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)

Thrombocytopenia occurs frequently in newborn infants with sepsis, but the exact mechanism remains obscure in those infants who do not have evidence of disseminated intravascular coagulation. Since recent work has suggested a possible immune mechanism for thrombocytopenia observed in adults with sepsis, we have investigated the role of platelet-associated immunoglobulin in severe neonatal infections. To detect PAIgG we use a method employing protein A and peroxidase-antiperoxidase as a labeled antibody. PAIgG was quantitated by phase contrast microscopy and expressed as a reactive index. Our control group included 16 normal newborn infants whose mean RI was 0.65 +/- 0.01 SE. In addition to the control group, five infants with nonimmune thrombocytopenia were included; their mean RI was 0.66 +/- 0.01 SE. Seventeen newborn infants with severe infections were assayed for PAIgG. Eight of nine infants with bacterial infections had increased RI, with a mean of 1.16 +/- 0.03 SE (P less than 0.01). Six of the eight infants with viral infections had elevated RI, with a mean of 1.23 +/- 0.03 SE (P less than 0.01). These findings suggest that an immune mechanism may be involved in the thrombocytopenia of severe neonatal infection.
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PMID:Immune thrombocytopenia in severe neonatal infections. 705 22

Unbound bilirubin, bilirubin binding capacity, and bilirubin binding affinity were determined by the horseradish peroxidase method at the time of maximum hyperbilirubinemia and/or before exchange transfusions in 13 preterm infants who later died and had autopsies performed. Five of the 13 infants had kernicterus at autopsy. There were no significant differences in weight, gestational age, highest indirect bilirubin level, albumin concentration, severity of acidosis, use of assisted ventilation, sepsis, or other major clinical complications between the five infants with kernicterus and the eight infants without kernicterus. Compared with the eight nonkernicteric infants, the five kernicteric infants had significantly higher unbound bilirubin concentrations (13 +/- vs 27 +/- 9 nmoles/liter, respectively, P less than .05) and significantly lower bilirubin binding capacity and affinity. The data suggest an association between low bilirubin binding capacity and affinity, increased unbound bilirubin, and kernicterus in preterm infants with severe clinical complications.
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PMID:Unbound bilirubin and kernicterus in low-birth-weight infants. 720 Feb 29

Free bilirubin concentration, bilirubin-binding capacity, and bilirubin-binding affinity were determined by peroxidase oxidation in 66 newborn infants. Twelve healthy term infants whose unconjugated bilirubin concentration was 15.8 +/- 3.7 mg/dl (mean +/- SD) had a binding capacity of 31.9 +/- 3.7 mg/dl (bilirubin: albumin molar ratio = 0.89 +/- 0.07) and Ka = 28 +/- 11 x 10(7)/M. Twelve term infants with clinical complications of asphyxia, acidosis, respiratory distress, or sepsis, and 17 preterm infants with no complications had lower serum albumin concentrations and slightly reduced binding capacity and affinity compared to the healthy term infants. Free bilirubin concentrations were similar in these three groups, averaging 8 to 9 nmol/l in each group. Twenty-five preterm infants with complications had significantly higher free bilirubin (19 +/- 11 nmol/l), lower binding capacity, and lower binding affinity than any of the other three groups (P less than 0.01 for all comparisons). Five of the 25 sick preterm infants had kernicterus at autopsy. These five infants were similar to the other 20 in birth weight, gestational age, serum bilirubin, and serum albumin level, but had significantly higher free bilirubin and significantly lower binding capacity and affinity. The data suggest that serious neonatal illness is associated with a marked reduction in bilirubin-binding capacity and affinity and an increased risk of kernicterus in preterm infants. The mechanism by which neonatal morbidity decreases bilirubin binding is not known.
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PMID:Free bilirubin concentrations and bilirubin-binding affinity in term and preterm infants. 735 54

Ethanol is a potent immunosuppressive agent that impairs neutrophil effector function. The purpose of this study was to determine whether granulocyte colony-stimulating factor (G-CSF), a cytokine that increases neutrophil number and functional activity, could prevent the ethanol-induced impairment of antibacterial host defense. Rats were injected with human recombinant G-CSF for 2 days. Eight hr after the last injection of G-CSF, animals were infused with ethanol (or saline) for 1 hr before the subcutaneous injection of live Escherichia coli. The infusion of alcohol was continued after the bacterial challenge and produced blood alcohol levels of 275-300 mg/dl. In control animals, the injection of E. coli resulted in a marked leukopenia. There was an influx of leukocytes into the subcutaneous space where the bacteria were injected, and neutrophil accumulation in tissues adjacent to the focus of infection (i.e., dorsal skin and muscle). Based on myeloperoxidase activity, there was no detectable accumulation of neutrophils in other soft tissues. In acutely intoxicated rats, leukocyte migration to the inflammatory site was impaired, and the number of viable bacteria isolated from the subcutaneous pocket was markedly increased. G-CSF prevented the sepsis-induced leukopenia, increased the influx of neutrophils in to the infection site, reduced the number of bacteria in the subcutaneous lavage fluid, and decreased the incidence of bacteremia in ethanol-treated rats when compared with rats not receiving G-CSF. These results demonstrate that G-CSF is a potent immunomodulator that stimulates neutrophil recruitment selectively to the site of infection and that can be used to ameliorate the ethanol-induced impairment in bacterial host defense.
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PMID:Granulocyte colony-stimulating factor prevents ethanol-induced impairment in host defense in septic rats. 750 76

Increased gut permeability (GP) following burn injury has been implicated in the predisposition to sepsis and multiple systems organ failure (MSOF). Since previous studies have identified only "global" alterations in GP, we examined the jejunum, ileum, and colon individually for GP using probes of two different sizes: fluorescein isothiocyanate-dextran-3 (FDEX, molecular weight 4387 d) and horseradish peroxidase (HRP, molecular weight 40,000 d). Animals were examined for GP at 1, 2, or 4 days following burn. The GP was significantly increased in all segments combined following burn injury to both the small probe (FDEX, p < 0.001) and the larger probe (HRP, p < 0.06) versus controls. The GP was significantly greater for FDEX versus HRP (p < 0.001). Jejunal permeability to FDEX and HRP increased most at 24 hours. Ileal and colonic GP to FDEX increased early also, but were higher at days 2 and 4. These results suggest that, following burn injury, there is differential GP that is size and site dependent, and that increased GP may last well beyond 24 hours postburn despite feeding.
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PMID:Differential changes in intestinal permeability following burn injury. 751 7

Many studies indicate a pivotal role for neutrophil adhesion in sepsis-associated lung injury. Neutrophil adhesion to endothelium depends on activation and expression of selectin and integrin adhesion receptors. We studied the effects of pretreatment with a dual-binding porcine anti-E- and anti-L-selectin monoclonal antibody (EL-246) on a porcine model of sepsis-induced lung injury. Four groups were studied for 5 h. Group 1 (control animals) received intravenous saline only. Group 2 (septic) received a 1-h infusion of Pseudomonas aeruginosa. Group 3 (EL-246 pretreatment) received EL-246 (1 mg/kg) prior to Pseudomonas infusion. Group 4 (EL-246 controls) received EL-246 infusion only. Group 2 animals showed rapid, significant decline in arterial pH and oxygen tension whereas, in Group 3, physiologic deterioration was significantly attenuated. Bronchoalveolar lavage at 5 h showed a significant increase in neutrophil count and protein content in Group 2. Group 3, however, showed no significant differences in these parameters compared with control animals. Despite severe neutropenia, lung myeloperoxidase content at 5 h was significantly reduced in Group 3 compared with Group 2. There was no significant difference in pulmonary and systemic hemodynamics between Groups 2 and 3. Group 4 animals exhibited a transient neutropenia, but otherwise no other differences in measured parameters were found compared with Group 1 control animals. In conclusion, EL-246 significantly reduced neutrophil accumulation in lung and attenuated sepsis-induced lung injury, but failed to attenuate deranged pulmonary and systemic hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A dual-binding antibody to E- and L-selectin attenuates sepsis-induced lung injury. 754 Dec 77

Oxidant-mediated toxicity resulting from acute pulmonary inflammation has been demonstrated in acute lung injury. A potent biological oxidant, peroxynitrite, is formed by the near diffusion-limited reaction of nitric oxide with superoxide. In addition to having hydroxyl radical-like oxidative reactivity, peroxynitrite is capable of nitrating phenolic rings, including protein-associated tyrosine residues. Nitric oxide does not directly nitrate tyrosine residues, therefore, demonstration of tissue nitrotyrosine residues infers the action of peroxynitrite or related nitrogen-centered oxidants. Lung tissue was obtained from formalin-fixed, paraffin-embedded autopsy specimens, and specific polyclonal and monoclonal antibodies to nitrotyrosine were visualized by diaminobenzidene-peroxidase staining. Acute lung injury resulted in intense staining throughout the lung, including lung interstitium, alveolar epithelium, proteinaceous alveolar exudate, and inflammatory cells. In addition, staining of the vascular endothelium and subendothelial tissues was present in those patients with sepsis-induced acute lung injury. Antibody binding was blocked by coincubation with nitrotyrosine or nitrated bovine serum albumin but not by aminotyrosine, phosphotyrosine, or bovine serum albumin. Reduction of tissue nitrotyrosine to aminotyrosine by sodium hydrosulfite also blocked antibody binding. In control specimens with no overt pulmonary disease, there was only slight staining of the alveolar septum. These results demonstrate that nitrogen-derived oxidants are formed in human acute lung injury and suggest that peroxynitrite may be an important oxidant in inflammatory lung disease.
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PMID:Evidence for in vivo peroxynitrite production in human acute lung injury. 769 61

It has been proposed that the reduction in mortality in animal models of sepsis by activated protein C (APC) is mediated by an antiinflammatory property rather than the well-characterized anticoagulant action. Human recombinant APC was examined for potential antiinflammatory activity in the pentobarbital-anesthetized rat. In the dermal reversed passive Arthus model, APC (20.0 mg/kg/h, i.v.) elevated clotting time 10-fold 3 h after the Arthus challenge, at which time, the wet-weights from Arthus dermal samples in APC rats (120.0 +/- 1.5 mg, n = 10) did not differ from controls (120.1 +/- 1.5 mg, n = 10) but were 30% heavier than remote noninflamed skin (92.0 +/- 2.0 mg, n = 10), indicating that APC treatment did not diminish tissue edema associated with immune-complex deposition. Skin-lesion myeloperoxidase (neutrophil marker enzyme) activities from APC rats were not significantly different from controls but was 21-fold more than remote noninflamed skin, indicating that APC treatment did not diminish dermal recruitment of neutrophils. In the intestinal ischemia/reperfusion model, 1 h complete occlusion of the superior mesenteric artery and an additional 4 h reperfusion was associated with a 2.87-fold increase in lung myeloperoxidase activity compared to sham-operated rats. APC (1.0 mg/kg/h, i.v.) did not diminish the elevation in this index of lung neutrophil sequestration. In conclusion, APC did not produce an antiinflammatory effect in the rat models used.
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PMID:Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation. 771 66

The proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) are produced within the lung during sepsis, and may induce neutrophil sequestration resulting in neutrophil-mediated lung injury. We hypothesized that, if there is a cause and effect between TNF alpha or IL-1 production and lung neutrophil sequestration during chronic sepsis, TNF alpha mRNA and IL-1 mRNA levels in the lung after cecal ligation and puncture should correlate with the number of sequestered neutrophils as measured by the myeloperoxidase (MPO) content of the lung. To test this hypothesis, Swiss Webster mice were subjected to varying degrees of infectious challenge by single and double-puncture cecal ligation and puncture, or simultaneous antibiotic treatment, and their lungs and blood were harvested at 24 h. Lung TNF alpha and IL-1 beta mRNAs were measured by the reverse-transcription differential polymerase chain reaction, and MPO was measured by colorimetric assay. TNF alpha serum levels showed no correlation with the MPO content of the lung, whereas IL-1 levels were undetectable. Lung TNF alpha mRNA correlated weakly, and IL-1 beta mRNA exhibited a strong correlation with lung MPO (r = .9, p < .01), but administration of anti-TNF alpha- or anti-IL-1-neutralizing antibodies did not prevent a rise in lung MPO. IL-1 beta mRNA in bronchoalveolar macrophages correlated well with whole lung tissue IL-1 beta mRNA levels (r = .91, p < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Passive immunization against tumor necrosis factor and interleukin-1 fails to reduce lung neutrophil sequestration in chronic sepsis. 774 65

Anticytokine therapies have been promulgated in gram-negative sepsis as a means of preventing or neutralizing excessive production of proinflammatory cytokines. However, systemic administration of cytokine inhibitors is an inefficient means of targeting excessive production in individual tissue compartments. In the present study, human gene transfer was used to deliver to organs of the reticuloendothelial system antagonists that either inhibit tumor necrosis factor-alpha (TNF-alpha) synthesis or block its interactions with cellular receptors. Mice were treated intraperitoneally with cationic liposomes containing 200 micrograms of either a pCMV (cytomegalovirus)/p55 expression plasmid that contains the extracellular domain and transmembrane region of the human p55 TNF receptor, or a pcD-SR-alpha/hIL-10 expression plasmid containing the DNA for human interleukin 10. 48 h later, mice were challenged with lipopolysaccharide (LPS) and D-galactosamine. Pretreatment of mice with p55 or IL-10 cDNA-liposome complexes improved survival (p < 0.01) to LPS-D-galactosamine. In additional studies, intratracheal administration of IL-10 DNA-liposome complexes 48 h before an intratracheal LPS challenge reduced pulmonary TNF-alpha levels by 62% and decreased neutrophil infiltration in the lung by 55% as measured by myeloperoxidase activity (both p < 0.05). Gene transfer with cytokine inhibitors is a promising option for the treatment of both the systemic and local sequelae of septic shock.
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PMID:Human tumor necrosis factor receptor (p55) and interleukin 10 gene transfer in the mouse reduces mortality to lethal endotoxemia and also attenuates local inflammatory responses. 776 15


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