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)

Reconstituted high-density lipoproteins (rHDLs) have the ability to bind bacterial lipopolysaccharide and to reduce its endotoxin activity in vitro and in vivo. The aim of the present studies was to investigate the therapeutic potential of rHDL in bacteremia models. Gram-negative sepsis was induced in anesthetized rabbits by intravenous infusion of Escherichia coli organisms (4 x 10(9) CFU/kg infused over 2 hours) and treated with appropriate antibiotics. rHDL or placebo was infused either before (prophylaxis) or 1 hour after (therapy) the beginning of the bacterial challenge. In the control groups, the bacterial challenge resulted in transient bacteremia, high plasma levels of lipopolysaccharide, secretion of TNF, and symptoms of sepsis, including hypotension and acidosis. rHDL had no influence on blood bacterial counts; however, plasma lipopolysaccharide levels were significantly reduced. Peak plasma TNF concentrations were reduced after prophylactic but not after therapeutic rHDL administration. Both prophylactic and therapeutic rHDL improved clinical outcome: acidosis was significantly attenuated and blood pressure tended to be higher in the rHDL groups. No effects of rHDL were seen in a similar model of gram-positive sepsis induced by the infusion of Staphylococcus aureus.
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PMID:Protective effects of reconstituted high-density lipoprotein in rabbit gram-negative bacteremia models. 749 May 14

The serum levels of soluble TNF receptors I (sTNFR I) and sTNFR II were measured frequently in 14 patients with sepsis to evaluate the pattern of these TNF antagonists in relation to TNF alpha, Soluble TNFR I and II could be detected in all samples with significantly higher levels (p < 0.001) compared to healthy controls. The concentration of sTNFR I as well as sTNFR II was significantly higher in nonsurvivors compared to survivors during the first 36 h of sepsis (p < 0.001). Levels remained elevated throughout the evaluation with maximal values in patients who died. A positive correlation exists between both receptors and between soluble receptors and simultaneously obtained sepsis score (p < 0.01) while TNF immunoreactivity detected in 80% of all samples did not correlate to soluble receptor levels or sepsis score. Soluble receptors were constantly found in the circulation representing the inflammatory state throughout the evaluation even when TNF activity was undetectable.
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PMID:Pattern of soluble TNF receptors I and II in sepsis. 749 2

The L-arginine:nitric oxide (NO) biosynthetic pathway has been proposed as an important mediator in host defense mechanisms and may therefore play a role in the acute allograft response. We have studied NO generation in liver allograft rejection and determined its value in immunological monitoring. Stable end products of this pathway have been determined serially in 50 primary liver recipients and compared with 2 known mediators and markers of acute allograft rejection (IL-2R positive lymphocytes and circulating TNF alpha). Plasma concentrations of acid-labile nitrosocompounds (NOx), which increased during acute allograft rejection (P < 0.0001), correlated with rejection severity and were reduced after administration of supplemental high dose glucocorticoids. Concentrations were significantly lower in nonrejection graft complications but were elevated during episodes of sepsis. Correlations between plasma NOx levels and circulating TNF-alpha (r = 0.451, P < 0.001) and IL-2R-positive lymphocytes in peripheral blood (r = 0.781, P < 0.001) were demonstrated. In a logistic analysis of these variables, plasma NOx was the most predictive parameter of an episode of acute cellular rejection. Nitric oxide generation in FK506-treated patients was lower compared with patients receiving a CsA-based immunosuppression regimen and was associated with a reduced frequency of acute rejection in the FK506 group. These data are consistent with a role for NO in the cellular alloantigen immune response and indicate that monitoring of plasma levels of NOx may be useful in the detection of acute allograft rejection.
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PMID:Nitric oxide generation. A predictive parameter of acute allograft rejection. 752 65

We and others have proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. An effect of NO on cardiac sarcolemmal L-type calcium channels has also recently been proposed. The spontaneous beating rate of neonatal cardiac myocytes is regulated by the sarcolemmal L-type calcium channel. Accordingly, we sought to determine if cytokine-stimulated NO production could also regulate beating rates of neonatal cardiac myocytes. Treatment of neonatal rat cardiac myocytes with TNF, IL-1, IL-6, 10(-5)M NMA, or 10(-3)M NMA significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 hours (p < or = .01; n = 12 for each). Only IL-1 treatment resulted in significant nitrite levels vs. control over 48 hours (4.2 +/- 0.7 vs. 0.3 +/- 0.2 nmoles/1.25 x 10(-5) cells, respectively) (n = 12). Nitrite production by IL-1 was inhibited by 10(-3)M NMA but not 10(-5)M NMA (0.3 +/- 0.2 vs. 4.1 +/- 0.6 nmoles; p < .01; n = 12). The addition of 10(-5)M NMA to TNF, IL-1, and IL-6 did not alter the effect of the cytokines on the spontaneous beating rates of the cardiac cells (p < or = .01; n = 12 for each). These results strongly suggest that cytokines and NMA affect cardiac myocyte spontaneous beating rates through mechanisms independent of NO.
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PMID:Chronotropic effects of cytokines and the nitric oxide synthase inhibitor, L-NMMA, on cardiac myocytes. 752 6

Nitric Oxide (NO) has been implicated in the pathologic vasodilation of sepsis. Because NO can be measured in the exhaled gas of animals and humans, we hypothesized that increases in exhaled NO would occur in a septic model. Using a blinded design, 10 male Sprague-Dawley rats (300 to 400 g) were anesthetized, paralyzed, tracheotomized, and randomized (5/group) to receive an intravenous injection of either lipopolysaccharide (LPS) (Salmonella typhosa, 20 mg/kg) or placebo (equal volume of saline). Thereafter, exhaled gas was collected and measurements of NO concentration were made using chemiluminescence every 20 min for 300 min during ventilation (RR 40 breaths/min, VT 3 ml; PEEP 0, FIO2 0.21). Another group of 10 animals (5 LPS; 5 control) were treated in the same fashion and then killed at 240 min and an arterial blood sample obtained for blood gas and TNF alpha determinations. Pressure volume (PV) curves were constructed and lungs removed, preserved, and submitted for histologic evaluation. LPS-treated rats had lower mean arterial pressures than the control group, p < 0.0001. No significant differences in static lung compliance and PV curves were found in the two groups. TNF alpha levels were greater in the LPS group (1.40 +/- 0.24 ng/ml) versus control group (0.09 +/- 0.04 ng/ml), p < 0.001. By contrast to the control group, exhaled NO concentration rose in all LPS-treated rats at approximately 100 min and at about 160 min reached a plateau that was 6 times greater than control levels (p < 0.0001). There was greater interstitial, airspace, and total lung injury in the LPS group (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased nitric oxide in exhaled gas as an early marker of lung inflammation in a model of sepsis. 753 2

Granulocyte colony-stimulating factor (G-CSF) increases the number of circulating granulocytes and decreases TNF production while improving survival in sepsis models. To study the effects of G-CSF administration on sepsis and rejection, 37 primary liver allograft recipients received intravenous recombinant human G-CSF (rhG-CSF; 5-10 micrograms/kg/day) for the first 7-10 days following transplantation, targeting a blood absolute granulocyte count of between 10,000 and 20,000 cells/mm3. These recipients were monitored prospectively for sepsis and rejection, as were the previous 49 primary liver allograft recipients who did not receive G-CSF. Both groups utilized identical protocol immunosuppression and standardized diagnosis and treatment of sepsis and rejection. Univariate and logistic regression analysis of risk factors for sepsis and rejection revealed no difference between the two patient groups. G-CSF-treated patients developed an increased absolute granulocyte count over time (P < 0.0001, repeated-measures analysis of variance). G-CSF-treated patients had a decreased number of sepsis episodes per patient (0.92 +/- 1.5 vs. 2.18 +/- 2.8, P < 0.02, t test), and a lower percentage of sepsis-related deaths (8% vs. 22%, P < 0.04, chi-square test). The incidence of acute rejection was decreased in the G-CSF-treated group (22% vs. 51%, P < 0.01, chi-square test). These pilot data support further investigation into G-CSF's favorable effects on sepsis and rejection.
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PMID:The use of granulocyte colony-stimulating factor after liver transplantation. 753 58

The activation of endothelial and phagocytic cells, with concomitant formation of a range of adhesive molecules and inflammatory mediators, are integral parts of the host response to injurious agents (trauma, infection, altered antigens, toxins, chemicals etc.). The excessive mediator responses are associated with increased morbidity and lethality. Cytokines, soluble mediators secreted by cells, play an integral role in the metabolic and immune responses to the injurious agents. Widespread tissue damage, when associated with fulminant sepsis may induce massive release of cytokines (TNF, IL-1, IL-6), triggering certain steps of reactions involving multiple organs and culminating in the systemic inflammatory response syndrome, sepsis syndrome or multiple organ failure syndrome. (Fig. 2, Ref. 21.)
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PMID:[Inflammation, immunity and surgery]. 755 89

Tumor necrosis factor-alpha (TNF alpha), a cytokine that is produced in a variety of inflammatory diseases associated with cholestasis, is believed to be the primary mediator of the systemic effects of endotoxin. Thus, we have investigated the role of TNF alpha in the pathogenesis of endotoxin-induced cholestasis in intact animals, and in the uptake of taurocholate by cultured hepatocytes. Male Sprague-Dawley rats received either intravenous (IV) endotoxin (7.5 mg/kg) or monoclonal anti-TNF alpha antibody followed by endotoxin. Basal bile flow and bile salt excretion were measured for a 2-hour period, after which all animals received an IV bolus of taurocholate (10 mumol/100 g body weight). Endotoxin decreased basal bile flow by 41% and bile salt stimulated bile flow by 38% (n = 12; P < .01). Basal bile salt excretion was decreased 86% after endotoxin administration. Passive immunization with anti-TNF alpha antibody blocked this endotoxin-associated cholestasis. In addition, rat hepatocytes were isolated and cultured in the presence of either endotoxin (10 micrograms/mL) or TNF alpha (100 ng/mL) for 24 hours. These primary hepatocyte cultures exhibited a dose- and time-dependent, noncompetitive, inhibition of taurocholate uptake. We postulate that TNF alpha is an important mediator of the cholestasis of sepsis.
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PMID:Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. 755 81

Postsplenectomy bacterial sepsis may be fatal, due to defects in both cellular and humoral immune responses. The objective of this study was to assess the efficacy of peritoneal macrophage antibacterial function in the early postsplenectomy period. Murine models of splenectomy and sham operation were characterized and peritoneal macrophages were harvested 24 h to 1 wk after surgery. Cells from splenectomized animals demonstrated a nonsignificant delay in phagocytosis of Escherichia coli at 24 h with, however, significantly impaired killing of intracellular organisms at 24 h and 1 wk compared to the sham group. Paradoxically, the production of the macrophage antibacterial product superoxide anion was not impaired at either time point in the splenectomy group compared with sham-operated and control mice. Nitric oxide release was significantly lower in the splenectomized group (p = 0.006), a possible explanation for reduced bacterial killing. Mortality from bacterial peritonitis was significantly higher with concomitant splenectomy than in the sham splenectomy group at 24 h (p < 0.02). The production of TNF from macrophages was up-regulated immediately following splenectomy, a cytokine which may contribute to mortality from bacteremic shock. Local defects in macrophage antimicrobial function may contribute significantly to bacteremia and to subsequent mortality in the early postsplenectomy period.
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PMID:Characterization of the defects in murine peritoneal macrophage function in the early postsplenectomy period. 760 13

Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in non-human primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or placebo (n = 3). One hour after pretreatment, animals were infused with 5-10 x 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:PEG-BP-30 monotherapy attenuates the cytokine-mediated inflammatory cascade in baboon Escherichia coli septic shock. 763 Jan 20


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