UMLS:C0243026 - FACTA Search

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)

Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses. Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30+/-5 mmHg for 90 min) followed by adequate fluid resuscitation. 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resuscitation. At 2 h after resuscitation, the mice were killed, and spleens were harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed. In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days. A significant decrease in splenocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-gamma release, and decreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-alpha and -beta expression was observed in the vehicle-treated group after TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH. ER-alpha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER-beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.
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PMID:The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis. 1102 55

Recent reports support the concept that the major defect in polymicrobial sepsis is an impaired immunologic response to infection. Oligodeoxynucleotides containing CpG sequence motifs (CpG-ODN) were previously shown to induce immune protection in models of chronic infection with intracellular bacteria, parasites, and viruses due to their ability to augment IFN-gamma-dependent Th1 responses. Here, we demonstrate that challenging mice with CpG-ODN substantially increases the resistance against acute polymicrobial sepsis. Systemic levels of IL-12, IL-18, and IL-10 were not altered in CpG-ODN-treated mice as compared with controls. In contrast, administration of CpG-ODN resulted in a strongly enhanced accumulation of neutrophils at the primary site of infection. Neutrophils of CpG-ODN-treated mice exhibited an up-regulation of phagocytic receptors, an increased phagocytic activity, and an elevated production of reactive oxygen metabolites. These results suggest that the protective effects of CpG-ODNs in acute polymicrobial sepsis are related to an enhanced effector cell response of innate immunity. CpG-ODN may therefore represent potent agents for the treatment of sepsis-associated immunoparalysis.
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PMID:Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response. 1103 94

The expression of NF-kappaB was studied in freshly isolated peripheral blood mononuclear cells (PBMC) of patients with severe sepsis and major trauma. The expression of p65p50 heterodimer, the active form of NF-kappaB, was significantly reduced for all patients as compared with control subjects. The p50p50 homodimer, an inhibitory form of NF-kappaB, was reduced in the survivors of sepsis and in patients with trauma. Subsequent in vitro stimulation of PBMC with lipopolysaccharide (LPS) did not induce further NF-kappaB nuclear translocation: the survivors of sepsis and trauma patients showed low expression of both p65p50 and p50p50, whereas nonsurvivors of sepsis showed a predominance of the inactive homodimer and a low p65p50/p50p50 ratio when compared with control subjects. In the later group of patients there was a reverse correlation between plasma IL-10 levels and the p65p50/p50p50 ratio after in vitro LPS stimulation (r = -0.8, p = 0.04). The reduced expression of nuclear NF-kappaB was not due to its inhibition by IkappaBalpha, as very low expression of IkappaBalpha, as well as low levels of p65 and p50 were found in the cytoplasm of PBMC from patients with sepsis and trauma when compared with control subjects. These results demonstrate that upon LPS activation, PBMC of patients with systemic inflammatory response syndrome show patterns of NF-kappaB expression that resemble those reported during LPS tolerance: global down-regulation of NF-kappaB in survivors of sepsis and trauma patients and the presence of large amounts of the inactive homodimer in the nonsurvivors of sepsis.
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PMID:NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. 1106 29

In this study we investigated the capacity of morphine to modulate expression of cytokines in peritoneal macrophages. Mice were implanted subcutaneously with a 75-mg morphine slow-release pellet, and 48 h later resident peritoneal macrophages were harvested. Control groups received placebo pellets, naltrexone pellets, or morphine plus naltrexone pellets. Adherent cells were stimulated with lipopolysaccharide (LPS: 10 microg/mL) plus interferon-gamma (IFN-gamma: 100 units/mL) to induce cytokine production. After 24 h RNA was extracted for analysis of cytokine mRNA levels by reverse transcriptase-polymerase chain reaction, or supernatants were collected after 48 h for determination of cytokine production by enzyme-linked immunosorbent assay (ELISA). Morphine enhanced mRNA expression of interleukin (IL)-12 p40 and tumor necrosis factor alpha (TNF-alpha) compared with controls, whereas IL-10 levels were unchanged by drug treatment. ELISA data showed that both IL-12 p40 and p70 were increased by morphine. The enhancement of IL-12 at both the mRNA and protein levels was antagonized by naltrexone, indicating that the modulation of this cytokine by morphine is via a classic opioid receptor. These results are particularly interesting in light of our previous observation that 48 h after morphine pellet implantation, the peritoneal cavity is colonized with gram-negative and other enteric bacteria. The enhancement of IL-12 by morphine might be related to morphine-induced sepsis.
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PMID:Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages. 1107 13

Twelve patients with leptospirosis were enrolled in a study to evaluate whether a correlation exists between disease severity and plasma levels of TNF-alpha and IL-10 as determined by enzyme-linked immunoassay. Six patients had less severe disease by analysis of liver, kidney and lung involvement, and 6 patients had severe disease, 2 of whom died. The results of the study confirm an association between high levels of TNF-alpha and poor outcome in leptospirosis. Levels of IL-10 were in a similar range in the 10 surviving and the 2 non-surviving patients. The ratio of IL-10/TNF-a correlated with disease severity in that a high ratio was associated with less severe disease and survival. The possibility is raised that treatment approaches to change this cytokine profile may be more effective in this type of inflammatory condition than it has been in bacterial sepsis.
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PMID:The ratio of plasma levels of IL-10/TNF-alpha and its relationship to disease severity and survival in patients with leptospirosis. 1110 29

The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells. Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production. Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages. The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth. Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome.
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PMID:The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system. 1112 11

The aim of this study was to monitor hepatic function in patients with pneumonia meeting the sepsis criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) and to determine if hepatic dysfunction is related to the systemic inflammatory response. Twenty patients were recruited. The monoethylglycinexylidide (MEGX) test was carried out on days 1-10 after admittance to the intensive care unit. Blood samples for determination of serum concentrations of hyaluronic acid, C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10 and conventional liver function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, albumin) were also drawn. Patients were classified into two groups according to illness severity estimated by the simplified acute physiology score (SAPS II) on the day of admission. Patients in group I (n=10) had a SAPS II probability of mortality >3% while those in group II (n=10) had a SAPS II < 3%. The MEGX level over the first five days was significantly lower in group I than in group II (p<0.0001). Significant inverse correlations during the first 5 days were observed between the MEGX 30 min test results and IL-6, CRP and SAPS II and more modest correlations with hyaluronic acid (p=0.0025) and IL-10 (p=0.021). The conventional liver function tests did not differ between the two groups and were mostly within the respective reference ranges. We conclude that the MEGX test is a sensitive marker of liver dysfunction early in sepsis and that low MEGX values are associated with an enhanced inflammatory response.
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PMID:The monoethylglycinexylidide (MEGX) test as a marker of hepatic dysfunction in septic patients with pneumonia. 1115 41

Current immunosuppressive strategies are aimed at abrogating the allospecific T-cell response against donor tissues or organs. However, little information is yet available on the potential influences of these drugs on innate immune responses. In order to address this, we have employed a whole blood model. Human whole blood was pretreated with sirolimus, cyclosporine A or tacrolimus in therapeutic as well as supra therapeutic doses, and subsequently stimulated with lipopolysaccharide (LPS), peptidoglycan (PepG) or lipoteichoic acid (LTA). Plasma cytokine analyses revealed a potent inhibitory effect of sirolimus on interleukin(IL)-10 production induced by all bacterial products tested. In contrast, cyclosporine A and tacrolimus inhibited the tumour necrosis factor (TNF)-alpha production in response to LPS, but not to PepG and LTA. Using a quantitative mRNA analyses, we also observed that sirolimus significantly decreased the IL-10 mRNA accumulation to sub-basal levels in peripheral blood mononuclear cells (PBMC). This suggests that the sirolimus inhibits IL-10 production by interfering with the IL-10 gene transcription. However, the molecular mechanism of this inhibition remains unclear. Based on the present study and observations by others, we postulate that the clinical use of the sirolimus may be associated with a dysregulated innate immune response to bacterial infection and thus an increased risk of hyperinflammation and sepsis.
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PMID:Sirolimus interferes with the innate response to bacterial products in human whole blood by attenuation of IL-10 production. 1116 23

Inflammatory cytokines have been implicated in myocardial function, severe congestive heart failure and sepsis. The present study tested the hypothesis that cytokine levels are elevated after low-risk coronary artery bypass surgery (CABG), and that they may be associated with postoperative cardiac dysfunction. Twenty male patients undergoing elective CABG in cardiopulmonary bypass (CPB) were studied. Plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, and IL-10 were measured before anesthesia induction, 5 minutes after, and 1, 4, and 20 hours after reperfusion to the myocardium. Levels of the MB isoenzyme of creatine kinase (CK-MB) were measured postoperatively. Hemodynamic data were also recorded. Myocardial ischemia was followed by an increase in the plasma levels of IL-6, IL-8, and IL-10. The duration of IL-6 response lasted throughout the postoperative period studied. Plasma cytokine levels at 1 hour after reperfusion correlated with the maximum CK-MB value (IL-6, r = 0.587, p < 0.01; IL-8, r = 0.460, p < 0.05; IL-10, r = 0.570, p < 0.05). Higher plasma IL-6 and IL-8 levels after reperfusion tended to be linked with lower cardiac index. The present results confirm that the levels of inflammatory cytokines IL-6, IL-8, and IL-10 are elevated after CABG. Increased systemic pro-inflammatory cytokine levels were partially associated with postoperative myocardial dysfunction. </hea
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PMID:Cytokine Responses in Low-Risk Coronary Artery Bypass Surgery. 1117 83

Sepsis predisposes the host to a number of infectious sequelae, particularly the development of nosocomial pneumonia. Mechanisms by which sepsis results in impairment of lung antibacterial host defense have not been well defined. Alveolar macrophages (AM) represent important immune effector cells of the lung airspace. In this study, we examined the effects of cecal ligation and puncture (CLP) on murine AM function ex vivo, including the expression of proinflammatory cytokines and AM phagocytic activity. AM were harvested from mice subjected to a sham operation and CLP 24 h after laparotomy, adherence purified, and challenged with lipopolysaccharide (LPS) or left unstimulated. Both unstimulated and LPS-stimulated AM from mice subjected to CLP (CLP mice) produced significantly smaller amounts of proinflammatory cytokines tumor necrosis factor alpha and interleukin (IL-12) and C-X-C chemokines KC and macrophage inflammatory protein 2 than similarly treated AM from animals subjected to a sham operation. Furthermore, AM isolated from CLP mice displayed a marked impairment in phagocytic activity, as determined by flow cytometry, with this defect persisting to 48 h post-CLP. Induction of peritoneal sepsis syndrome resulted in a time-dependent increase in IL-10 in plasma and peritoneal fluid. Interestingly, the impairment in AM proinflammatory-cytokine production and phagocytic activity observed in AM from CLP mice was partially reversed by the in vivo neutralization of IL-10 prior to AM harvest. These observations suggest that abdominal sepsis syndrome results in significant impairment in AM effector cell function, which is mediated, in part, by sepsis-induced expression of IL-10.
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PMID:Alveolar macrophage deactivation in murine septic peritonitis: role of interleukin 10. 1117 4

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