellular elements of the immune system, act as mediators in activating the metabolic and other physiological changes characteristic of the sepsis syndrome. We will review in depth various aspects of the major, central mediator, i.e., tissue necrosis factor (TNF)/cachectin, and also briefly discuss the interleukins IL-6 and IL-1.
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PMID:The role of cachectin/TNF and other cytokines in sepsis. 192 35

It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.
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PMID:Mechanisms of cancer cachexia. 202 66

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

Pertussis toxin, and also cholera toxin are capable of inhibiting the effects of LPS in the elicitation of the generalized Schwartzman reaction. This is a potentially lethal generalized thrombo-haemorrhagic hypersensitivity and inflammatory-type response that occurs after two consecutive injections of LPS. The two exotoxins furnish significant protection against the lethal outcome of this reaction. It is known that the acute haematological and haemodynamic changes are accompanied by alterations in the levels of various endogenous mediators: glucocorticoid hormones, prostaglandins, arachidonic acid metabolites, cytokines and proteases. In vitro effects of LPS on murine leukocyte cell lines can be antagonized by pertussis toxin, implicating a Gi-like regulatory protein in the mediation of these effects. Experiments designed to study the involvement of particular second messenger systems (cAMP and phosphatidylinositol) used by LPS in vivo, revealed that the protective effects conferred by these exotoxins are associated with the antagonization of alterations caused by LPS. No correlation was found between the levels of IL-6 and the mortality rate in this experimental mouse model. The results indicate that G proteins play a role in the generation of the Schwartzman reaction and open a new approach for pharmacological intervention in endotoxemia and in clinical settings with Gram-negative sepsis.
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PMID:Cholera and pertussis exotoxins protect mice against the lethal Schwartzman reaction and antagonize the effects of lipopolysaccharide on second messenger systems. 216 28

Previously we studied levels of the cytokine IL-6 and activation of the complement and contact system and of neutrophils in a group of 48 patients with sepsis. Some of these inflammatory parameters appeared to be associated with a poor prognosis. Here we report on the relationships of C4a and C3a (complement activation products), of factor XII and prekallikrein (contact system proteins), of elastase (a protease released by activated neutrophils) and of the cytokine IL-6 to hemodynamic and biochemical parameters measured in those 48 patients at the time of admission to the Intensive Care Unit. No significant correlations between any inflammatory parameter and either systemic vascular resistance or cardiac index were found. Mean arterial pressure significantly correlated with both factor XII and prekallikrein levels. Lactate correlated with C3a and C4a, with elastase, and in particular, with IL-6, whereas it did not correlate with either factor XII or prekallikrein. Platelet numbers inversely correlated with both C3a and C4a, as well as with elastase and IL-6, whereas they positively correlated with factor XII and prekallikrein. Based on these findings we propose a model for the interplay of these inflammatory mediators in the pathogenesis of sepsis. This model takes into consideration the occurrence of capillary leakage, shock, disseminated intravascular coagulation, thrombocytopenia and of acute phase reactions in sepsis.
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PMID:A model for the interplay of inflammatory mediators in sepsis--a study in 48 patients. 228 88

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.
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PMID:Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage. 238 17

A number of clinical studies have shown that multiple and severe trauma causes immunosuppression and increases the susceptibility to sepsis. However, because there is a close temporal relationship between trauma and hemorrhage in humans, it is difficult to dissociate the effects of tissue trauma versus hemorrhage on immunity in the clinical setting. Studies in mice have shown that simple hemorrhage per se as well as laparotomy alone produces a marked depression in cellular immunity and no difference was seen in the extent of depression at 2 h if these two insults were combined. Nonetheless, it remains unknown whether the combined model of trauma-hemorrhage produces a more protracted depression in immune function. To study this, 5 days after either sham operation, laparotomy (i.e. trauma), hemorrhage alone (35 mmHg for 1 h, followed by resuscitation), or the combination of laparotomy and hemorrhage, mice (C3H/HeN) were sacrificed, after which splenocyte and peritoneal macrophage cultures were established. The proliferative capacity of the splenocytes, as well as their ability to release IL-2 and IL-3, was markedly decreased in the trauma-hemorrhage animals but was normal in the other groups. Furthermore, the release of IL-6 by peritoneal macrophages from animals that underwent trauma-hemorrhage was also significantly depressed. These results support the concept that traumatic injury in the form of a midline laparotomy combined with hemorrhage produces a more protracted impairment in cell-mediated immunity than laparotomy or hemorrhage alone.
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PMID:Trauma-hemorrhage causes prolonged depression in cellular immunity. 749 1

The role of IFN-gamma in the regulation of host resistance of Staphylococcus aureus was studied using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice in a model of S. aureus-induced septicemia and arthritis. IFN-gamma R-/- mice and wild-type controls were inoculated intravenously with a toxic shock syndrome toxin-1-producing S. aureus LS-1 strain. IFN-gamma R-/- mice displayed significantly more frequent and more severe arthritis compared with wild-type littermates (p < 0.01) throughout the course of infection. Notably, IFN-gamma R-/- mice developed severe sepsis with high mortality early after the inoculation with staphylococci. However, the mortality of wild-type mice became significantly higher at later stages of the disease compared with IFN-gamma R-/- mice (p < 0.05). This differential outcome of sepsis-related mortality was associated with deficiencies of bacterial elimination from blood and parenchymatous organs and correlated well to serum levels of IL-6 and spleen IL-1 beta and TNF-beta mRNA expression. Thus, bacterial growth and proinflammatory cytokines IL-1 beta, TNF-beta, and IL-6 were higher at the early stage of infection in IFN-gamma-/- mice but increased at the later stage in wild-type littermates. Our data indicate that the absence of IFN-gamma R leads to harmful as well as beneficial effects in S. aureus infection, depending on the stage of the disease and the localization of the infection.
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PMID:Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. 749 61

Cytokine-inducible nitric oxide (NO) production has been implicated in the pathogenesis of septic shock. The present study was designed to determine which cytokines induce expression of the NO synthase gene in rat aortic vascular smooth muscle cells (VSMC) in vitro and whether NO synthase gene expression is inducible in vivo. NO synthase mRNA appeared after 4-h exposure to interleukin-1 beta (IL-1 beta), and levels continued to increase up to 24 h. Levels of NO synthase transcripts were greatest in VSMC treated with IL-1 beta (1 nM), lower in VSMC treated with Escherichia coli lipopolysaccharide (LPS; 100 micrograms/ml), and just detectable in VSMC treated with tumor necrosis factor-alpha (TNF-alpha; 1 nM). IL-1 beta, TNF-alpha, and LPS each induced NO synthase activity, assessed by release of nitrite, conversion of L-arginine to L-citrulline, and increased levels of guanosine 3',5'-cyclic monophosphate, whereas IL-2, IL-6, and interferon-gamma were ineffective. IL-1 beta was more potent and effective than TNF-alpha; however, submaximal concentrations of TNF-alpha acted synergistically with IL-1 beta to induce NO synthase gene expression and activity. Inducible NO synthase mRNA was present in aorta from rats 6 h after treatment with LPS (5 mg/kg), but not at 24 h. Synergistic activation of NO synthase gene expression in VSMC by IL-1 beta and TNF-alpha may contribute to hypotension in sepsis.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. 751 63

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