Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of tumor necrosis factor-alpha (TNF alpha) stimulation of endothelial cells on the increase in endothelial permeability induced by H2O2. Bovine pulmonary microvascular endothelial cells (BPMVEC) were grown to confluence on a microporous filter and the 125I-albumin clearance rate across the monolayer was determined. Pretreatment with TNF alpha (100 U/ml) for 6 h had no direct effect on transendothelial 125I-albumin permeability. However, TNF alpha pretreatment enhanced the susceptibility of BPMVEC to H2O2; that is, H2O2 (10 microM) alone had no direct effect, whereas H2O2 increased 125I-albumin permeability more than threefold when added to monolayers pretreated for 6 h with TNF alpha. Determination of lactate dehydrogenase release indicated that increased permeability was not due to cytolysis. We measured the intracellular contents of GSH and catalase to determine their possible role in mediating the increased susceptibility to H2O2. TNF alpha treatment (100 U/ml for 6 h) decreased total GSH content and concomitantly increased the oxidized GSH content, but did not alter the cellular catalase activity. The role of GSH was examined by pretreating endothelial cells with 2 mM GSH for 3 h, which produced an 80% increase in intracellular GSH content. GSH repletion inhibited the increased sensitivity of the TNF alpha-treated endothelial cells to H2O2. We tested the effects of xanthine oxidase (XO) inhibition since XO activation may be a source of oxidants responsible for the decrease in cellular GSH content. Pretreatment with 0.5 mM oxypurinol attenuated the synergistic effect of TNF alpha and H2O2 on endothelial permeability. The results indicate that decreased oxidant buffering capacity secondary to TNF alpha-induced reduction in intracellular GSH content mediates the increased susceptibility of endothelial cells to H2O2. This mechanism may contribute to oxidant-dependent vascular endothelial injury in septicemia associated with TNF alpha release.
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PMID:Tumor necrosis factor-alpha-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H2O2. 154 73

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

The effect of Kupffer cell blockade on hepatic function during sepsis was evaluated in this study. Methyl palmitate suspension 100 mg/100 g administered intravenously suppressed the phagocytic activity as the phagocytic index K decreased from 0.0493 +/- 0.0089 to 0.0150 +/- 0.0035 in rats. Sepsis was produced by the method of cecal ligation and needling perforation (CLP). At the end of 15 hours after CLP the hepatic adenosine triphosphate (ATP) level and ketone body ratio decreased significantly. But in rats pretreated with methyl palmitate 24 hours prior to CLP, the ATP level returned to the normal control level (1.6906 +/- 0.06-2.2323 +/- 0.13 mumol/g) and ketone body ratio remained at significantly higher values (0.26 to 0.68). After CLP, the liver lipoperoxide (LPO) concentration increased and glutathione (GSH) contents decreased significantly. When the septic rats were pretreated with methyl palmitate, both the LPO and GSH returned to the normal control level (62.69 +/- 1.7 to 44.62 +/- 2.12 and 159.85 +/- 9.7 to 222.27 +/- 11.34). It is concluded that the hepatic dysfunction is modulated at least to a greater extent by many of the toxic mediators released by the activated Kupffer cells during sepsis.
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PMID:The role of Kupffer cells in the development of hepatic dysfunction during sepsis. 157 68

Our previous experimental studies showed that the liver is firstly and most severely involved in metabolic damage among various organs after hypoperfusion and sepsis. Changes of metabolites in liver and other organs as well as the function of circulating leukocytes were measured in three rat models with liver ischemia, or systemic hypoperfusion and sepsis. Partial liver ischemia 120 minutes after reperfusion not only resulted in significant decline of ATP and GSH levels in ischemic liver lobes but also in metabolic disorders in non-ischemic liver lobes, kidney, and small intestine. The amount of circulating white blood cells and zymosan stimulated chemoluminescence was increased. The findings showed that ischemic injury in partial liver may accelerate the whole liver damage and aggravate the metabolic disorders in other organs as well as the deterioration of homeostasis. Changes of liver sulfhydryl group levels and related metabolism were estimated. Significant decrease in liver sulfhydryl group levels during hypoperfusion and sepsis may contribute to various cellular metabolic disorders and destruction in early liver damage.
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PMID:[The liver in the pathogenesis of multiple organ failure]. 191 99

Experimental sepsis in rats induces a restriction in spontaneous food intake and a drop in liver glutathione, cytochrome P-450 (P-450) and aminopyrine demethylase (AD) activity. The present study was designed to assess the effects of antibiotics alone or when combined with food deprivation on these variables. Eighty-nine male Sprague-Dawley rats were assigned to six groups: control (C), acute infection (experimental pyelonephritis, I), acute infection with antibiotics and food given ad lib. (IA), control with antibiotics (CA), acute infection with antibiotics pair-fed to I (IAR), and sham-operated pair-fed to I (SR). Liver glutathione, P-450 and AD activities were reduced by 45.2, 79.8 and 41.2% respectively in group I. Glutathione and AD significantly increased only in those infected rats given antibiotics and allowed free access to food. P-450 did not normalize within the study period in infected rats receiving antibiotics and food repletion. The risk of drug hepatotoxicity in acute septic states is therefore closely related to the nutritional status. From this point of view, nutritional support is almost as important as treatment of infection.
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PMID:Influence of antibiotics and food intake on liver glutathione and cytochrome P-450 in septic rats. 785 19

Critical illness is associated with both immunosuppression and glutathione deficiency. We determined if in vivo depletion of glutathione would adversely affect immune status. Rats with normal glutathione levels and those with glutathione stores depleted by diethyl maleate underwent analysis of splenocyte function and mesenteric lymph node lymphocyte function. Lymphocytes of the spleen and mesenteric lymph nodes were tested for concanavalin A proliferative response and interleukin 2 production. Tumor necrosis factor and interleukin 6 secretion by splenic adherent cells was also measured. Glutathione-depleted animals had significantly decreased lymphocyte proliferation and decreased production of tumor necrosis factor and interleukin 6 but unaltered interleukin 2 production. These findings indicate that in vivo glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness.
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PMID:Glutathione depletion in rats impairs T-cell and macrophage immune function. 841 77

The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats. Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure. Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes. In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point. At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05). Glutathione and myoloperoxidase levels were less affected. Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO. Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator. Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals. In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis. Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.
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PMID:Protective effects of hydroxyethyl starch-deferoxamine in early sepsis. 860

The effect of acute endotoxin-induced septic shock on myocardium oxidative stress after low or high vitamin C and/or E dietary supplementation was studied in guinea pigs, laboratory animals which, like human, do not have capacity for ascorbate synthesis. Neither the antioxidant enzymes or GSH were modified by endotoxin and vitamin treatments. Vitamin E showed a strong capacity to protect the myocardium against both enzymatic and non-enzymatic lipid peroxidation even in the presence of endotoxin. Vitamin C supplementation increased heart ascorbate whereas endotoxic shock totally depleted the heart ascorbate of vitamin C supplemented animals without changing vitamin E. Endotoxin significantly increased myocardium uric acid, a marker of ischemia induced oxidative stress, in animals fed with low vitamin C levels. This increase was totally prevented in vitamin C supplemented, but not in vitamin E supplemented animals. Strongly depressed levels of plasma vitamin C have been recently described in sepsis in human patients. The results suggest that ascorbate is a primary antioxidant target in the heart of endotoxin treated mammals lacking the capacity to synthesize ascorbate and that ascorbate can have a protective value against endotoxin-induced free radical damage in the myocardium. Implications of these results for the possible preventive role of vitamin C in humans during sepsis are discussed.
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PMID:Endotoxin depletes ascorbate in the guinea pig heart. Protective effects of vitamins C and E against oxidative stress. 876 Oct 15

In present study, lipid peroxidation products (thiobarbituric acid reactive substances (TBARS) and diene conjugates (DC)) and markers of blood antioxidant status (serum antioxidative capacity (AOC) and red blood cells glutathione (RBC-GSH)) were measured to compare the extent of oxidative stress in 12 cardiac surgery and 10 septic general surgery patients. In heart surgery, arterial TBARS were significantly increased 15 min after the start and 15 min after cessation of cardiopulmonary bypass, while AOC at these times was decreased. Eighteen hours after surgery all parameters, except antioxidative capacity, had returned to preoperative levels. In septic patients, the preoperative level of lipid peroxidation was significantly higher and antioxidative capacity lower than in heart surgery patients. Surgery had no influence on oxidative stress markers in this group of patients. Increase in lipid peroxidation and reduction in blood antioxidant capacity, induced either by sepsis or cardiopulmonary bypass, were of comparable extent.
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PMID:The evidence of oxidative stress in cardiac surgery and septic patients: a comparative study. 920 11

Although it is well known that malnourished patients who become septic have an increased risk of organ failure and death compared to normally nourished individuals, the pathological processe(s) underlying this observation are unknown. To evaluate one possible explanation for this finding, we tested the hypothesis that malnutrition depresses hepatic antioxidant stores and accelerates hepatic release of oxygen free radicals in an animal model of sepsis. Male rats were either fasted (n = 14) or fed (n = 14) for 3 days prior to receiving lipopolysaccharide (LPS, 17 mg/kg intraperitoneally). Animals were weighed daily and then sacrificed 6 and 24 hr after LPS administration to determine hepatic superoxide anion (an oxygen free radical) release and liver glutathione (GSH, an antioxidant) content. Fasted rats were severely malnourished as indicated by a 23% decrease in body weight compared to fed rats, which gained 11% (P < 0.05). Liver GSH was depressed by 30% (P < 0.05) and 20% (P = 0.066) in the fasted compared to fed animals 6 and 24 hr after LPS administration. In addition, hepatic superoxide anion release was 210 and 75% higher in the fasted animals 6 and 24 hr after LPS injection (P < 0.05 at both time points). Liver superoxide anion release and GSH content were negatively correlated (P < 0.001, R = - 0.73) indicating that superoxide anion release increased as GSH content fell. Malnutrition leads to depletion of liver antioxidant stores with accelerated release of hepatic oxygen free radicals. Oxidant-mediated organ damage may be one cause of increased morbidity and mortality in malnourished, systemically infected patients.
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PMID:Starvation enhances hepatic free radical release following endotoxemia. 922 1


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