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)

Monophosphoryl lipid A (MPL) is a less toxic derivative of lipid A that enhances survival from endotoxemia. This study examined whether MPL induced resistance to Gram-positive sepsis and cytokines. Mice were administered MPL or saline (phosphate-buffered saline) and challenged 24 h later with live Staphylococcus aureus (SA), staphylococcus enterotoxin B (SEB), toxic shock syndrome toxin (TSST-1), and tumor necrosis factor (TNF). Survival was determined at 72 h. A separate set of animals was phlebotomized for determination of cytokines. MPL increased survival from S. aureus bacteremia from 20 to 87% (p < .05). Interleukin-6 (IL-6) and interleukin-1 (IL-1) and TNF were also significantly decreased. SEB and TSST survival were enhanced from 10 to 90% (p < .05). In SEB-treated animals, TNF and IL-6 levels were significantly decreased. Survival from TNF infusion was increased from 20 to 100% with MPL, however, no significant differences in cytokines were observed. These data suggest that MPL induces resistance to Gram-positive sepsis and cytokine-mediated activity.
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PMID:Monophosphoryl lipid A protects against gram-positive sepsis and tumor necrosis factor. 775 20

The concentration and accessibility of endotoxin can increase following antibiotic killing of gram-negative bacteria. There are indications that antibiotics may differ in this respect. We measured endotoxin levels in RPMI 1640 and tumor necrosis factor alpha (TNF-alpha) and interleukin-6 production in whole blood ex vivo after exposure of log-phase Escherichia coli to antibiotics belonging to different classes, in a final concentration of 0.5, 5, or 50 times the MIC. After 4 h of incubation at 50 times the MIC, ceftazidime and ciprofloxacin treatment resulted in levels of endotoxin, TNF-alpha, and interleukin-6 significantly higher than those of imipenem and gentamicin (P < 0.001). Similar differences in cytokine induction were measured after 8 h of incubation. At 0.5 times the MIC, the differences between the antibiotics in measured endotoxin and cytokine levels were small, with levels comparable to the levels in untreated cultures. Polymyxin B and, to a lesser degree, recombinant bactericidal/permeability-increasing protein 21 (rBPI-21) were found to be potent inhibitors of TNF-alpha release, supporting the concept that the differences between the antibiotics in cytokine production were indeed due to differences in amounts of biologically active endotoxin. The presence of serum from patients suffering from untreated sepsis decreased TNF-alpha production significantly, in a concentration-dependent manner.
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PMID:Release of tumor necrosis factor alpha and interleukin 6 during antibiotic killing of Escherichia coli in whole blood: influence of antibiotic class, antibiotic concentration, and presence of septic serum. 776 3

The influence of pentoxifylline (PTX) on mortality and some important mediators was studied in a model of cecal perforation with fulminant intra-abdominal sepsis in rats. Cumulative mortality was registered in three groups of animals: untreated sepsis (n = 36), sepsis + PTX 20 mg/kg/24 h (n = 24), and sepsis + PTX 80 mg/kg/24 h (n = 24). PTX therapy was started at sepsis induction or after 4 h, and mortality was reduced from 89% in untreated sepsis to 60-66% in the PTX groups. Levels of sepsis mediators were studied in two groups: untreated sepsis and sepsis + PTX 40 mg/kg started 1 h after sepsis induction. In both groups 6-10 animals were sacrificed at 4 and 8 h to measure blood levels of bacteria, endotoxin, tumor necrosis factor (TNF), interleukin-6 (IL-6), endothelin-1, lactate, neutrophils, and packed cell volume. Cecal perforation gave high levels of bacteria, endotoxin, TNF, IL-6, and endothelin-1, leading to dehydration, lactacidosis, neutropenia, and death. Treatment with PTX did not modify dehydration, neutropenia, or concentrations of bacteria and endotoxin. Release of endothelin-1 was delayed, TNF burst was nearly abolished, and levels of IL-6 and lactate were substantially suppressed. In summary, PTX improves survival and reduces blood concentrations of TNF, IL-6, lactate, and endothelin-1 in fulminant intra-abdominal sepsis in rats. The primary effect of PTX in this sequence is probably reduction of TNF.
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PMID:Pentoxifylline improves survival and reduces tumor necrosis factor, interleukin-6, and endothelin-1 in fulminant intra-abdominal sepsis in rats. 777 1

In view of the immunosuppressive action of glucocorticoids (GCs), the activation of the hypothalamo-pituitary-adrenal axis in patients with sepsis or septic shock is paradoxical. At the same time, administration of GCs to these patients is not clearly beneficial. We investigated the role of GCs in severe illness by measuring the sensitivity of peripheral blood mononuclear leukocytes to GCs in a mitogen-stimulated lymphocyte proliferation assay. In addition, we studied the role of interleukin-2 and several other cytokines in this system. Cells from patients with sepsis or septic shock (n = 15) were more sensitive to the antiproliferative action of GCs than were cells from normal controls (IC50 6.7 +/- 2.1 nmol/L for patients vs. 19.5 +/- 2.5 nmol/L for controls; P < 0.01). This increased sensitivity of the peripheral mononuclear cells to dexamethasone during the period of sepsis normalized during the ensuing period of clinical recovery of these patients. Dexamethasone inhibited the production of interleukin-2 in the mitogen-stimulated cells. Addition of interleukin-2 antagonized the suppressive effects of dexamethasone in a dose-dependent manner, both in cells from controls and in cells from patients with sepsis. To a lesser extent, the combination of interleukin-1, interleukin-6, and tumor necrosis factor-alpha also counteracted the effects of dexamethasone. In conclusion, our results suggest that not only the activity of the hypothalamo-pituitary-adrenal axis but also the sensitivity to GCs is regulated during sepsis and septic shock. Generally there is an increased sensitivity to GCs, which might help to protect the organism as a whole through supportive effects on metabolism and vasculature. This hypersensitivity is counteracted, possibly at the site of inflammation, by high local concentrations of cytokines. This would enable an adequate local response of the immune system in the presence of elevated cortisol levels. In view of the increased sensitivity of peripheral leukocytes to GCs, treatment of these patients with high doses of GCs may not be beneficial or may even be harmful.
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PMID:Differential adaptation of glucocorticoid sensitivity of peripheral blood mononuclear leukocytes in patients with sepsis or septic shock. 777 26

The concentrations of endotoxin, interleukin-6 (IL-6) and group II phospholipase-A2 (PLA2-II) were measured in serum or plasma during cytotoxic chemotherapy, fever of unknown origin and sepsis in 56 patients with hematological malignancies and during sepsis and viral infections in 22 non-hematological patients. High concentrations of IL-6, PLA2-II and endotoxin were detected in sepsis, the levels being similarly elevated in hematological and non-hematological patients. The levels of IL-6 and PLA2-II correlated closely with that of C-reactive protein (CRP). The levels of PLA2-II and IL-6 declined earlier than the level of CRP during the course of antimicrobial treatment. The levels of IL-6 also rose earlier than the level of CRP. The ability of IL-6 and PLA2-II and endotoxin to discriminate between sepsis and other causes of fever was comparable to that of CRP. IL-6 and PLA2-II are, together with CRP, valuable tools for the detection of sepsis in patients with hematological malignancies who undergo cytotoxic medication. Endotoxin is not suitable for routine laboratory diagnosis of sepsis.
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PMID:Endotoxin, interleukin-6 and phospholipase-A2 as markers of sepsis in patients with hematological malignancies. 778 12

In recent studies, production of interleukin-6 (IL-6) in cultured enterocytes was stimulated by lipolysaccharide (LPS). In other cell types, IL-6 production was inhibited by nitric oxide (NO). We tested the hypothesis that LPS-induced IL-6 production in the enterocyte is regulated, at least in part, by NO. IEC-6 cells (a rat intestinal epithelial cell line) were cultured for 3 days with different combinations of LPS (1-10 micrograms/ml), the NO synthase inhibitor N-omega-nitro-L-arginine (NNA, 3-300 microM), L-arginine (10 mM), the NO donor sodium nitroprusside (SNP, 0.5-1 microM), or medium alone as control. IL-6 levels in the culture medium were determined by the B9 murine hybridoma bioassay. Nitrite, a stable end product of NO metabolism, was measured by HPLC. PCR was performed to determine inducible NO synthase (iNOS) mRNA expression in the IEC-6 cells. Treatment of IEC-6 cells with LPS stimulated IL-6 production. LPS-induced IL-6 production was further increased by NNA in a dose-dependent fashion. This effect of NNA was abolished by the addition of L-arginine. SNP caused a dose-dependent decrease in IL-6 production. Nitrite production was increased in a dose-dependent fashion after LPS treatment. PCR revealed an increase in iNOS mRNA expression in IEC-6 cells after administration of 1 microgram/ml LPS. The results suggest that NO inhibits LPS-induced IL-6 production in the enterocyte. NO may be an important regulator of intestinal cytokine response during sepsis and endotoxemia.
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PMID:Nitric oxide inhibits LPS-induced IL-6 production in enterocytes. 779 30

Although lymphocyte-derived cytokines are known to augment macrophage cytokine production in vitro, their effect on macrophage tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) secretion during gram-negative bacterial sepsis has not been characterized. The purpose of this study was to examine the effect of lymphocyte-derived cytokines on macrophage TNF-alpha and IL-6 secretion during gram-negative bacterial peritonitis. To examine this problem, uninfected and infected mice were studied. Mice were infected with Escherichia coli O111:B4 and two subgroups were examined consisting of those pretreated iv 1 hr prior to bacterial challenge with either (1) saline or (2) anti-E. coli O111:B4 LPS mAb 2A3, the latter administered to abrogate the effects of LPS in vivo. Thus, three groups of mice were studied in relation to pretreatment and infectious challenges: (1) saline/saline (control); (2) saline/E. coli (saline); and (3) mAb 2A3/E. coli (mAb 2A3). Nonadherent splenocytes (> 95% lymphocytes by histologic staining criteria) harvested 16 hr later from mice in each group were incubated in culture ex vivo for 3 hr to obtain supernatants containing lymphocyte-derived cytokines. These supernatants containing lymphocyte-derived cytokines then were incubated in vitro with naive splenic macrophages with or without E. coli O111:B4 LPS. Macrophage TNF-alpha and IL-6 levels were determined using L929 and B9 bioassays.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lymphocyte-derived cytokines augment macrophage tumor necrosis factor-alpha and interleukin-6 secretion during experimental gram-negative bacterial sepsis. 779 54

Animal study results have suggested a role in sepsis for human interleukin for DA1.a cells/leukemia inhibitory factor (HILDA/LIF). HILDA/LIF and interleukin-6 (IL-6) levels were prospectively studied by serial ELISAs in 34 septic patients. HILDA/LIF was detected in 11 of 34 patients at plasma levels of 100-37,000 pg/mL. Peak HILDA/LIF levels correlated with increased temperature and creatinine and IL-6 and with decreased arterial CO2 (P < .05). Multivariate analysis showed that shock and decreased arterial CO2 accounted for 75% of peak HILDA/LIF plasma variations (R2 = .753). Fatal outcome was most often associated with detectable HILDA/LIF (> 56 pg/mL) and peak IL-6 plasma levels > 850 pg/mL (sensitivity, 83%; specificity, 87%), but both (at respective levels of > 480 and > 850 pg/mL) were associated with fatal outcome. HILDA/LIF was detected in septic patients exhibiting shock, and its levels correlated with higher mortality and shorter survival.
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PMID:Increased plasma levels of human interleukin for DA1.a cells/leukemia inhibitory factor in sepsis correlate with shock and poor prognosis. 779 71

The potential effects of cytokines on hepatocellular transport functions remain undefined. Interleukin-6 (IL-6) is a cytokine that is produced in sepsis, hepatitis, and other inflammatory conditions often associated with cholestasis. Using cultured rat hepatocytes, we have investigated the effects of IL-6 on hepatocellular bile salt uptake. Because hepatocyte Na(+)-K(+)-adenosinetriphosphatase (ATPase) produces the electrochemical gradient that drives sodium-dependent bile salt contransport, we also examined the effects of IL-6 on Na(+)-K(+)-ATPase activity. Hepatocytes cultured for 20 h in media containing IL-6 exhibited a dose-dependent noncompetitive inhibition of [3H]taurocholate uptake, which was maximal at an IL-6 dose of 100 U/ml. IL-6 treatment had no effect on hepatocyte sodium-independent taurocholate uptake. Northern blotting of RNA from cultured hepatocytes revealed that IL-6 had no effect on steady-state RNA levels of the Na(+)-taurocholate transporter (Ntcp). Hepatocytes incubated with IL-6 for 20 h, however, exhibited a 55% decrease in hepatocyte Na(+)-K(+)-ATPase activity. This effect also was dose dependent, with maximal inhibition occurring at an IL-6 dose of 100 U/ml. Similar treatment with IL-6 did not influence hepatocyte Mg(2+)-ATPase activity. The inhibition of Na(+)-K(+)-ATPase activity induced by IL-6 provides a putative mechanism for the observed inhibition of sodium-dependent taurocholate uptake. Since modulation of bile salt transport and Na(+)-K(+)-ATPase activity occurred at IL-6 concentrations comparable to the serum levels observed in patients with severe inflammatory states, these findings have potential pathophysiological relevance for the cholestasis of sepsis and other inflammatory disorders.
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PMID:Interleukin-6 inhibits hepatocyte taurocholate uptake and sodium-potassium-adenosinetriphosphatase activity. 781 Jun 56

Pneumolysin is a cytoplasmic virulence factor of Streptococcus pneumoniae that can interfere with phagocyte function in vitro. We have examined the effects of pneumolysin in vitro and in vivo and have found that it protects intravenously injected pneumococci against infection-induced host resistance. We employed a virulent capsular type 2 pneumococcal strain, D39, and its isogenic pneumolysin-negative mutant, PLN. Strain D39 exhibited exponential net growth in mice (doubling time, 1.4 h); 24 to 28 h after infection with 10(4) CFU, the numbers of pneumococci reached 10(9) to 10(10) CFU/ml and the mice died. Strain PLN yielded identical net growth in mice until reaching 10(6) to 10(7) CFU/ml at 12 to 18 h postinfection. At this time, the increase in the level of PLN CFU per milliliter ceased and remained constant for several days. PLN exhibited wild-type growth kinetics in mice when coinfected simultaneously with strain D39. This observation suggests that pneumolysin exerts its effects at a distance. By 12 to 18 h postinfection with PLN, mice exhibited the following evidence of an induced inflammatory response: (i) elevated plasma interleukin-6, (ii) a halt in the net growth of PLN, and (iii) control of the net growth of pneumolysin-producing D39 pneumococci upon subsequent challenge. Our data suggest that pneumolysin plays a critical role in sepsis during the first few hours after infection by enabling pneumococci to cause acute sepsis rather than a chronic bacteremia. However, once chronic bacteremia was established, it appeared that pneumolysin was no longer able to act as a virulence factor.
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PMID:A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice. 782 9


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