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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is a constellation of clinical signs and symptoms resulting from excessive systemic host inflammatory response to infection. This inflammatory response is largely mediated by cytokines, which are released into the systemic circulation. Plasma concentrations of specific cytokines, TNF alpha, IL-1 beta, IL-6 and IL-8 are frequently elevated in human sepsis and cytokine concentrations correlate with severity and outcome of sepsis. In addition to pro-inflammatory cytokines, soluble cytokine receptors, cytokine receptor antagonists and counter-inflammatory cytokines are also produced in large quantities in patients with sepsis; however, the specific role of these molecules in sepsis remains undefined. A complex interaction of cytokines and cytokine-neutralizing molecules probably determines the clinical presentation and course of sepsis. Intervening in this sequence of events to modify the host inflammatory responses may prove to be a beneficial treatment strategy for sepsis, but currently tested anticytokine therapies have been largely unsuccessful.
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PMID:Sepsis and cytokines: current status. 870 20

It is apparent from preclinical and clinical research to date that continued evaluation of new and alternative treatment strategies is required to eliminate the obligate periods of neutropenia and thrombocytopenia after acute high-dose irradiation. Future treatment strategies may involve new combinations of cytokines to affect hematopoietic stem cell proliferation and "engineered" cellular grafts to provide short-term in vivo expansion of neutrophils and platelets in an effort to bridge the cytopenic gap until endogenous or transplanted stem cells regenerate the hematopoietic and immune systems. Cytokine-mobilized peripheral blood and cord blood will provide alternative sources of allogeneic stem and progenitor cells in support of primary engraftment, delayed engraftment or secondary failure of the initial graft, as well as starting populations for various ex vivo expansion protocols. Further insights into the relative quality of stem cell populations and the factors that regulate their survival and self renewal, and the identification and roles of adhesion molecules in stem cell mobilization, engraftment, and interaction with the adult marrow microenvironment will provide the basis for future treatment strategies for the radiation-induced hematopoietic syndrome. As our ability to treat the hematopoietic syndrome improves, damage to other organ systems such as the skin, lung, and/or gastrointestinal tissue will emerge as dose-limiting. At the same time, the characterization of receptors for inflammatory cytokines, cytokine receptor antagonists, and anti-endotoxin antibodies has allowed significant insights into the mechanisms and pathogenesis of sepsis. However, translation of this knowledge into a treatment modality for septic patients is precluded by the lack of any clear-cut beneficial effect from the many clinical trials. The research and clinical results presented in this volume and recent conferences reflect the body of knowledge that will lead to further developments in assessment, prophylaxis, and treatment of radiation injuries in the areas of infectious disease and the hematopoietic, gastrointestinal, and cutaneous syndromes.
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PMID:Therapy of radiation injury. 936 12

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.
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PMID:Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. 955 30

Fever is defined as a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous cytokines, some functioning as pyrogens and others as antipyretics. Previous data obtained with the use of traditional pharmacological techniques, such as the injection of neutralizing antibodies, implicate interleukin (IL)-1 and IL-6 as endogenous pyrogens or inducers of fever. In almost all instances in which the endogenous actions of IL-1 or IL-6 are antagonized, fevers are attenuated. Other cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and IL-10, are thought to act as endogenous antipyretics or inhibitors of fever. In several studies, the inhibition of TNF action has enhanced fever. Recently, mice genetically engineered to lack cytokines or their receptors in all tissues of the body have been used to examine the regulation of IL-1, IL-6, TNF, and IL-10 on fever. Data obtained with these mice shed new light on our understanding of cytokine interactions in fever and, in some instances, contradict data obtained with pharmacological methods. This review summarizes the responses of cytokine and cytokine receptor knockout mice to fevers induced by lipopolysaccharide, turpentine, and sepsis.
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PMID:Invited review: cytokine regulation of fever: studies using gene knockout mice. 1201 85

Tissue factor is a transmembrane procoagulant glycoprotein and a member of the cytokine receptor superfamily. It activates the extrinsic coagulation pathway, and induces the formation of a fibrin clot. Tissue factor is important for both normal homeostasis and the development of many thrombotic diseases. A wide variety of cells are able to synthesize and express tissue factor, including monocytes, granulocytes, platelets and endothelial cells. Tissue factor expression can be induced by cell surface components of pathogenic microorganisms, proinflammatory cytokines and membrane microparticles released from activated host cells. Tissue factor plays an important role in initiating thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. Recent findings suggest that tissue factor can also function as a receptor and thus may be important in cell signaling. The present minireview will focus on the role of tissue factor in the pathogenesis of septic shock, infectious endocarditis and invasive aspergillosis, as determined by both in vivo and in vitro models.
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PMID:Endothelial cells, tissue factor and infectious diseases. 1288 52

We hypothesized that acute measles infection imposes severe metabolic demands on malnourished children. Nigerian rural communities, characterized by severe poverty and extensive malnutrition, served as site for this study. Sixty-five children (mean [+/-SD] age 2.67 +/- 1.96 years) with measles and a randomly selected equal number of children (age 2.83 +/- 1.23 years) from the same communities but measles-free were studied. Both groups were serologically negative for human immunodeficiency virus. The percentages of nonmeasles group who were underweight and wasted as exemplified by weight for age (WAZ) and weight for height (WHZ) scores less than -2.0 SD were 43% and 23%, respectively. Comparative values for the measles group (66% and 54% respectively) were significantly (P < 0.01 or 0.001) different. Compared to the controls, measles-infected children had significantly (P < 0.001) higher plasma cortisol level, marked hyporetinemia (plasma retinol 0.62 +/- 0.24 micromol/L) and prominent reduction (P < 0.002) in the sum of serum essential amino acids. Measles promoted a TH(1) to TH(2) cytokine shift, with severe depletion of plasma interleukin (IL)-12, a key cytokine in the development of cell mediated immunity. IL-6, a key stimulator of hepatic acute phase protein response, was prominently (P < 0.002) increased in plasma in measles-infected children. Glucocorticoids exert effects on cytokine expression, as well as on cytokine receptor expression and cytokine-regulated biological responses. They enhance synergistically, the effects of IL-1 and IL-6 type cytokines on many acute phase proteins. Because of the prominent increase in circulating level of cortisol in acute measles, glucocorticoid treatment for associated sepsis may pose serious problems. Additionally, glucocorticoids antagonize several effects of retinoids at cellular and transcriptional levels, thus suggesting that hypercortisolemia may increase the requirement for retinoids.
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PMID:Metabolic effects of acute measles in chronically malnourished Nigerian children. 1513 52

Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-kappaB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.
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PMID:Regulation of IL-1 and TNF receptor expression and function by endogenous macrophage migration inhibitory factor. 1698 23

Immunotherapy in the critically ill is an appealing notion because of the apparent abnormal immune and inflammatory responses seen in so many patients. The administration of a medication that could alter immune responses and decrease mortality in patients with sepsis could represent a 'magic bullet'. Various approaches have been tried over the last 20 yr: steroids; anti-endotoxin or anti-cytokine antibodies; cytokine receptor antagonists; and other agents with immune-modulating side-effects. However, in some respects, research along these lines has been unsuccessful or disappointing at best. The current state of knowledge is summarized with particular reference to sepsis and the acute respiratory distress syndrome.
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PMID:Immunomodulation in the critically ill. 1947 16

Tissue factor (TF) is a member of the cytokine receptor superfamily and binds FVII/VIIa. The TF:FVIIa complex has both procoagulant and signaling activities. It functions in many biological processes, including hemostasis, thrombosis, inflammation, angiogenesis and tumor growth. Importantly, TF is essential for hemostasis. However, increased TF expression within atherosclerotic plaques and elevated levels of circulating TF-positive micro particles promote thrombosis. TF increases inflammation by enhancing intravascular fibrin deposition, by increasing the formation of pro-inflammatory fragments of fibrin and by generating coagulation proteases, including FVIIa, FXa and thrombin, that activate protease-activated receptors (PARs). In endotoxemia and sepsis, TF-dependent thrombin generation and activation of PAR1 on dendritic cells enhance inflammation. Finally, the TF:FVIIa complex contributes to tumor growth by activating PAR2.
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PMID:The many faces of tissue factor. 1963 Jul 86

Sepsis progresses to multiple organ dysfunction due to the uncontrolled release of inflammatory mediators, and a growing body of evidence shows that neural signals play a significant role in modulating the immune response. Thus, similar toall other physiological systems, the immune system is both connected to and regulated by the central nervous system. The efferent arc consists of the activation of the hypothalamic-pituitary-adrenal axis, sympathetic activation, the cholinergic anti-inflammatory reflex, and the local release of physiological neuromodulators. Immunosensory activity is centered on the production of pro-inflammatory cytokines, signals that are conveyed to the brain through different pathways. The activation of peripheral sensory nerves, i.e., vagal paraganglia by the vagus nerve, and carotid body (CB) chemoreceptors by the carotid/sinus nerve are broadly discussed here. Despite cytokine receptor expression in vagal afferent fibers, pro-inflammatory cytokines have no significant effect on vagus nerve activity. Thus, the CB may be the source of immunosensory inputs and incoming neural signals and, in fact, sense inflammatory mediators, playing a protective role during sepsis. Considering that CB stimulation increases sympathetic activity and adrenal glucocorticoids release, the electrical stimulation of arterial chemoreceptors may be suitable therapeutic approach for regulating systemic inflammation.
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PMID:Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy. 2556 88


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