Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study ascertained the role of PGE2 in sepsis associated modulation of IL-2 and IL-10 production by T cells. Sepsis was induced in 225-250 g male rats (Sprague Dawley) by implanting fecal pellets containing Escherichia coli (100-150 CFU) and Bacteroides fragilis (10(4) CFU) into the abdominal cavity. Animals implanted with fecal pellets without the bacteria were designated as sterile. For the assessment of PGE2 role in sepsis, a group of septic and sterile rats were pretreated with indomethacin to inhibit endogenous PGE2 synthesis. Splenic T cells were obtained 48 h after septic or sterile implantations, and their IL-2 and IL-10 production was measured. A significant suppression in the levels of IL-2 production and mRNA expression was observed in T cells from septic rats compared with the T cells from sterile and control rats. IL-10 protein and mRNA expression was found to be significantly higher in septic rat T cell compared to sterile and control rat T cells. Although, treatment of animals with indomethacin significantly prevented the sepsis-related suppression of IL-2 production, such treatment of animals was associated with a further upregulation of IL-10 production. These data suggest that although PGE2 released during sepsis can cause T cell IL-2 down-regulation, it may not mediate the T cell IL-10 upregulation. The IL-2 down-regulation may not be an effect of IL-10 upregulation.
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PMID:Prostaglandin E2 down-regulation of T cell IL-2 production is independent of IL-10 during gram-negative sepsis. 1023 94

Patients (n=242) admitted to intensive care unit for longer than 48 hours were categorised for sepsis according to American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference criteria. Body temperature, leukocyte count, C-reactive protein (CRP) and procalcitonin (PCT) as well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, IL-10 and HLA-DR expression on monocytes were determined. Data of one randomly chosen day per patient entered analysis. Immunologic mediators contributing significantly to outcome were determined by logistic regression analysis. Area under the curves (AUC) of receiver operating characteristic curves of clinical markers of inflammation predicting prognosis were compared with AUC of relevant immunologic mediators. TNF-alpha, IL-6 and HLA-DR expression on monocytes were significantly associated with outcome; the AUC's were 0.835, 0.844 and 0.761 respectively. AUC's for clinical markers were 0.878, 0.811, 0.620 and 0.614 for PCT, CRP, leukocyte count and body temperature respectively. PCT had the highest AUC compared to other clinical markers. These data indicate that PCT might be a better marker than the classic criteria of inflammation, CRP, leukocyte count, and body temperature to identify patients endangered by severe infection or sepsis.
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PMID:Outcome prediction by traditional and new markers of inflammation in patients with sepsis. 1035 84

Procalcitonin (PCT), the precursor of calcitonin, was recently put forward as a diagnostic marker of systemic bacterial infection and sepsis. The major PCT production site in sepsis still remains unclear. Because of a certain association between increased levels of PCT and leukocyte-derived cytokines during sepsis, we assessed the possible expression of PCT in human peripheral blood mononuclear cells (PBMCs) and the modulation of PCT by lipopolysaccharides (LPS) and various sepsis-related cytokines by reverse transcriptase-polymerase chain reaction (RT-PCR) by using a novel primer set and flow cytometric analysis with intracellular staining with antibodies to the PCT components calcitonin and katacalcin. RT-PCR and flow cytometric analysis demonstrated that PBMCs express PCT both on mRNA and on protein levels. LPS and various proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), IL-2) had pronounced stimulatory effects on the expression of PCT mRNA. Under identical experimental conditions the anti-inflammatory cytokine IL-10 had no effect on the expression of mRNA for PCT. Flow cytometric analysis demonstrated increased intracellular amounts of PCT components after LPS stimulation. Thus we demonstrate for the first time that PCT is expressed in PBMCs. This expression is modulated by bacterial LPS and sepsis-related cytokines. Therefore PBMCs may be among the sources of elevated PCT levels in patients with sepsis.
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PMID:Procalcitonin expression in human peripheral blood mononuclear cells and its modulation by lipopolysaccharides and sepsis-related cytokines in vitro. 1040 59

The host response to Gram-negative LPS is characterized by an influx of inflammatory cells into host tissues, which is mediated, in part, by localized production of chemokines. The expression and function of chemokines in vivo appears to be highly selective, though the molecular mechanisms responsible are not well understood. All CXC (IFN-gamma-inducible protein (IP-10), macrophage inflammatory protein (MIP)-2, and KC) and CC (JE/monocyte chemoattractant protein (MCP)-1, MCP-5, MIP-1alpha, MIP-1beta, and RANTES) chemokine genes evaluated were sensitive to stimulation by LPS in vitro and in vivo. While IL-10 suppressed the expression of all LPS-induced chemokine genes evaluated in vitro, treatment with IFN-gamma selectively induced IP-10 and MCP-5 mRNAs, but inhibited LPS-induced MIP-2, KC, JE/MCP-1, MIP-1alpha, and MIP-1beta mRNA and/or protein. Like the response to IFN-gamma, LPS-mediated induction of IP-10 and MCP-5 was Stat1 dependent. Interestingly, only the IFN-gamma-mediated suppression of LPS-induced KC gene expression was IFN regulatory factor-2 dependent. Treatment of mice with LPS in vivo also induced high levels of chemokine mRNA in the liver and lung, with a concomitant increase in circulating protein. Hepatic expression of MIP-1alpha, MIP-1beta, RANTES, and MCP-5 mRNAs were dramatically reduced in Kupffer cell-depleted mice, while IP-10, KC, MIP-2, and MCP-1 were unaffected or enhanced. These findings indicate that selective regulation of chemokine expression in vivo may result from differential response of macrophages to pro- and antiinflammatory stimuli and to cell type-specific patterns of stimulus sensitivity. Moreover, the data suggest that individual chemokine genes are differentially regulated in response to LPS, suggesting unique roles during the sepsis cascade.
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PMID:Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. 1041 57

Sepsis is often a fatal condition, and excessive production of host inflammatory mediators including cytokines, are considered to be responsible for its lethality. We investigated the biology of TNF-alpha, IL-1, IL-6, and IL-10 with particular emphasis on its role in murine gut-derived sepsis due to Pseudomonas aeruginosa and found that these cytokine levels in serum showed significant increases at lethal conditions. Furthermore, we studied the cytokine levels in serum and BALF of mice after pulmonary infection with Klebsiella pneumoniae. The results showed that inflammatory cytokines in BALF demonstrated high levels at the early stage of infection in response to local inflammation of the lung. On the other hand, cytokine levels in serum abruptly increased at the late stage of infection in response to systemic inflammation. These results revealed that it is important to discriminate between systemic inflammation and local inflammation to diagnose sepsis.
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PMID:[Diagnosis of sepsis based on the host response]. 1043 65

Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis.
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PMID:Relationship of plasma leptin to plasma cytokines and human survivalin sepsis and septic shock. 1043 92

Major surgery, multiple injury, and severe sepsis lead to an impaired immune response. The suppressed status of the immune system is reflected by a reduced TNFalpha production of whole blood after stimulation with endotoxin in vitro and by a decreased HLA-DR expression on monocytes. In the present study, the effect of the immunostimulating hematopoetic growth factor GM-CSF on whole blood cultures of multiple injury, cardiac surgery, and severe sepsis patients was investigated. Endotoxin-induced TNFalpha production and HLA-DR expression was reduced in blood cultures of these patients compared to healthy donors. Preincubation with GM-CSF in vitro increased cytokine production in volunteers' and all patients' blood specimens in a dose-dependent manner. The elevation of cytokine response in cardiopulmonary bypass patients' blood, caused by in vitro preincubation with GM-CSF, equaled that of normal patients, whereas GM-CSF caused a lower rise of TNFalpha-producing capacity in blood of multiple-injury and sepsis patients. Further, GM-CSF treatment in vitro increased the down-regulated HLA-DR expression on monocytes prepared after cardiac surgery to a degree comparable to preoperative levels. Finally, GM-CSF incubation in vitro elevated TNFalpha synthesis in normal monocytes and in cells treated with a combination of the anti-inflammatory mediators IL-10, TGFbeta, and PGE2. These experiments show that hyporesponsiveness of whole blood induced by trauma, sepsis, or cardiac surgery is not irreversible but can be, at least in vitro, overridden by the immunostimulating compound GM-CSF.
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PMID:Influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) on whole blood endotoxin responsiveness following trauma, cardiopulmonary bypass, and severe sepsis. 1046 47

RU 41740 (Biostim) is an immunomodulator extracted from Klebsiella pneumoniae (strain O1:K2). In humans, it is able to reduce the number and duration of infectious exacerbations of chronic bronchitis. Using a mouse model of experimental infection, we found that oral RU 41740 administration strongly protected against gram-negative infections by preventing lethal septicemia, and, to a lesser extent, protected against the gram-positive intracellular pathogen L. monocytogenes. Oral administration of RU 41740 leads to the mobilization of newly dividing T and B cells in the thoracic duct lymph, reflecting the ability of the drug to induce an immune response in gut-associated lymphoid tissue. In cells isolated from mesenteric lymph nodes and spleen, RU 41740 leads to preferential release of the proinflammatory cytokines interleukin (IL)-12 and/or interferon (IFN)-gamma, as well as IL-10, a cytokine involved in inhibiting the synthesis of these latter cytokines. RU 41740 also increases the serum total immunoglobulin (Ig)M concentration and elicits IgM and IgG antibodies against the drug. Infection of mice with Klebsiella pneumoniae has similar functional consequences. Pretreatment of infected mice with RU 41740 leads to a fall in the high levels of proinflammatory cytokines (which could be detrimental), and to an increase in IgG antibodies (which are protective).
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PMID:Protective effects of RU 41740, a bacterial immunomodulator, against experimental infections: induction of cytokine and immunoglobulin release in mice after oral administration. 1050 25

Despite important advances in critical care medicine during the last two decades, the mortality rate of sepsis has remained high, probably because the pathogenesis of sepsis is still incompletely understood. Recent studies have shown that sepsis is a bimodal entity. The first phase is characterized by the systemic release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and IL-8, and by activation of the complement and coagulation cascades. In the second phase, anti-inflammatory mediators such as transforming growth factor-beta (TGF-beta), IL-10 and prostaglandin E2 (PGE2) may be released in an effort to counteract ongoing inflammation. Depending whether the pro- or anti-inflammatory response predominates, sepsis results in a systemic inflammatory response syndrome (SIRS), or a compensatory anti-inflammatory response syndrome (CARS). So far, most efforts to intervene in the immunopathogenesis of sepsis have been directed at the pro-inflammatory response. None of these interventions has been shown to improve the prognosis of sepsis, possibly because many patients were already in a state in which anti-inflammatory responses dominated. Recently, it has been shown that decreased expression of HLA-DR on monocytes in patients with sepsis constitutes a marker for CARS. We suggest that HLA-DR expression on monocytes might constitute a useful indicator of the immunological status of the individual patient with sepsis and a guide for treatment. Patients with CARS, as manifested by low HLA-DR expression, might benefit from immunostimulants, while patients with SIRS and normal or high monocyte HLA-DR expression should receive treatment directed to interfere with pro-inflammatory pathways.
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PMID:The central role of monocytes in the pathogenesis of sepsis: consequences for immunomonitoring and treatment. 1050 72

Almost all of respiratory diseases except benign lung tumors and lung dysplasia entail acute lung injury (ALI). The many clinical conditions associated with acute lung injury include aspiration pneumonia, bacterial pneumonia and sepsis. Acute lung injury is the end results of common pathways initiated by a variety of local or systemic insults leading to diffuse damage to the pulmonary parenchyma. Despite the accumulation of abundant information regarding the physiological and cellular basis of lung injury and increasing sophisticated intensive care, an improvement in prognosis has lagged behind. It has become clear that there is not one mediator responsible for ALI, but rather a complex interplay exists between diverse proinflammatory (e.g., lipopolysaccharide, complement products, cytocains, chemocains, reactive oxygen species and arachidonic acid products) and anti-inflammatory (IL-10, IL-1-RA, PGI2) mediators. Early in the course of ALI, large numbers of neutrophils are sequestered in and emigrate from the pulmonary capillaries. The fundamental cause of ALI is pulmonary vascular hyperpermeability caused by the activated neutrophils which release oxygen radicals and proteases. In these processes several adhesion molecules play very important roles. Neutrophil elastase inhibitors become very useful therapeutic agents against acute exacerbation of idiopathic interstitial pneumonia (IIP), because this pathological conditions is a type of ALI. Similarly, N-acetyl cystein could also become a useful therapeutic agent against IIP, because it is a precursor of glutathione, which is the major antioxidant in the fluid lining of the bronchial epithelium.
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PMID:[The 74th Annual Meeting President Lecture. Pathogenesis and therapy of acute lung injury]. 1053 83


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