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)

We carried out a study in patients with severe neutropenia from hematologic malignancy and suspected gram-negative sepsis to evaluate the clinical significance of endotoxin concentrations in plasma before and during a therapeutic intervention with a human polyclonal immunoglobulin M (IgM)-enriched immunoglobulin preparation (Pentaglobin; Biotest, Dreieich, Germany). Twenty-one patients with acute leukemia or non-Hodgkin's lymphoma entered the study upon the development of clinical signs of gram-negative sepsis and received the IgM-enriched immunoglobulin preparation every 6 h for 3 days (total dose, 1.3 liter with 7.8 g of IgM, 7.8 g of IgA, and 49.4 g of IgG), in addition to standardized antibiotic treatment. Concentrations of endotoxin and IgM and IgG antibodies against lipid A and Re lipopolysaccharide (LPS) in plasma were determined by a modified chromogenic Limulus amebocyte lysate test and semiquantitative enzyme linked immunosorbent assay, respectively, before each immunoglobulin infusion and during the following 25 days. Seventeen patients were endotoxin positive; in five of these patients, gram-negative infection was confirmed by microbiologic findings. Prior to therapy, endotoxemia correlated significantly with the occurrence of fever, and a quantitative correlation between the endotoxin concentration and body temperature was found during the individual course of infection in 8 of the 17 patients. Overall mortality from endotoxin-positive sepsis was 41% (7 of 17) and 64% (7 of 11) in patients with symptoms of septic shock. Nonsurvivors had significantly higher maximum concentration of endotoxin in plasma compared with those of survivors at the first study day (median of 126 versus 34 pg/ml; P < 0.05) and during the whole septic episode (median of 126 versus 61 pg/ml; P < 0.05). In survivors, immunoglobulin therapy resulted in a significant decrease in endotoxin levels in plasma within the initial 18-h treatment period, from a pretreatment median value of 28 pg/ml to a value of 8 pg/ml (P< 0.05). In the seven patients who died from uncontrollable infection, no effect of therapy on endotoxin levels in plasma was observed. IgM and IgG antibodies against lipid A and Re LPS increased significantly under immunoglobulin treatment, with significant correlations between antibodies against lipid A and Re LPS. These data strongly suggest a prognostic significance of the endotoxin levels in plasma and a potential effect of treatment with a polyclonal IgM-enriched immunoglobulin preparation. Further studies are needed to substantiate these findings and to assess the impact on the clinical course by way of a prospective placebo-controlled clinical trial.
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PMID:Endotoxin concentration in neutropenic patients with suspected gram-negative sepsis: correlation with clinical outcome and determination of anti-endotoxin core antibodies during therapy with polyclonal immunoglobulin M-enriched immunoglobulins. 144 93

Macrophages contribute to the systemic inflammatory response that characterizes the sepsis syndrome through the production of inflammatory cytokines such as tumor necrosis factor (TNF). Liposome-encapsulated hemoglobin (LEH), a potential red cell substitute, is cleared by fixed tissue macrophages. In these studies, in vitro incubation of alveolar macrophages with stored LEH was shown to inhibit the expression of TNF induced by endotoxin (lipopolysaccharide, LPS) stimulation. This effect was dependent on LEH dose but independent of the period of exposure to the LEH. Despite inhibition of TNF expression, Northern blot analysis of total cellular RNA from LPS-stimulated macrophages revealed accumulations of TNF-specific transcripts in cells treated with or without LEH. Thus the mechanism of LEH inhibition of TNF expression appears to involve a posttranscriptional event. Although these results suggest a potential advantage of resuscitation with LEH when sepsis complicates hemorrhagic shock, immunomodulation in vivo remains to be defined.
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PMID:Liposome-encapsulated hemoglobin inhibits tumor necrosis factor release from rabbit alveolar macrophages by a posttranscriptional mechanism. 146 39

Sepsis has been shown to impair ventilatory muscle function. To determine whether this can be attributed to direct effects of inflammatory mediators on muscle fibers, we carried out in vitro studies on hamster costal diaphragm. Baseline measurements included supramaximal peak twitch (Pt) and tetanic tension (Po), twitch half relaxation time (1/2RT) and time-to-peak tension (TTP), and force frequency response (15 to 80 Hz). Fatigability was evaluated using 60-Hz stimulations at a duty cycle of 0.4 until tension fell to 50% of baseline. Preparations were then incubated in one of the following for 60 min: (1) Krebs solution (n = 5), (2) nonstimulated monocyte supernatant (n = 5), or (3) lipopolysaccharide-stimulated monocyte supernatant (n = 5). Baseline Pt, Po, 1/2RT, TTP, force frequency response, and fatigue profile were similar between groups. After incubation there was a significant fall in Pt (mean +/- SD, 538 +/- 65 to 288 +/- 13 g/cm2, p < 0.05) and Po (1,268 +/- 132 to 921 +/- 64 g/cm2, p < 0.05) in the LPS group, with no change in the other groups. There was no change in TTP; however, 1/2RT was lower in the LPS-stimulated group after incubation (p < 0.05). There was a rightward shift in the force frequency response for the LPS-stimulated group (p < 0.05). When normalizing for initial Po, there was no significant change in the time to fatigue for any of the three groups. This study demonstrated that monocyte secretory products impair diaphragmatic contractility in vitro by a direct effect on muscle fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monocyte inflammatory mediators impair in vitro hamster diaphragm contractility. 148 41

There is increasing experimental and clinical evidence that a number of cytokines play a major role in the response to injury and infection and in the development of organ damage in critically ill patients. Tumour necrosis factor (TNF) is now proposed to be a key mediator of organ injury during sepsis. It is elevated early in the course of septic shock and high levels correlate with unfavourable outcome. In animals it can produce the effects of endotoxin. The prophylactic administration of anti-TNF antisera protects mice and rabbits from lethal effects of lipopolysaccharide. Interleukin-1 (IL-1) is an endogenous pyrogen which induces leukocytosis and muscle catabolism. It causes hypotension and tachycardia by reducing smooth muscle contractility. IL-1 receptor blockers have been shown to diminish mortality in experimental endotoxic shock. Interleukin-6 (IL-6) is a pyrogen and lymphocyte activator. It is the major stimulus to acute phase protein production by the liver. A recently described neutrophil-activating peptide (Interleukin-8; IL-8) may be involved in the pathogenesis of ARDS. High blood levels of IL-8 have been found in patients with septic shock. Platelet-derived growth factor (PDGF) has been shown to stimulate TNF production, leukocyte chemotaxis and pulmonary vasoconstriction in response to endotoxin. Other cytokines and growth factors have not yet been studied in critical illness. The cytokine network can be either protective or damaging. Its activation during critical illness triggers complex and still poorly understood interactions. A better comprehension of its role in protection from infection and in the pathogenesis of multiple organ failure may allow therapeutic manipulations aimed at minimising adverse effects while retaining immunological protection.
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PMID:The cytokine network in the critically ill. 152 67

The chemiluminescence of isolated neutrophils, stimulated with N-formyl-L-methionyl-L-leucyl-L-phenylalanine, latex, lipopolysaccharide from Escherichia coli, zymosan A, or 4 beta-phorbol 12 beta-myristate 13 alpha-acetate was inhibited up to 99% by the dose-dependent oxygen radical scavenging activity of 6 mmol/l ascorbic acid. The chemiluminescence of neutrophils in blood, stimulated with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, or with zymosan A was inhibited 35% or 48%, respectively, by 6 mmol/l ascorbic acid. Ascorbic acid, up to 6 mmol/l, did not inhibit the release of beta-N-acetylglucosaminidase and elastase from isolated neutrophils activated by the above stimulatory agents. During neutrophil/nylon fibre interaction ascorbic acid reduced the oxygen radical production dose-dependently (77% inhibition of the chemiluminescence response at 6 mmol/l ascorbic acid), whereas the adherence was unaffected. Hypoxanthine/xanthine oxidase-generated oxygen radicals were scavenged by ascorbic acid in a dose-dependent manner (99% inhibition of the chemiluminescence response at 100 mumol/l ascorbic acid). From these results, ascorbic acid can highly be recommended for animal experiments and clinical studies in patients with trauma, shock and sepsis and for studies to prevent or reduce reperfusion injuries.
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PMID:Effect of ascorbic acid on neutrophil functions and hypoxanthine/xanthine oxidase-generated, oxygen-derived radicals. 152 46

Although tumor necrosis factor (TNF) is undoubtedly a major mediator of the antitumor and shock-inducing activities of lipopolysaccharide (LPS), the outcome of a challenge with TNF is highly dependent on the presence or absence of other substances or conditions. We have previously shown that to obtain lethality in mice after TNF administration both TNF receptor (TNF-R) types have to be triggered. This is illustrated by the fact that recombinant human (rh) TNF, which is a selective murine (m) TNF-R55 agonist, is not lethal, whereas mTNF, which binds both mTNF-R55 and mTNF-R75, is lethal in mice. Triggering of TNF-R75 is, however, no longer needed when sensitizers such as galactosamine or low doses of LPS or interleukin (IL)-1 are also present. Here, we report that this selective species specificity of TNF is also reflected in patterns of induced IL-6: both rmTNF and rhTNF could induce considerable IL-6 peak levels in the plasma (up to 10 ng/ml) 2 to 3 h after TNF administration. However, only rmTNF was capable of inducing the same pattern of sustained IL-6 levels previously observed after lethal LPS doses, while rhTNF only caused induction of transient IL-6 levels, as found after nonlethal LPS doses. We also observed that the sensitizer IL-1 could complement rhTNF to induce such a sustained IL-6 induction. Since we were interested in sensitizers with a defined mechanism of action, we further investigated the effects of the glucocorticoid and progesterone inhibitor RU38486 on the lethal and IL-6-inducing properties of TNF. We observed that RU38486 closely mimicked IL-1: both had similar effects on IL-6 induction and sensitized mice to the lethal effects of TNF with comparable efficiency and kinetics. Using a monoclonal anti-IL-1R antibody, we finally observed that the effects of RU38486 were most probably not mediated by IL-1. These observations suggest that a glucocorticoid-antagonistic activity might be a key factor in the pathways leading to septic shock and that such activity could be a key target for the pharmacological manipulation of sepsis.
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PMID:The glucocorticoid antagonist RU38486 mimics interleukin-1 in its sensitization to the lethal and interleukin-6-inducing properties of tumor necrosis factor. 153 65

Previous work in our laboratory demonstrated increased sensitivity of senescent (24-month-old) mice to cecal ligation and puncture (CLP) sepsis compared with that of mature (12-month-old) mice. In this study the median lethal dose of the strain of Escherichia coli most frequently isolated during CLP sepsis was determined. No significant age-associated difference in the mean lethal dose or the mean survival time was noted; however, sham surgery before injection of E. coli decreased the mean lethal dose by at least 100-fold. With surgical manipulation, the average time to death after bacterial injection simulated more closely that observed after CLP surgery. Host responses to CLP sepsis were investigated by measuring the levels of corticosterone, glucose, and tumor necrosis factor (TNF) in the sera of mature and senescent mice at 2-h intervals after surgery. Corticosterone levels increased gradually during the course of sepsis in mature mice; however, senescent mice demonstrated a pronounced elevation in hormone levels at 2 and 4 h after surgery. At subsequent sampling intervals the corticosterone levels remained elevated, although they were similar for both ages. At all sampling intervals, the glucose levels in serum were lower in senescent mice than in mature mice. Pronounced hypoglycemia (less than 80 mg/dl) was observed in senescent mice at 8 h postsurgery. TNF was detected in serum within a narrow time frame in both age groups at 6, 8, and 10 h postsurgery. Although elevated TNF levels in serum were not seen in every mouse in each group (approximately 50%), the data hinted that senescent animals produced larger quantities of TNF during CLP sepsis than did mature animals. E. coli lipopolysaccharide (1 mg/kg) was injected intraperitoneally, and the TNF levels in serum and peritoneal lavage fluid were measured at 30, 60, and 90 min. Senescent mice demonstrated a level of TNF in serum at 90 min after lipopolysaccharide treatment that was 20-fold higher than that of mature mice (299,877 pg/ml versus 15,594 pg/ml). The amount of TNF produced locally in the peritoneum was also substantially higher in senescent mice than in mature animals (1,716 pg/ml versus 776 pg/ml). The increased production of TNF in senescent animals, despite elevated circulating corticosterone levels, suggested an age-related defect in glucocorticoid-directed downregulation of TNF production. This was confirmed in lipopolysaccharide-treated animals given exogenous dexamethasone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lipopolysaccharide-tumor necrosis factor-glucocorticoid interactions during cecal ligation and puncture-induced sepsis in mature versus senescent mice. 154 72

TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
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PMID:N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. 154 68

One percent of circulating IgG in humans recognizes galactose alpha 1,3 galactose residues (anti-Gal) and is synthesized in response to stimulation by enteric bacteria. In this study, we found that the prevalence of binding of anti-Gal to blood isolates is significantly higher than its binding to normal stool isolates. When anti-Gal bound onto the lipopolysaccharide of a representative blood isolate, Serratia marcescens #21, it blocked its alternative complement pathway (ACP) lysis and made the organism serum resistant. In contrast, when anti-Gal bound to the capsular polysaccharide of a serum sensitive Serratia, #7, it increased ACP killing of this strain. The mechanism of blockade of ACP lysis by anti-Gal did not involve a decrease in the number of C3 molecules deposited onto Serratia #21 or an inhibition of the binding of C3b to its LPS, nor did it change the iC3b and C3d degradation products of bound C3b or prevent membrane attack complex formation on this organism. Our findings suggest that the effect of anti-Gal on immune lysis is dependent on the bacterial outer membrane structure to which it binds. We postulate that anti-Gal may play a role in the survival of selected Enterobacteriacae in Gram-negative sepsis by blocking ACP-mediated lysis of such bacteria by the nonimmune host, and that this effect depends on where anti-Gal finds its epitope on the bacterial outer membrane.
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PMID:Human natural anti-Gal IgG regulates alternative complement pathway activation on bacterial surfaces. 155 84

Freedom from infection is the result of many tiers of immune defenses that harmoniously interact to rid the body of microorganisms and their products, which are perceived as foreign. The ability to distinguish self from nonself is embodied in lymphocytes, which serve both effector and regulatory functions. Through the elaboration of cytokines and immunoglobulins, lymphocytes recruit nonspecific immune effectors, focus their activity, and modulate the intensity of the immune response. The phylogenetically more primitive complement system serves a similar function. Although congenital defects in immune function occur, by far the most common causes of immunodeficiency are acquired and occur in patients treated for cancer with myelosuppressive, cytolytic drugs and in transplant recipients treated with immunosuppressants. HIV infection and malnutrition are responsible for even larger numbers of immunocompromised patients worldwide. The nature and severity of infections that occur as a result of immunodeficiency vary as a function of the immune effector targeted and the degree to which it is dysfunctional. Granulocytopenia is well tolerated unless the absolute number of circulating cells falls below 500/mm3. Profound granulocytopenia and deficits of neutrophil function are often manifest as bacterial or fungal infections. Complement deficiency predisposes to infection with encapsulated bacteria such as pneumococci, meningococci, and Haemophilus influenzae. T cells play such a central role in the immune response that their derangement is associated with susceptibility to almost any potential pathogen. These patients often succumb to mortal opportunistic infections. Recent advances in hybridoma and recombinant DNA technology have provided us with immunologic reagents that enable us to manipulate the immune response. Anti-CD3 monoclonal antibody has permitted salvage of solid organ transplants in well-defined clinical settings. Monoclonal antibodies against TNF-alpha and lipopolysaccharide may alter the consequences of gram-negative sepsis. Alternatively, recombinant cytokines have been associated with clinically significant tumor regression in selected patients, presumably by enhancing the nascent antitumor immune response. The development of immunologic reagents such as these in concert with our growing understanding of the immune system may translate to improved care for immunocompromised patients.
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PMID:Immune function and dysfunction. A primer for the radiologist. 157 Mar 93


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