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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical similarities between the sepsis syndrome seen in severe acute pancreatitis (AP) and that seen after burns, postoperative infection and trauma led to a series of investigations to elucidate the nature of immunological compromise in cases of severe AP. Significant alterations in lymphocyte surface marker antigen expression were demonstrated with reduced total T-lymphocyte (CD3), T-helper (CD4) and T-suppressor (CD8) cell numbers (P < 0.001, Mann-Whitney U test) during the acute phase of severe attacks compared with mild attacks. These abnormalities were reversible with increased CD3 (P < 0.005, Student's t test), CD4 (P < 0.01) and CD8 (P < 0.05) numbers in the convalescent phase of severe attacks. Experiments with a murine model of acute pancreatitis demonstrated further cellular immune abnormalities in AP as have previously been documented in models of burn, trauma and sepsis. Decreased interleukin-2 production by mononuclear cells (P < 0.005) was associated with susceptibility to endotoxin challenge. Immunomodulatory therapy in the form of exogenous IL-2 therapy or with induction of endotoxin tolerance not only led to increased IL-2 production (P < 0.01) but also to significantly reduced mortality after endotoxin exposure compared with control animals (P < 0.05, Wilcoxon-Gehan statistic). Cellular immune dysfunction in acute pancreatitis is seen in humans and in a murine model; it is associated with endotoxin exposure and with susceptibility to the deleterious effects of endotoxin and can be partially reversed by exogenous IL-2 therapy and by induction of endotoxin tolerance.
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PMID:Endotoxin, cellular immune dysfunction and acute pancreatitis. 894 39

Monocyte/T-cell interactions play 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 cells secrete interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13. In volunteers systemic endotoxin administration initiates many features of gram-negative sepsis including cytokine release, but the patterns (i.e., Th1/Th2 patterns) have not yet been studied. In this institutional review board-approved study we investigated the effect of an intravenous bolus of endotoxin from Escherichia coli (4 ng/kg body weight) on the Th1/Th2 response in four female and four male volunteers (mean age 27.1 +/- 0.8 years). Plasma cytokine levels for IL-2, IL-4, IL-10, IL-12, and IFN-gamma and heart rate, mean arterial pressure, temperature, white blood cell, and differential blood count were determined before and hourly for 5 hours after endotoxin administration. All volunteers had tachycardia, decreased mean arterial pressure, fever, and leukocytosis. IL-10 was significantly (p < 0.05) elevated (9.4 +/- 3.9 pg/ml vs 60.9 +/- 19.3 pg/ml) 3 hours after endotoxin was administered, whereas IL-2 levels were decreased (69 +/- 26 U/ml vs 30.6 +/- 14.9 U/ml). IL-4 and IFN-gamma were not detectable in plasma. No changes were seen in the plasma levels of IL-12. Systemic responses did not correlate with changes in cytokine levels. Cytokine patterns found in this study suggest that after low-dose endotoxin administration the T-cell immune response is shifted towards the Th2 cell type response. This early shift towards a Th2 cell response may contribute to the depressed cell-mediated immune response associated with sepsis.
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PMID:The 1996 Moyer Award. Effects of endotoxin on the Th1/Th2 response in humans. 895 35

Platelet-activating factor (PAF) was tested for its ability to alter yields of human interferon (IFN) produced from peripheral blood mononuclear cells (PBMC). Using different concentrations of phytohemagglutinin (PHA) we could not demonstrate a consistent effect of PAF at any concentration tested on the yield of IFN-gamma. Similarly, although PAF was associated with a slight enhancement of IFN-gamma yields when PBMC were induced by interleukin-2 (IL-2), the results were not statistically significant. No effect was observed on the accumulation of human IFN-gamma mRNA induced by PHA. Furthermore, PAF did not enhance yields of IFN-gamma when the cells were induced by poly I:poly C. We conclude that although PAF may have a role in sepsis, it is not likely that this is in any way related to its ability to significantly alter the yield of interferons.
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PMID:Platelet-activating factor and the production of human interferon-gamma. 905 17

Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.
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PMID:Cytokine networks with infection: mycobacterial infections, leishmaniasis, human immunodeficiency virus infection, and sepsis. 908 11

Gut-origin sepsis is a serious medical complication of military injuries following hemorrhage. Splanchnic ischemia induces intestinal necrosis leading to systemic bacteremia. Rat and mouse models of hemorrhagic shock were used to investigate bacterial translocation from the gut. Orally administered ameliorative treatments using the cytokine interleukin-6 (IL-6) were able to reduce or eliminate sepsis following hemorrhage. To mimic battlefield wounds and hemorrhage, anesthetized mice were bled from the femoral artery, held at a mean arterial blood pressure of 35 mm Hg for 1 hour, and then resuscitated with shed blood and 2-fold volume lactated Ringer's solution. Anesthetized rats were bled from the carotid artery at a rate of 15 ml/kg at 1 ml/minute. Bacteriological cultures of livers and mesenteric lymph nodes from hemorrhaged animals given recombinant IL-6 had significantly fewer colonies per gram of tissue than saline-fed controls. 125I-labeled IL-6 remained in the gut for up to 6 hours giving regional protection, whereas labeled interleukin-2 was disseminated throughout the body in the same time. In vivo and vitro studies of IL-6 showed that long incubations with high doses of trypsin, chymotrypsin, or intestinal contents were necessary to inactivate the bioactivity of this cytokine. Electron microscopy showed that epithelial cells from hemorrhaged mice fed saline had sparse or missing villi and vacuolated cytoplasm. Epithelial cells from control mice or mice hemorrhaged and fed cytokine appeared completely normal. Oral administration of IL-6 on the battlefield may be an important treatment for the prevention of sepsis following hemorrhage.
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PMID:Systemic sepsis following hemorrhagic shock: alleviation with oral interleukin-6. 915 11

Altered host defense mechanisms after major surgery or trauma are considered important for the development of infectious complications and sepsis. In the present study, we demonstrate that major surgery results in a severe defect of T-lymphocyte proliferation and cytokine secretion in response to coligation of the antigen receptor complex and CD28. During the early postoperative course, reduced cytokine secretion was observed for interleukin-2 (IL-2), gamma interferon, and tumor necrosis factor alpha, which are associated with the Th1 phenotype of helper T lymphocytes, and for IL-4, the index cytokine of Th2 cells. During the late postoperative course, T-cell cytokine secretion increased to normal levels. Production of the anti-inflammatory cytokine IL-10 was altered, with different kinetics being selectively elevated during the late postoperative course. In contrast, the capacity of peripheral blood monocytes to present bacterial superantigens and to stimulate T-cell proliferation was normal or enhanced after surgery despite a significant loss of cell surface HLA-DR molecules. Thus, the level of major histocompatibility complex class II protein expression does not appear to predict the antigen-presenting capacity of monocytes obtained from surgical patients with uneventful postoperative recovery. Secretion of IL-1beta and IL-10 by endotoxin-stimulated peripheral blood monocytes was increased at different time points after surgery. Major surgery therefore results in a distinct pattern of immune defects with a predominant defect in the T-cell response to T-cell receptor- and CD28 coreceptor-mediated signals rather than an impaired monocyte antigen-presenting capacity. Suppression of T-cell effector functions during the early phase of the postoperative course may define a state of impaired defense against pathogens and increased susceptibility to infection and septic complications.
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PMID:Distinct mechanisms of immunosuppression as a consequence of major surgery. 916 65

The results of using recombinant interleukin-2 from yeast for the treatment of patients with the sepsis syndrome are discussed. It is noted that there was a marked immunomodulating effect, the amount of endogenous interleukin-2 increased. The patients' state was shown to become less severe (according to the SAPS criterion), the patients felt better. A conclusion is made of the possibility in principle and expediency of using cytokines for the treatment of patients with the sepsis syndrome.
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PMID:[The principle of cytokine therapy in the sepsis syndrome (a preliminary report)]. 923 67

The activity of glutaminase is high in lymphoid organs, lymphocytes and macrophages and increases in the popliteal lymph node in response to an immunological challenge. Consistent with this high activity, glutamine is utilised at a high rate by resting lymphocytes and macrophages in culture. Mitogenic stimulation of lymphocytes increases both glutaminase activity and the rate of glutamine utilisation. The major products of glutamine utilisation by lymphocytes and macrophages in culture are glutamate, aspartate, lactate and ammonia; < 25% of the glutamine used is completely oxidised. It is suggested that the high rate of glutamine utilisation by cells of the immune system serves to maintain a high intracellular concentration of intermediates of biosynthetic pathways such that optimal rates of DNA, RNA and protein synthesis can be maintained. In the absence of glutamine, lymphocytes do not proliferate in vitro; proliferation increases greatly as the glutamine concentration increases. The synthesis of interleukin-2 by lymphocytes and of interleukin-1 by macrophages is glutamine-dependent. Macrophage-mediated phagocytosis is influenced by glutamine availability. Glutamine is synthesized in skeletal muscle. Skeletal muscle and plasma glutamine levels are lowered by sepsis, injury, burns, surgery and endurance exercise and in the overtrained athlete. These observations indicate that a significant depletion of the skeletal muscle glutamine pool is characteristic of trauma and it has been suggested that the lowered plasma glutamine concentration contributes, at least in part, to the immunosuppression which accompanies such situations. Beneficial effects of the provision of glutamine or its precursors have been reported in patients following surgery, radiation treatment or bone marrow transplantation or suffering from injury, sepsis or burns.
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PMID:The proposed role of glutamine in some cells of the immune system and speculative consequences for the whole animal. 926 77

To systematically elucidate the gene expression of inflammatory and immune modulators following middle cerebral artery occlusion (MCAO) in the rat, we studied interleukin-10 (IL-10) along with tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interleukin-2 (IL-2). Gene expression of these cytokines was studied ipsilateral and contralateral to the MCAO, with mRNA expression levels evaluated 2, 4, 6, 8 and 12 h following permanent MCAO by reverse transcriptase polymerase chain reaction (RT-PCR). In the ischemic hemisphere TNF-alpha and IL-1beta mRNA increased at 2 h following MCAO and peaked at 6 h, with IL-10 mRNA detected only at 6 h. Contralaterally, both TNF-alpha and IL-1beta mRNAs were expressed with a similar pattern to that in the ischemic hemisphere, but at lower levels, with no contralateral IL-10 expression. There was no difference in IL-2 gene expression between control and experimental animals in either hemisphere. These results demonstrate that IL-10 and TNF-alpha, IL-1beta gene expression is induced early following MCAO. The temporal profile of these cytokines is similar to that seen in sepsis, where TNF-alpha induces IL-10; subsequently IL-10 inhibits TNF-alpha expression. The similarity of the temporal profile of cytokine expression in sepsis and cerebral ischemia suggests that IL-10 should be studied as a potential inhibitor of TNF-alpha production in ischemic brain tissue. The factors inducing contralateral expression of the inflammatory cytokines, TNF-alpha and IL-1beta, along with the potential clinical significance of this remote cytokine gene expression, merit further study.
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PMID:Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion. 941 30

Nitric oxide is an uncharged free radical that mediates a range of physiologic processes in the vasculature. As a principal determinant of vascular tone, the overproduction of nitric oxide has been implicated in the pathogenesis of sepsis- and cytokine-induced hypotension. The enzyme that produces nitric oxide, nitric oxide synthase, exists in three isoforms. One of the three isoforms, inducible nitric oxide synthase, is expressed in many cell types only after stimulation by cytokines and/or endotoxin. Compared to the constitutive nitric oxide synthase enzymes, the inducible enzyme generates larger quantities of nitric oxide for longer periods. Expression of the inducible isoform in vitro requires stimulation by a mixture of cytokines including interferon-gamma, tumor necrosis factor-alpha, and interleukin-1 beta. These proinflammatory cytokines are known mediators of sepsis and are also produced in the serum of cancer patients during interleukin-2 therapy, thereby leading to excessive production of nitric oxide. Interleukin-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are indistinguishable from those seen in septic shock. Many of these hemodynamic effects have been linked to the overproduction of nitric oxide via a cytokine-inducible nitric oxide pathway. In this regard, inhibition of nitric oxide synthesis represents a novel approach to limit the cardiovascular toxicity associated with interleukin-2 therapy and to improve its therapeutic index. Clinical trials to evaluate the efficacy of nitric oxide synthase inhibitors in reversing the hypotension associated with IL-2 therapy are now underway.
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PMID:The role of nitric oxide in interleukin-2 therapy induced hypotension. 954 27


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