Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Elevated systemic levels of tumor necrosis factor (TNF) have been directly correlated with increased mortality during experimental gram-negative bacterial sepsis. Although monoclonal antibodies (mAbs) directed against gram-negative bacterial lipopolysaccharide (endotoxin, LPS) decrease TNF production in vitro and enhance survival in vivo, the precise relationship between inhibition of TNF secretion and protective capacity has not been defined. We hypothesized that protective anti-LPS mAbs inhibited LPS-stimulated TNF production. To test this hypothesis, we first produced and characterized three anti-LPS mAbs. We then examined the ability of these mAbs to decrease TNF secretion in an in vitro assay using cells from the murine macrophage cell line RAW 264.7. Subsequently, we assessed the protective capacities of these anti-LPS mAbs in a murine mucin peritonitis model of sepsis using live Escherichia coli 0111:B4 bacterial challenge. Our results demonstrated that those anti-LPS mAbs that decreased LPS-stimulated TNF secretion in vitro were protective in vivo. We concluded that inhibition of TNF secretion in vitro reflected protective capacity and that anti-LPS mAbs may confer protection via abrogation of macrophage TNF secretion. Inhibition of TNF production in vitro may provide a valuable test that may facilitate the selection of protective anti-LPS mAbs.
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PMID:Protective anti-lipopolysaccharide monoclonal antibodies inhibit tumor necrosis factor production. 159 69

While a number of clinical studies indicate that elevated serum cytokine [interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)] levels are associated with enhanced mortality in sepsis, the time course and the role that different macrophage (M phi) populations play in releasing these cytokines remain to be determined. To study this, polymicrobial sepsis was induced in C3H/HeN mice by cecal ligation and puncture (CLP). The animals were then sacrificed at 1, 4, or 24 hr post-CLP. Blood was taken for serum cytokine level determination. Macrophages, of either peritoneal (PM phi) or alveolar (AM phi) origin, were harvested by lavage, and their innate vs. inducible cytokine productive capacities were assessed by incubation with or without endotoxin (lipopolysaccharide; LPS). Serum levels of TNF were significantly enhanced 1 hr post-CLP (CLP = 3.8 +/- 2.4* vs. sham = 0.4 +/- 0.9 U/ml; P less than 0.05 by t test). However, not until 4 hr post-CLP were marked increases in IL-6 observed (CLP = 318.0 +/- 209.0* vs. sham = 1.1 +/- 0.5 U/ml), which remained elevated through 24 hr post-CLP (CLP = 11.3 +/- 15.0* vs. sham = 0.03 +/- 0.02 U/ml). Cytokine release (IL-1, IL-6, TNF) from PM phi (without the addition of LPS) was detectable only in cells harvested 1 h following CLP. Alveolar M phi from septic mice showed little in vivo activation. Septic PM phi IL-1 and IL-6 production was markedly depressed at all time points with LPS stimulation, but TNF release remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Polymicrobial sepsis selectively activates peritoneal but not alveolar macrophages to release inflammatory mediators (interleukins-1 and -6 and tumor necrosis factor). 161 4

The incidence and mortality, pathogenesis, clinical manifestations, and management of sepsis and the sepsis syndrome are reviewed, and the use of antiendotoxin monoclonal antibodies to treat patients with sepsis is discussed. The sepsis syndrome and septic shock are induced by the presence of endotoxin, a lipopolysaccharide found in the outer membrane of gram-negative bacteria. Proper management of gram-negative sepsis includes appropriate antimicrobial therapy, fluids and electrolytes, nutritional support, administration of vasopressors, and mechanical ventilation if necessary. To date, two antiendotoxin monoclonal antibodies have been produced and subjected to extensive clinical testing. HA-1A, a human cell line-derived monoclonal immunoglobulin M (IgM) antibody that contains only a small fragment of murine protein, was tested in one trial. HA-1A significantly reduced mortality in patients with sepsis and gram-negative bacteremia and produced better resolution of major morbidities than placebo in those patients. E5, an IgM antibody produced entirely via murine monoclonal antibody technology, was evaluated in two trials. Results from the first trial showed that E5 significantly reduced mortality in patients with gram-negative infection who were not in refractory shock. In contrast, results from the second trial did not show any significant reduction in mortality among patients with gram-negative infection who received E5. However, resolution of major morbidities occurred more frequently among E5 recipients in both trials. HA-1A and E5 were both well tolerated in the trials. The cost of therapy is expected to be $3000-$4000 per treatment course. The antiendotoxin monoclonal antibodies represent the next step along the path toward important reductions in morbidity and mortality from gram-negative infection. However, the financial implications of the use of HA-1A and E5 are enormous, and stringent patient selection criteria for administration of these products will have to be developed.
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PMID:Gram-negative sepsis, the sepsis syndrome, and the role of antiendotoxin monoclonal antibodies. 161 15

The endogenous adrenocortical response to sepsis is critical for host survival. The in vivo interactions among the endogenous glucocorticoid response, the induction of cytokines, and host survival during endotoxemia were explored in this study by use of the glucocorticoid receptor antagonist RU 486. Male Lewis rats underwent sterile insertion of a right jugular venous catheter. After a 72-h recovery period, animals received a 50% lethal dose of Escherichia coli endotoxin (2.5 mg/kg) via the catheter after pretreatment for 30 min prior to lipopolysaccharide (LPS) treatment with (i) vehicle alone intravenously (i.v.) (-corticosterone [-Cort]/-RU 486/+LPS) (n = 10), (ii) the antiglucocorticoid RU 486 (10 mg/kg) i.v. (-Cort/+RU 486/+LPS) (n = 11), or (iii) RU 486 (10 mg/kg) i.v. in animals that had undergone subcutaneous implantation of a corticosterone pellet at the time of catheter insertion (+Cort/+RU 486/+LPS) (n = 10). Except in animals receiving corticosterone pretreatment, baseline plasma corticosterone levels were low in all groups. Plasma corticosterone levels increased significantly (P less than 0.001) above the baseline following LPS administration. Animals in the -Cort/+RU 486/+LPS-treated group exhibited significantly increased mortality (P less than 0.001), with only 9% of the animals surviving at 72 h, as well as significantly increased plasma interleukin-6 levels, compared with animals receiving the vehicle alone (-Cort/-RU 486/+LPS), which showed 50% mortality. Pretreatment with corticosterone and RU 486 (+Cort/+RU 486/+LPS) significantly (P less than 0.001) reversed the mortality observed with RU 486 pretreatment alone (-Cort/+RU 486/+LPS), with 70% of the animals surviving at 72 h, and significantly attenuated the peak plasma tumor necrosis factor and interleukin-6 responses to LPS, compared with those in the animals treated with vehicle alone. These data demonstrate that the blockade of glucocorticoid binding by RU 486 increases LPS-induced mortality. The reversal of this effect by the induction of hypercorticosteronemia prior to RU 486 and LPS exposure (+Cort/+RU 486/+LPS) improves survival and is further associated with significant attenuation of cytokine production. Therefore, these data suggest that the protective effect of the endogenous glucocorticoid response to acute endotoxemia may result from the down-regulation of a potentially lethal cytokine response.
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PMID:In vivo effects of the antiglucocorticoid RU 486 on glucocorticoid and cytokine responses to Escherichia coli endotoxin. 161 34

Hepatocellular dysfunction, as a result of sepsis or endotoxemia, plays a critical role in the pathogenesis of multiple systems organ failure. Conventional methods to assay hepatic ATP require large tissue samples, making repeat measurements in the same animal impossible, and are unable to detect the minimal changes in metabolism consistent with early or reversible cellular injury. 31P NMR is a modality available for the in vivo measurement of high energy phosphates. Inorganic phosphate (Pi) and phosphomonoester (PME) ratios (markers of cellular metabolism and viability) as well as fractionated ATP may be repeatedly quantitated. To assess the early effects of endotoxemia on hepatic function, phosphorus spectra of the liver were obtained using a 1.7-cm surface coil in six rats after the ip administration of 4 mg/kg Escherichia coli lipopolysaccharide. Conventional assay was performed on 24 matched controls. Pi, PME, alpha-, beta-, and gamma-ATP peaks (expressed as percentage total signal area) were collected over 20 min, integrated, and analyzed. Pi/beta-ATP decreased over time until 6 hr reflecting ongoing uptake of inorganic phosphate and continued cellular metabolism. PME/beta-ATP ratios, which indicate cellular viability, became significantly elevated at 6 hr. Using 31P NMR, beta-ATP best reflected the early subtle energy changes present prior to cell death and subsequent organ failure with significant decreases at 2, 4, and 6 hr. Conventional assay for ATP confirmed similar trends. We conclude that 31P NMR is a valuable tool for the study of reversible hepatic energy changes during early endotoxemia.
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PMID:In vivo [31P]NMR assessment of early hepatocellular dysfunction during endotoxemia. 161 20

Pentoxifylline (PTX), a methylxanthine, can suppress polymorphonuclear leukocyte (PMN) activation and attenuate sepsis-induced acute lung injury. We investigated whether PTX prevents non-PMN-dependent lung injury. First we studied four groups of granulocyte-depleted guinea pigs (control, PTX, Escherichia coli, and E. coli + PTX). Lung injury was assessed by wet-to-dry lung weight (W/D) ratio and lung tissue-to-plasma 125I-albumin ratio (albumin index, AI). The E. coli group showed a significant increase in the lung W/D ratio and AI compared with the control and PTX groups. However, PTX did not prevent the E. coli-induced increase in the lung W/D ratio and AI. Next we investigated the effects of PTX on endothelial cell monolayer permeability and adenosine 3',5'-cyclic monophosphate (cAMP) levels. Whereas E. coli lipopolysaccharide (LPS) alone increased the endothelial permeability, PMNs added to the endothelial monolayers and exposed to LPS enhanced the increase. PTX attenuated the permeability increase mediated by LPS-exposed PMNs. PTX did not prevent the LPS-induced increase in permeability when PMNs were not present, although PTX increased endothelial cell cAMP levels. These data demonstrate that 1) PTX does not prevent lung injury in granulocyte-depleted guinea pigs; 2) PTX does not prevent LPS-induced increases in endothelial cell permeability, despite increased cAMP levels; and 3) PTX attenuates PMN-dependent increases in endothelial cell permeability.
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PMID:Pentoxifylline does not attenuate acute lung injury in the absence of granulocytes. 165 91

Continuous infusion of a nonlethal dose of Escherichia coli lipopolysaccharide (LPS) (0.5 mg/kg) induced early (3 h) accumulation of polymorphonuclear leukocytes (PMNL) in rat liver followed by later (30 h) greater extravasation of mononuclear phagocytes (MNP) (E. B. Rodriguez de Turco and J. A. Spitzer, J. Leukocyte Biol. 48:488-494, 1990). Nonparenchymal liver cells from rats treated for 3 and 30 h with LPS were recovered by centrifugal elutriation, yielding a 23-ml/min fraction (endothelial cells) and a 45-ml/min fraction (PMNL, Kupffer cells, and MNP), and compared for their capacity for basal and agonist-stimulated superoxide (O2-) production. Stimulation with phorbol myristate acetate and opsonized zymosan caused a dose-dependent release of O2- from the 45-ml/min fraction derived from rats treated for 3 h with saline, but not from the 23-ml/min fraction. Further purification of the 45-ml/min fraction by discontinuous density gradient centrifugation into a Kupffer and a PMNL fraction revealed that most of the agonist-induced O2- release was generated by infiltrating PMNL at this early time point of LPS infusion. By 30 h of LPS infusion, although enhancement of the phorbol-12-myristate-13-acetate- and opsonized zymosan-stimulated release of O2- was observed in the 45-ml/min fraction, but not in the 23-ml/min fraction, the maximum release of O2- was smaller than that observed in the rats treated for 3 h. Our results support the following conclusions: (i) after a 3-h LPS infusion, PMNL found in the liver in increased numbers are also highly primed for agonist-stimulated release of O2-, while Kupffer cell priming is of a lesser extent; (ii) after a 30-h infusion of LPS, infiltrating MNP found in the liver in increased numbers are primed for agonist-induced O2- release, while priming of PMNL has diminished; (iii) at both 3 and 30 h of LPS infusion, liver endothelial cells are not significantly primed for agonist-stimulated O2- release; and (iv) in vivo priming by LPS infusion at both 3 and 30 h was not reversed by the experimental method used for cell recovery (ca. 3 h), thus suggesting that in vivo LPS priming of O2- release may ultimately lead to severe impairment of liver function and metabolism observed during endotoxemia and sepsis if not therapeutically blocked at an early time point.
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PMID:Continuous infusion of Escherichia coli endotoxin in vivo primes in vitro superoxide anion release in rat polymorphonuclear leukocytes and Kupffer cells in a time-dependent manner. 165 86

Interferon-gamma and other cytokines enhance macrophage (M phi) antimicrobial function and have been considered for therapeutic use in sepsis. Systemic sequelae of macrophage activation, however, are unclear. This study examined the effects of M phi activating cytokines (interferon-gamma [IFN-gamma] and interleukin-4 [IL-4]) and monoclonal antibodies directed against these cytokines in modulating the acute septic response. CFW/Swiss Webster mice (n = 345) received endotoxin (lipopolysaccharide [LPS]: 60 mg/kg body weight intraperitoneally) and were randomized to five treatment groups: IFN-gamma (10(4) units), IL-4 (10(4) units), IgG1 isotype antibody (TRFK5: 200 micrograms), anti-IFN-gamma (200 micrograms), or anti-IL-4 (200 micrograms) monoclonal antibodies (MAbs) given simultaneously or 2 hours after LPS. Animals were divided into two groups and studied for mortality or measurement of peritoneal M phi superoxide anion release (O2-), tumor necrosis factor (TNF), and IL-6 production 6 hours after administration of LPS +/- experimental regimens. Serum TNF and IL-6 also were assessed at 2 and 4 hours after LPS, respectively. Administration of LPS resulted in a 27% survival compared with 10% in the IFN-gamma and 13% in the IL-4 groups. Treatment with anti-IFN-gamma offered protection against LPS lethality (93%-100% survival, p less than 0.001 vs. other groups) when given either simultaneously or 2 hours after LPS. Anti-IFN-gamma also significantly decreased PM phi O-2 and TNF release. Thus anti-IFN-gamma may have an important role in the modulation of the acute septic response.
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PMID:Inhibition of macrophage-activating cytokines is beneficial in the acute septic response. 165 39

A number of human monoclonal antibodies (HmAb) recognizing type-specific determinants expressed by the lipopolysaccharide (LPS) of Pseudomonas aeruginosa and by the capsular polysaccharide (CPS) of Klebsiella were generated for potential treatment of nosocomial infections. The goal is to administer these type-specific HmAb prophylactically as a "cocktail" providing broad coverage. Lymphoblastoid cell lines (LCL) secreting HmAb recognizing P. aeruginosa LPS, toxin A or Klebsiella CPS were obtained by Epstein Barr Virus (EBV) transformation of peripheral blood lymphocytes (PBL) from donors immunized with either a polyvalent Klebsiella CPS or P. aeruginosa O-polysaccharide-toxin A conjugate vaccine. LCL secreting antibodies of the desired specificities were fused to a heteromyeloma cell line. Stable clones were selected by limiting dilution. Hybridomas secreting IgM HmAb which recognized P. aeruginosa Habs serotype 3 and 4 and all 7 Fisher immunotypes were isolated. All were able to prevent fatal experimental P. aeruginosa sepsis in mice when passively transferred. In addition, 4 lines secreting IgG HmAb which neutralize the cytotoxic activity of toxin A were characterized. IgM and IgA secreting hybridoma cells with specificity for Klebsiella CPS of 22 different serotypes were also isolated. Preliminary studies indicate that these HmAb are opsonic.
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PMID:Human monoclonal antibodies to Pseudomonas aeruginosa type-specific lipopolysaccharides, toxin A and Klebsiella capsular polysaccharides. 169 65

O-specific polysaccharide (O-PS) isolated from serotype 18 Escherichia coli lipopolysaccharide (LPS) was covalently coupled to either Pseudomonas aeruginosa toxin A (TA) or or cholera toxin (CT). The conjugates were nontoxic and nonpyrogenic. The conjugates were well tolerated on parenteral administration to human volunteers, with only mild, transient local reactions reported. Immunization engendered an IgG antibody response to both the O-PS and carrier protein. Anti-LPS antibody promoted the uptake and killing of an E. coli O18 strain bearing the K1 capsule by human polymorphonuclear leukocytes, which was complement dependent. Antibody to carrier protein neutralized the activity of native TA or CT in cell culture assays. Passively transferred IgG isolated from the serum of immunized donors provided a significant (P less than .01) degree of protection against fatal experimental E. coli O18 sepsis in mice. This study illustrates the potential use of such conjugates as vaccines against E. coli extraintestinal infections.
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PMID:Safety and immunogenicity of Escherichia coli O18 O-specific polysaccharide (O-PS)-toxin A and O-PS-cholera toxin conjugate vaccines in humans. 170 98


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