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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Electron transfer from iron or copper ions to oxygen is an important example of cellular free radical initiation. Oxygen derived free radicals have been implicated as mediators of cellular injury in several model systems. To evaluate the importance of iron, copper and zinc levels on lipid peroxidation in peritonitis, we measured peritoneum malondialdehyde (MDA) as a marker of lipid peroxidation, zinc, copper, and iron levels during an animal model of intraperitoneal sepsis. Additionally the effects of the free radical scavenger alpha-tocopherol administration was studied. The peritoneum MDA, iron, copper and zinc levels were increased after induction of peritonitis with Escherichia Coli. The treatment with alpha-tocopherol was decreased the peritoneum MDA, iron and copper levels significantly, except the zinc level (p < 0.001, p < 0.001, p < 0.001, respectively). Additionally the alpha-tocopherol treatment for three days prior to injection of E.Coli more decreased MDA, copper and iron levels than that of the treatment with alpha-tocopherol at the time of injection of E. Coli (p < 0.001, p < 0.001, p<0.001, respectively). Our results indicated that copper, iron and zinc had important effects on peroxidation events in E. Coli induced peritonitis, and alpha-tocopherol treatment can improve the oxidant status.
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PMID:Trace element levels in the experimental peritonitis. 1178 75

A sepsis model induced by cecal ligation and puncture was used to study the role of endogenous carbon monoxide in hypotension pathogenesis of rats during septic shock. After administration of zinc deuteroporphyrin 2,4-bisglycol (ZnDPBG),an inhibitor of heme oxygenase (HO),blood pressure (BP),HO activity and carbon monoxide (CO) release from vascular muscle tissue were measured. The results showed that BP of sepsis rats, including systolic and diastolic arterial BP, decreased significantly while HO activity and CO content were significantly increased. In contrast, after administration of ZnDPBG, BP of sepsis rats was significantly increased while the HO activity and CO production were significantly decreased. These findings suggest that HO activity and CO release within vascular musculature are increased during septic shock; inhibition of HO may elevate BP of rats during septic shock through a decrease of endogenous CO production. It is concluded that endogenous CO derived from vascular muscle cells plays an important role in regulating vascular tone, and the up-regulation of HO activity followed by subsequent CO production contributes to hypotension pathogenesis during septic shock.
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PMID:Role of endogenous carbon monoxide in the pathogenesis of hypotension during septic shock. 1197 67

Pentoxifylline, a methylxanthine derivative and nonspecific type 4 phosphodiesterase inhibitor, has been used to improve survival of animals with sepsis and to attenuate lung injury in acute lung inflammation. The purpose of this study was to examine whether pentoxifylline would inhibit the expression of inflammatory cytokines, particularly tumor necrosis factor alpha (TNF), and thereby decrease the pathophysiology of acute porcine pleuropneumonia. E. coli lipopolysaccharide (LPS) and bacterial extracts of A. pleuropneumoniae--induced elevations in TNF mRNA which were fully abrogated by addition of pentoxifylline in both alveolar macrophage and neutrophil cultures. A 30% reduction in the level of LPS-induced interleukin (IL)-1beta mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL-1alpha or IL-8 expression in vitro. Pentoxifylline therapy in vivo significantly reduced the number of band neutrophils in swine but did not reduce the pathology associated with pleuropneumonia, including changes in serum zinc, iron, or haptoglobin. Neither did it alter TNF, IL-1, IL-6, or IL-8 expression. Measurement of pentoxifylline and its metabolites in pig sera suggested that efficacious doses of pentoxifylline were probably not achieved in vivo. However, subcutaneous doses of pentoxifylline higher than 25 mg/kg produced transient diarrhea, vomiting, and tremors. These results suggest that pentoxifylline is an effective pharmacological tool for the dissection of cytokine regulation in vitro, but inhibitory concentrations may not be achievable for in vivo pharmacological use in swine.
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PMID:Effects of pentoxifylline on inflammatory cytokine expression and acute pleuropneumonia in swine. 1199 42

The advantages of breastfeeding are briefly summarized and some strategies for promoting breastfeeding, based on the results of recently conducted studies on Costa Rica and the Philippines, are described. Advantages of breastfeeding include 1) the presence of elements in human milk which provide protection against infectious diseases and other substances which make it difficult for bacteria to survive; 2) the electrolyte composition of breast milk makes it unnecessay to provide infants with water, thereby reducing the risks associated with drinking contaminated water; and 3) the biochemical composition of human milk which reduces the risk of aminoacid imbalance and facilitates the absorption of irom, zinc and other elements. Breastfeeding also encourages closer contact between the mother and the infant and facilitates the bonding process. In addition, breastfeeding is economically less costly than bottle feeding. Despite these advantages there is a trend toward bottle feeding in developing countries. Only traditional rural societies, eg, Bangladesh, Peru, and zaire, at present carry on universal breastfeeding. Studies in the Philippines and in Costa Rica demonstrate that this trend can be countered by interventions such as such rooming-in in maternity hospitals and by providing effective follow-up support for breastfeeding mother after they leave the hospital. In a large maternity unit in a Costa Rica hospital these intervention techniques proved highly successful. Before the intervention in 1977, 20% of the infants were never breastfed, and 66% of all infants were artificially feed at 3 months of age. After intervention, 95% of the infants were successfully breastfeeding during their hospital stay, and at follow-up 3 months later, 80% of the infants were still being breastfed. In another hospital study in Costa Rica preterm and high risk babies were feed from a colostrum pool and the incidence rates for diarrheal illness, sepsis, acute respiratory infection, and meningitis greately declined.
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PMID:Protection, energy and nutrients. 1226 84

This article offers a protocol for reducing high case fatality rates from malnutrition. Most child deaths from malnutrition occur in the first few days of treatment. Treatment should involve stabilization followed by rehabilitation. The article describes the treatment procedures for hypoglycemia, hypothermia, dehydration, and missed infections and discusses feeding during the stabilization and rehabilitation phases of treatment. All severely malnourished children have excess body sodium but high intracellular and low plasma levels. Malnourished children have deficiencies of potassium and magnesium that may take 2 weeks to correct. Edema is partly due to deficiencies in potassium and magnesium. A high sodium intake can be corrected by rehydrating with a modified oral rehydration solution and the special starter formula. Family food should be prepared without salt. Magnesium and potassium should be added directly to foods. All severely malnourished children have vitamin and mineral deficiencies. Deficiencies may include vitamin A, zinc, copper, selenium, and folic acid. Multivitamin supplements can correct for micronutrient deficiencies. It is advised that zinc should not be ignored, since it is responsible for repair of intestinal mucosa, halting diarrhea, healing of ulcerated skin lesions, restoration of appetite, improved immune function, and lean tissue synthesis. Iron should not be given until growth starts, infections are controlled, and antioxidant status is improved (usually 1 week after admission). Early introduction of iron poses a risk of enhancing pathogen increases and stimulating production of toxic free radicals. Relapses can be reduced by training parents how to feed their child frequently with energy and nutrient dense foods. The regimen was tested in a South African project and found to reduce mortality from 30% to 20%. After greater hospital attention to treatment of sepsis and hypoglycemia, case fatality declined to 6%.
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PMID:Severe malnutrition in children: high case-fatality rates can be reduced. 1232 Dec 37

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca2+, Zn2+, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca2+ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms.
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PMID:[Metabolic aspects of endotoxin as a model of septic shock--approached from oxidative stress]. 1497 49

Chemotherapeutic efficacy is hampered by occurrence of drug resistance. Several mechanisms cause this phenomenon. A final common factor is the reduced capacity of resistant cells to go into apoptosis following treatment with DNA-damaging agents. It is therefore interesting to search for ways to facilitate this apoptotic process following use of chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), FasL and TNF-related apoptosis-inducing ligand (TRAIL) might be interesting candidates as they are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands potentiate chemotherapeutic drug effects in preclinical models. For the clinical application of TNF, FasL and TRAIL, it is of primary importance that their safety be guaranteed. RhTNF is the only ligand currently used in humans. However, systemic rhTNF has shown low antitumor activity and higher doses induce severe sepsis-like toxicity. Perfusion setting aimed at limb preservation with rhTNF plus melphalan is currently used in sarcoma patients. A number of options have been tested in the preclinical setting that might allow circumvention of TNF toxicity in the clinic. Systemic rhFasL administration in humans is not yet feasible because of observed severe liver toxicity in mice due to Fas-mediated apoptosis of hepatocytes. Measures to circumvent liver toxicity have not yet been exploited. Another option for using FasL in the clinic may be to identify an alternative route of administration. In the animal model, FasL appeared to be less toxic for the liver compared with anti-Fas antibodies when administered intraperitoneally. There are relatively nontoxic modulators of the Fas death pathway, such as interferon and nonsteroidal antiinflammatory drugs (NSAIDs), which might prove interesting in combination with chemotherapy. Finally, it may be possible to produce a modified FasL with a reduced toxicity profile. TRAIL, produced as soluble, zinc-stabilized rhTRAIL seems to be without preclinical toxicity. Agonistic DR4 and DR5 antibodies against their TRAIL death receptor are being studied as another potential clinical option to induce apoptosis. Due to the synergistic effect observed in the preclinical setting between death receptor ligands and other modulators of the death receptor pathways and chemotherapy, it may well be that this approach is especially of value in the clinic when combined with chemotherapy. Ideally, choices for specific (modified) death receptor ligands for the treatment of patients can be rationally made based on tumor characteristics.
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PMID:Modulation of death receptor pathways in oncology. 1498 48

Post-traumatic inflammation and sepsis induce changes in the lung microvasculature causing increased permeability. Pericytes, contractile cells positioned abluminally to endothelial cells, play a role in regulating this response. An in vitro model of microvascular lung pericytes (MLP) was used to investigate the effect of inhibiting heme oxygenase-1 (HO-1), a stress-induced enzyme, in the presence of varying levels of lipopolysaccharide (LPS), a mediator in the initiation of inflammation, on pericyte contractility. Rat MLP were cultured on collagen gel matrices. Cells were exposed to three concentrations of LPS in the presence of zinc protoporphyrin IX (ZnPP-9), a known inhibitor of HO-1. After 24 hours, the surface area of the collagen disks was quantified, thereby measuring pericyte contraction. ZnPP-9 caused a significant attenuation of the LPS-induced relaxation of the pericytes (P < or = 0.003). The effects of ZnPP-9, however, depended on the concentration of LPS to which the pericytes were exposed. Greater concentrations of LPS decrease the attenuating power of ZnPP-9. The inhibition of HO-1 diminished MLP relaxation triggered by LPS. The effect of ZnPP-9, however, is dependent on the concentration of LPS to which the MLP are exposed, indicating its saturation. ZnPP-9 may antagonize the microvascular response to trauma.
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PMID:Inhibition of heme oxygenase-1 in microvascular lung pericytes diminishes at high concentrations of an inflammatory mediator. 1501 17

Endotoxin (lipopolysaccharide, LPS)-induced tumor necrosis factor-alpha (TNF-alpha) release from Kupffer cells is critically involved in the pathogenesis of alcohol-induced liver injury. We recently reported that inhibition of alcohol-induced plasma endotoxin elevation contributes to the protective action of zinc against alcoholic hepatotoxicity. The present study was undertaken to determine whether zinc interferes with the endotoxin-TNF-alpha signaling pathway, and possible mechanism(s) by which zinc modulates the endotoxin-TNF-alpha signaling. Administration of LPS to metallothionein (MT)-knockout (MT-KO) mice and 129/Sv wild-type (WT) controls at 4 mg/kg induced hepatic TNF-alpha elevation at 1.5 hours, followed by liver injury at 3 hours. Zinc pretreatment (two doses at 5 mg/kg) attenuated TNF-alpha production and liver injury in both MT-KO and WT mice, indicating a MT-independent action of zinc. Immunohistochemical detection of the phosphorylation of I-kappaB and nuclear factor (NF)-kappaB in the liver of MT-KO mice demonstrated that zinc pretreatment abrogated LPS-induced NF-kappaB activation in the Kupffer cells. Fluorescent microscopy of superoxide by dihydroethidine and of zinc ions by Zinquin in the liver of MT-KO mice showed that zinc pretreatment increased the intracellular labile zinc ions and inhibited LPS-induced superoxide generation. These results demonstrate that zinc inhibits LPS-induced hepatic TNF-alpha production through abrogation of oxidative stress-sensitive NF-kappaB pathway, and the action of zinc is independent of MT. Thus, zinc may be beneficial in the treatment of LPS-induced liver injuries, such as sepsis and alcoholism.
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PMID:Abrogation of nuclear factor-kappaB activation is involved in zinc inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production and liver injury. 1511 1

By antiapoptotic effects and the induction of the heat-shock response, zinc is supposed to be a promising means of therapy during sepsis. As zinc also stimulates the expression of proinflammatory cytokines, its administration during the proinflammatory stage of septic shock might have adverse effects. Therefore, this study analyzes the influence of zinc during the acute phase of endotoxemia. In a pig model of acute endotoxemia, animals were divided into two groups: group I (n = 5) with saline treatment and group II (n = 5) with zinc treatment in close succession to lipopolysaccharide (LPS) (1.0 mu g/kg Escherichia coli endotoxin WO 111:B4). Hemodynamic and pulmonary monitoring was followed by combined reflection photometry, pulse oxymetry, blood gas samples, and temperature measurement. Plasma concentrations of tumor necrosis factor (TNF)alpha and interleukin (IL)-6 were analyzed by enzyme-linked immunosorbent assay (ELISA). Morphology included the weight of the lungs, the width of the alveolar septae, and the paracentral necrosis rate of the liver. After LPS infusion, group II (zinc) showed an impressive and significant deterioration of all pulmonary and most of the hemodynamical parameters compared to group I (saline). Levels of TNFalpha and IL-6 measured were significantly higher after zinc treatment. In accordance, we found significant more morphologic damages in group II (zinc). The almost simultaneous infusion of zinc and LPS complementary induced proinflammatory effects with a deleterious outcome. The same potentials characterizing zinc as a promising tool of prophylactic therapy in sepsis seem to ban its use during the acute phase.
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PMID:Deleterious effect of zinc in a pig model of acute endotoxemia. 1538 58


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