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)

An immune-neuroendocrine interaction that is mediated via beta2-adrenergic receptors has been demonstrated previously. Dopexamine is a substance with strong beta2-adrenergic effects and is used in the treatment of critically ill patients. We therefore investigated the effect of dopexamine infusion on survival and cellular immune functions during systemic inflammation. Sepsis (CLP) was induced in male NMRI mice that received either 0.9% saline, dopexamine (0.05 mg/kg/hour ip, DPX), the selective beta2-adrenergic antagonist ICI 118.551 (0.5 mg/kg ip every 12 hours, ICI) or a combination of both drugs. 48 hours after onset of sepsis, survival rate, splenocyte apoptosis, splenocyte proliferation, splenocyte IL-2, IL-6 and IFN-gamma release, and leukocyte distribution were monitored. Dopexamine increased splenocyte apoptosis and normalized the distribution of circulating lymphocytes but did not affect sepsis-induced mortality. ICI 118.551 induced a dramatic increase of mortality paralleled by a decreased splenocyte proliferation and the strongest increase in splenocyte apoptosis. Co-administration of dopexamine abolished the ICI 118.551-induced alterations but this effect seemed to be mediated via a pathway other than adrenergic beta2-receptors. We conclude that dopexamine modulates cellular immune functions during systemic inflammation and that different receptor systems are involved in the mediation of this process. Furthermore, the immunomodulatory effect of beta2-adrenergic blockade was demonstrated.
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PMID:Dopexamine and cellular immune functions during systemic inflammation. 1512 57

Although immune responses following soft-tissue trauma-hemorrhage are markedly different in young (6-8 weeks) and aged (18-20 months) mice, it remains unknown if there are any differences in immune responses in middle-aged and young mice following bone fracture, soft-tissue trauma-hemorrhage (Fx-TH). To study this, young (6-8 weeks) and middle-aged (approximately 12 months) C3H/HeN male mice were subjected to sham operation or Fx-TH followed by resuscitation with Ringer's lactate. The mice were sacrificed 2 h thereafter and splenocytes, bone marrow cells (BM) and Kupffer cells (KC) were harvested, purified and stimulated with ConA (for splenocytes) or LPS (for BM and KC) in vitro. Splenocyte release of Th1 (IL-2 and IFN-gamma) cytokines was decreased and Th2 (IL-4 and IL-10) cytokine release was increased following Fx-TH in both young and middle-aged mice. However, the decrease in IL-2 and increase in IL-10 were significantly more in middle-aged mice compared to young mice (p < 0.05). Furthermore, splenocyte proliferation was decreased more in middle-aged mice compared to young mice following Fx-TH (p < 0.05). Additionally, TNF-alpha production was more in BM from middle-aged compared to BM from young mice after Fx-TH (p < 0.05). The production of IL-6 and IL-10 was also significantly higher in KC from middle-aged mice compared to young ones following Fx-TH. These results suggest that at middle age, the immune responses to Fx-TH are significantly different from those observed in young mice in different compartments of the body. Although the mechanism of the difference in various compartments in middle-aged vs. young mice following Fx-TH remains unknown, the decreased IL-2 production along with other altered T cell and macrophage functions may contribute to an increased susceptibility to sepsis in middle-aged vs. young individuals.
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PMID:Are the immune responses different in middle-aged and young mice following bone fracture, tissue trauma and hemorrhage? 1515

Insulin decreases the mortality and prevents the incidence of infection and sepsis in critically ill patients. The molecular and cellular mechanisms by which insulin improves survival have not been defined. The purpose of the present study was to determine the effect of insulin on the inflammatory reaction during endotoxemia. Endotoxemic rats were randomly divided into two groups to receive either saline or insulin. The effects of insulin on hepatic signal transcription factor mRNA expression, proinflammatory and antiinflammatory cytokine mRNA and protein concentration were determined. Insulin administration did not change glucose or electrolyte levels, but significantly decreased proinflammatory signal transcription factors [CCAAT/enhancer-binding protein-beta, signal transducer and activator of transcription-3 and-5, RANTES (regulated on activation, normal T cell expressed and secreted)] and cytokine expression in the liver and serum levels of IL-1beta, IL-6, macrophage inflammatory factor, and TNFalpha. Insulin administration further decreased high mobility group 1 protein in the serum compared with controls. In addition, insulin increased antiinflammatory cytokine expression in the liver; serum levels of IL-2, IL-4, and IL-10; and hepatic suppressor of cytokine signaling-3 mRNA expression. Insulin modulates the inflammatory response by decreasing the proinflammatory and increasing the antiinflammatory cascade. Because glucose and electrolyte levels did not differ between insulin-treated patients and controls, we hypothesize that the effects are direct antiinflammatory mechanisms of insulin, rather than indirect, through modulation of glucose or electrolyte metabolism.
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PMID:Insulin attenuates the systemic inflammatory response in endotoxemic rats. 1519 48

Severe blunt chest trauma is frequently associated with multiple organ failure and sepsis. Posttraumatic immunosuppression seems to play a major role in their development. However, the immunologic alterations following pulmonary contusion are insufficiently elucidated. Specifically, it remains unknown whether immunocompetent cells located distant from the site of the impact are affected. We therefore aimed to characterize the influence of pulmonary contusion on lymphocytes and splenic macrophages. Male C3H/HeN mice (n = 8-10/group) were anesthetized and subjected to trauma or sham procedure. Blunt chest trauma was induced by a blast wave focused on the thorax. Two or 24 h later, splenocytes and splenic macrophages were isolated and stimulated for 48 h. The cytokine release (IFN-gamma, IL-2, IL-3, IL-10, IL-12, IL-18) from splenocytes as well as from splenic macrophages (TNF-alpha, IL-10, IL-12, IL-18) and plasma levels of TNF-alpha and IL-6 were quantified by ELISA. The results indicate that at 2 h after blunt chest trauma, plasma TNF-alpha and IL-6 were markedly increased. At the same time, no differences in splenocyte cytokine production were detectable. However, at 24 h a significantly depressed cytokine release was observed in trauma animals. Furthermore, splenic macrophages showed a significantly decreased production of TNF-alpha, IL-10, and IL-12 at 24 h and markedly increased release of IL-18 at 2 h after trauma. These results indicate that blunt chest trauma causes severe immunodysfunction of lymphocytes and splenic macrophages. Thus, lung contusion as a localized type of trauma causes dysfunction of immunocompetent cell populations, which are located distant from the site of injury.
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PMID:Blunt chest trauma induces delayed splenic immunosuppression. 1520 2

Severe sepsis and septic shock are important causes of death in intensive care units. Although Gram-negative infections were predominant in the 1960s, Gram-positive infections have increased in the past two decades and now account for about half of the cases of severe sepsis. In this study, we examined the effect of a Limulus anti-LPS factor (LALF)-derived peptide on lung and liver Th1/Th2 cytokine mRNA levels during a Gram-positive sepsis. We also examined the morphopathological changes observed in these organs during the disease. Mice challenged with a high dose of Staphylococcus haemolyticus showed severe damage in lung. In contrast, the liver of challenged mice showed an accumulation of bacterial particles in the sinusoids, associated with a severe inflammatory response due to high levels of tissue mRNA proinflammatory cytokines. Treatment with the peptide LALF(32-51) ameliorated the sepsis-induced effects in the lung and liver and increased the survival of mice in a dose- and time-dependent manner. Pretreatment with the peptide LALF(32-51) differentially regulates TNF-alpha, IFN-gamma, IL-12p40, IL-2 and IL-10 mRNA levels in lung and liver of peptide-treated mice, and limits the systemic inflammatory response. These findings support for the first time the effectiveness of an LALF-derived peptide in the treatment of a Gram-positive sepsis. Modulation of the Th1/Th2 pattern in tissues relevant for sepsis correlates with an improved outcome of the disease as denoted by increased survival.
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PMID:Differential regulation of Th1/Th2 in relevant tissues for sepsis pathogenesis with a Limulus anti-LPS factor-derived peptide increases survival in Gram-positive sepsis. 1531 32

The activation of a pro-inflammatory cascade after infection, major surgery, burn or trauma appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. It is well known that T-cell plays a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 lymphocytes produce IFN-gamma and IL-2, favoring cell mediated immunity; Th2 cells secrete IL-4, IL-5, IL-10, IL-13, favoring humoral immunity. Cytokines produced in systemic inflammatory response syndrome (SIRS) may effect Th subset predominance and subsequent immune responses. We measured Thl/Th2 balance in patients with severe sepsis, SIRS patients with non sepsis, and healthy subjects by flow cytometry. In patients with severe sepsis, Th2 antibody mediated (humoral) immune responses predominate. We believe that severe sepsis clearly induce polarization of T-helper lymphocyte activity with a clear shift in Th2 direction. This type of response may lead immunosuppression. Modulation of Th cell subset predominance may present a novel therapeutic option in the treatment of severe sepsis.
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PMID:[Th1/Th2 balance in systemic inflammatory response syndrome (SIRS)]. 1559 90

Bacterial factors stimulate the release of tissue factor as well as proinflammatory and antiinflammatory cytokines. TNF augments inflammation, TNF and IFN-gamma induce coagulation, and IL-1beta induces coagulation and fibrinolysis. IL-8 augments synergistic inflammation and coagulation. IL-6 augments coagulation and inhibits fibrinolysis. IL-10 inhibits inflammatory process and inhibits fibrinolysis. IL-4, IL-13, and TGF-beta act for anticoagulation. Administration of IL-2, G-CSF or IFN-gamma has been reported to have side effect of induction of coagulation. IL-12 induces coagulation first and fibrinolysis later. On the other, tissue factor induces proinflammatory (except TNF) and antiinflammatory cytokines, and thrombin enhances inflammation. Patients who died of SIRS/sepsis have been complicated with hypercoagulopathy and impaired fibrinolysis correlated with increased IL-10 production. Inhibition of IL-10 production or administration of fiblynolitic agents may be useful. Recently, activated protein C (APC) which has antiinflammatory effect has been paid attention in the treatment of SIRS/sepsis.
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PMID:[Correlation between intravascular coagulation/fibrinolysis system and cytokines]. 1559 92

Substantial attention has been paid to the role of the toll-like receptor (TLR) ligands of late and their role in regulating the innate immune response. They serve as exogenous danger signals important in informing and driving the distal adaptive immune response to pathogens. Less clear has been the role of the nominal endogenous danger signals released and recognized in stressed cells following genotoxic or metabolic stress as occurs in progressively growing tumors. HMGB1 (high-mobility group B1) is a nuclear protein well characterized for its ability to modify DNA access to transcriptional proteins that is released from necrotic cells as well as secreted through the endosomal route from hematopoietic cells, serving as a late mediator of sepsis. It interacts with high-affinity RAGE (receptor for advanced glycation end products) and TLR2 receptors. Here we show that HMGB1 enhances interferon gamma release from macrophage (but not dendritic cell)-stimulated NK cells. This is effective only when coupled with other pro-inflammatory cytokines particularly with IL-2 in combination with IL-1 or IL-12. We have used this information to suggest that HMGB1, which also promotes epithelial migration and proliferation, drives repair in the absence or inhibition of other factors but enhances inflammation in their presence. The implications for tumorigenesis and tumor progression are quite important as they may be for other states of chronic inflammation.
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PMID:Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. 1560 95

Studies have shown that following bacterial infection or endotoxin administration, immune functions are regulated differently in mice of different genetic background. Since the susceptibility to sepsis following trauma-hemorrhage is dependant on the severity of injury, it is important to determine whether genetic background of the animal influence immune functions after trauma-hemorrhage. The aim of our studies, therefore, was to assess differences in the immune functions in genetically different strains of age-matched C3H/HeN and C57BL/6 male mice following trauma-hemorrhage. The analysis for immune functions included: proliferation of splenocyte and bone-marrow cells, IL-2 and IFN-gamma release by splenocytes, and TNF-alpha and IL-10 release by splenic, peritoneal, liver (Kupffer cell), and bone-marrow macrophages. The results show significant differences in splenocyte and bone-marrow functions, and in the release of the mediators of immune function by immune competent cells: (a) between the two genetic strains, and (b) in each mouse strain following trauma-hemorrhage. Thus, genetic background appears to significantly influence the severity of immune responses in males following trauma-hemorrhage.
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PMID:Mouse genetic background influences severity of immune responses following trauma-hemorrhage. 1586 90

The current studies demonstrate protective and harmful effects of neutrophils (PMN) during experimental sepsis after cecal ligation and puncture (CLP). It is known that CLP induces signaling defects in blood PMN. When PMN were depleted 12 h after CLP, there were dramatic reductions in levels of bacteremia, evidence for reduced liver and renal dysfunction, sharp reductions in serum levels of cytokines (IL-1beta, IL-6, IL-10, TNF-alpha, and IL-2), and improved survival. In contrast, PMN depletion before CLP resulted in substantial increases in bacteremia and no evidence for attenuation of liver and renal failure dysfunction. These data suggest that at the onset of sepsis, PMN are important in regulating the levels of bacteremia, whereas after the onset of sepsis, as they lose innate immune functions, their presence is associated with higher levels of bacteremia and intensified organ dysfunction.
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PMID:Harmful and protective roles of neutrophils in sepsis. 1598 19


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