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 overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study, we assessed the role of monocyte chemoattractant protein-1 (MCP-1) as a mediator of sepsis in endotoxin-challenged mice. Intraperitoneal administration of LPS to CD-1 mice induced a substantial time-dependent increase in MCP-1 in plasma, lung, and liver. The passive immunization of mice with rabbit antimurine MCP-1 antiserum 2 h before endotoxin administration resulted in a striking increase in LPS-induced mortality from 10% in control animals to 65% in anti-MCP-1-treated animals. Importantly, the administration of anti-MCP-1 antibodies to endotoxin-challenged mice resulted in increases in peak TNF-alpha and IL-12 levels, and also in a trend toward decreased serum levels of IL-10. Conversely, the administration of recombinant murine MCP-1 intraperitoneally significantly protected mice from endotoxin-induced lethality, and resulted in an increase in IL-10 levels, a decrease in IL-12 levels, and a trend toward decreased levels of TNF. In conclusion, our findings indicate that MCP-1 is a protective cytokine expressed in murine endotoxemia, and does so by shifting the balance in favor of antiinflammatory cytokine expression in endotoxin-challenged animals.
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PMID:MCP-1 protects mice in lethal endotoxemia. 918 4

Endotoxin (LPS) can cause hepatocellular injury under several circumstances, and leukotrienes have been implicated as a contributing factor. Since ion channel activation has been associated with cytotoxicity, the aim of this study was to determine the circumstances under which LPS and/or leukotrienes activate ionic conductances in hepatocytes. LPS treatment of rats increased Cl- conductance in hepatocytes from 232+/-42 to 1236+/-134 pS/pF. Voltage dependence and inhibitor specificity of this conductance were similar to that of a swelling-activated Cl- conductance, and internal dialysis with nucleoside analogues suggested control by an inhibitory G protein. The lipoxygenase inhibitor nordihydroguaiaretic acid, the specific leukotriene D4 (LTD4) receptor antagonist MK-571, and the 5-lipoxygenase activating protein inhibitor MK-886 all significantly inhibited the conductance. Intracellular dialysis with LTD4 (1.5 microM) elevated intracellular Ca2+ from 143+/-6.5 to 388+/-114 nM within 6 min and stimulated an outwardly rectifying conductance from 642+/-159 to 1669+/-224 pS/pF (n = 9, P < 0.001). In hepatocytes prepared from untreated rats, this concentration of intracellular LTD4 neither raised intracellular Ca2+ nor activated the conductance. The LTD4 response could be induced in normal hepatocytes by culture with either conditioned medium from LPS-treated macrophages or purified TNF-alpha. In conclusion, intracellular LTD4 activates a chloride conductance in hepatocytes isolated from rats treated with LPS or primed in vitro with TNF-alpha. Changes in the hepatocellular accumulation of leukotrienes therefore mediate channel activation and may contribute to liver injury during sepsis and other inflammatory conditions.
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PMID:Leukotriene D4 activates a chloride conductance in hepatocytes from lipopolysaccharide-treated rats. 918 15

Previous studies indicate a profound suppression of tumour necrosis factor alpha (TNF-gamma), IL-1 beta and IL-6 release capacity by peritoneal macrophage (PM phi), splenic macrophage (SM phi) and Kupffer cells (KC) during late sepsis. Such a loss of functional capacity may reduce the animal's ability to ward off infection. Prolactin is known to enhance monocyte, T- and B-lymphocyte immune responses under normal conditions and has beneficial effects on cell-mediated immunity after haemorrhage. In the respect, the dopamine antagonist, metoclopramide, has been reported to increase circulating prolactin levels. Nonetheless, it remains unknown whether prolactin or metoclopramide have any salutary effect on macrophage (M phi) cytokine gene expression following sepsis. To study this, male C3H/HeN mice were subjected to sepsis and immediately thereafter were treated with prolactin (100 micrograms/25 g body weight, s.c.), metoclopramide (100 micrograms/100 g BW, s.c.) or given saline. PM phi, SM phi and KC (only SM phi and KC in metoclopramide-treated animals) were isolated at 24 h after sepsis. The monolayers were stimulated with or without LPS 10 micrograms/ml for 1 h in vitro. Total RNA was extracted and mRNA was detected by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). A significant depression of constitutive and inducible mRNA levels of IL-1 beta, IL-6 and TNF-alpha in all three M phi populations were observed, when compared with shams (with exception of KC IL-6 mRNA in unstimulated cells). Prolactin as well as metoclopramide treatment after the onset of sepsis caused significant elevation of constitutive and inducible cytokine gene expression in all macrophages examined. Thus, prolactin and metoclopramide enhance the depressed M phi gene expression and may be useful in improving cell-mediated immunity during sepsis.
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PMID:Effects of prolactin and metoclopramide on macrophage cytokine gene expression in late sepsis. 919 78

Early release of macrophage-derived proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, are important in the pathogenesis of septic shock and multisystem organ failure in various models of sepsis. IL-10 is a mediator that inhibits cytokine release from activated macrophages. The aim of this study was to determine if IL-10 would decrease serum cytokine elevation in a murine model of cecal ligation and puncture (CLP). CLP in animals is a model that closely mimics the physiologic changes seen in human sepsis. Four groups of 14 female Swiss-Webster mice were used. Group 1 underwent laparotomy alone, groups 2, 3, and 4 underwent laparotomy and CLP. Groups 1 and 2 received intraperitoneal (IP) saline injections to serve as control vehicle. Group 3 (prophylactic) received 10,000 U IP IL-10 1 hr prior to CLP and every 3 hr thereafter. Group 4 (therapeutic) received 10,000 U IP IL-10 1 hr following CLP and every 3 hr thereafter. Animals were sacrificed at 3 and 9 hr following CLP. Serum TNF-alpha, IL-1 beta, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA), CLP produced a significant rise in serum TNF,IL-6, and IL-1 in untreated controls. Prophylactic or therapeutic administration of IL-10 significantly attenuated this early rise in serum cytokines. These results support the hypothesis that (1) CLP produces an early systemic rise in macrophage-derived cytokines and (2) IL-10 given either before or after the onset of CLP-induced intraabdominal infection and sepsis is able to inhibit this early release of macrophage-derived systemic mediators. IL-10 has potential clinical benefits in the therapeutic management of intraabdominal infection and sepsis.
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PMID:Interleukin-10 prevents early cytokine release in severe intraabdominal infection and sepsis. 923 83

We describe a patient with self-induced disease who presented with repeated urinary tract infection and sepsis due to intravesical and intravenous injection of feces. Sepsis occurred repeatedly such that the patient exhibited 10 bouts of fever > 40 degrees C in a single month. This bacterial challenge led to massive activation of the monocyte system with high levels of TNF-alpha, IL-6, and monocyte colony-stimulating factor (M-CSF). This cytokine response was followed by strong expansion of the novel CD14+CD16+ monocyte subset. These results suggest that cytokines induce the development of CD14+CD16+ cells in human septicemia and that CD14+CD16+ cells may serve as indicator for previous bouts of excessive inflammation.
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PMID:Cytokine production precedes the expansion of CD14+CD16+ monocytes in human sepsis: a case report of a patient with self-induced septicemia. 924 16

The total-systems inflammatory response was assessed in patients with sepsis and multiple organ failure by measuring plasma cytokines TNF-alpha, IL-1 beta, and IL-6 and their clearance and total elimination in the course of permanent hemofiltration (PHF). Sepsis and multiple organ failure were found to involve a stable circulation of numerous cytokines, their levels reaching the peaks in some cases. No correlation between the content of individual cytokines in the plasma were detected. Appreciable amounts of TNF-alpha and IL-1 beta were eliminated during PHF, their clearance being approximately 15 ml/min, whereas elimination of IL-6 was negligible. Hence, PHF affects the mediator component in the pathogenesis of sepsis and the multiple organ failure syndrome.
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PMID:[Plasma contents of cytokines (TNF-alpha, IL-1 beta, IL-6) and their clearance during continuous hemofiltration in patients with sepsis and multiple organ failure]. 928 91

The aim of this study was to evaluate the impact of prematurity, sepsis and stress on the neutrophil respiratory burst activity (NRBA) of neonates. For this purpose 122 healthy neonates (89 term and 33 preterm), 33 preterm stressed neonates, 59 septic neonates (12 term and 47 preterm) and 26 healthy adults were studied. The NRBA was assessed after in vitro stimulation by PMA using a whole blood flow cytometric microassay with dihydrorhodamine 123 (DHR 123). It was found that the percentage of responding neutrophils in term neonates was comparable to that found in adults (medians 83.5 and 89.8%, respectively), whereas it was significantly lower in the healthy preterm neonates (median 70.6%, p < 0.05). The NRBA was further depressed in the stressed (median = 63%) and septic neonates, both term and preterm (medians 60.5 and 54.3%, respectively). No correlation with the levels of G-CSF, TNF-alpha and IL-1 beta, which were found to be higher in the stressed and septic neonates, was observed. These findings indicate that prematurity, sepsis and stress significantly depress the respiratory burst activity of neonatal neutrophils.
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PMID:Impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates. 933 91

To evaluate the role of tumour necrosis factor (TNF) in gut-derived sepsis, mice were given Pseudomomas aeruginosa strain D4 by bacterial suspension in their drinking water during which time ampicillin (200 mg/kg) was given to disrupt the normal indigenous bacterial flora. Cyclophosphamide was additionally administered to induce bacterial translocation of the P. aeruginosa that had colonized the gastrointestinal tract, and thereby to cause gut-derived sepsis. In this model, TNF-alpha was detected in serum from the next day after the second cyclophosphamide administration, increasing to level of 3 ng/ml in lethal conditions. Average serum TNF-alpha level was significantly higher in mice with bacteraemia than in those without bacteraemia. Treatment with 0.8 microg/kg of recombinant human TNF-alpha (rhTNF-alpha) did not affect the mortality, whereas administration of either 4 and 20 microg/kg of rhTNF-alpha significantly increased the mortality rate in comparison with saline-treated mice. Bacterial counts in liver and blood were significantly higher in 20 microg/kg of rhTNF-alpha treated mice than in saline-treated mice. Treatment with murine anti-TNF-alpha monoclonal antibody significantly reduced the mortality from septic infection. We conclude that TNF-alpha may facilitate bacterial translocation and causes deterioration of gut-derived sepsis due to P. aeruginosa in mice.
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PMID:Adverse effects of tumour necrosis factor in cyclophosphamide-treated mice subjected to gut-derived Pseudomonas aeruginosa sepsis. 934 9

Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
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PMID:Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. 934 17

Translocation of enteric bacteria or their components (or both) has been postulated to play a role in precipitating sepsis or the systemic inflammatory response syndrome. To simulate the effects of translocation on pulmonary host defenses, lipopolysaccharide was injected into the portal vein of normal rats that were subsequently challenged by aerosol inoculation with Pseudomonas aeruginosa. Injection of LPS into the portal vein resulted in increased serum tumor necrosis factor (TNF)-alpha levels and reduction in lung clearance of P. aeruginosa after aerosol challenge. There were corresponding reductions in alveolar neutrophil recruitment, diminished alveolar macrophage phagocytosis and superoxide anion (O2-) production, and diminished lung TNF recovered by bronchoalveolar lavage. Furthermore, prior intravenous injection of recombinant TNF-alpha reproduced the defective bacterial clearance, the altered recruitment of airspace neutrophils, and the defective alveolar macrophage phagocytosis. Thus, systemic TNF-alpha is important in altering pulmonary defenses, and this work supports the concept that bacterial translocation may adversely affect host defenses in distant organs.
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PMID:Intraportal lipopolysaccharide suppresses pulmonary antibacterial defense mechanisms. 935 31


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