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)

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

Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. Recently, a role for free radicals has been proposed in the mortality associated with Gram-negative bacterial sepsis. To determine if pretreatment with free radical scavengers can prevent endotoxin-induced mortality, mice rendered sensitive to endotoxin with actinomycin D were treated with either superoxide dismutase (SOD), N-acetylcysteine (NAC) or saline and were then challenged with a dose of endotoxin calculated to cause a mortality of greater than 80%. Mortality was assessed at 12-h intervals after challenge. Increased survival was seen in the SOD-treated group compared to the control group (p less than or equal to .05). In contrast, survival in mice treated with NAC, another potential scavenger, was not significantly different from the control group. These results support the hypothesis that superoxide and hydroxyl radicals contribute to mortality in Gram-negative bacterial sepsis.
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PMID:Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice. 304 86

In patients with refractory germ cell tumour who fail to achieve complete remission (CR) or which achieve CR but subsequently experience disease progression within 2 months of receiving cisplatin + vinblastine + bleomycin (PVB) the results of further treatment are poor. Similarly, third-line therapy after cisplatin with VP 16 salvage rarely produces clinically significant remission. From February 1983 to October 1984 we treated 53 patients with ifosfamide (1.2 g/m2 per day on days 1-5), VP 16 (75 mg/m2 per day on days 1-5), cisplatin (20 mg/m2 per day on days 1-5), and N-acetylcysteine (2.0 g p.o. every 6 h on days 1-7). This was repeated every 21 days for four to six cycles. One group of patients (group A, 20 pts) had achieved partial remission (PR) but still had nonresectable tumours after PVB therapy; a further group (group B, 4 pts) had achieved CR with PVB but then experienced disease progression within 2 months; the remaining patients (group C, 28 pts) had experienced disease progression after one or more salvage attempts, including therapy with cisplatin and VP 16. Of the original 53 patients, 51 were evaluable for response. Toxicity included moderate to severe myelosuppression in almost all patients, fever/sepsis in 8, creatinine greater than or equal to 6 mg% in 4, and hematuria in 4 patients. There were no drug-related deaths. CR was attained in 17/51 patients (34%), these being 8/20 in group A, 1/4 in group B, and 8/28 in group C, and 10 patients have remained in CR for periods ranging from over 1 month to over 17 months. PR was achieved in 20 patients (40%), but their median duration of remission was only 2 months. We feel these results, obtained in a poor-prognosis patient population, are sufficiently encouraging to warrant further study of this regimen, including investigation of its use as initial salvage therapy following PVB.
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PMID:VP 16 plus ifosfamide plus cisplatin as salvage therapy in refractory testicular cancer. 381 18

Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.
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PMID:Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. 672 59

Oxygen radicals and oxygen radial mediators are thought to be important components in the development of acute lung injury, sepsis, and multiple organ failure. Injured patients, patients with pulmonary diseases, and multiple trauma patients also showed an elevated lipid peroxidation, indicating increased oxidant stress. N-Acetylcysteine (NAC) has been used as an antioxidant in a wide variety of experiments. NAC has been suggested to act by raising concentrations of cysteine, and hence glutathione, and by scavenging of oxidant species [1, 11, 17, 29]. The present study was designed to investigate whether the application of NAC in intubated patients has an effect on concentrations of reduced glutathione in plasma and bronchoalveolar lavage fluid (BAL) and on the lipid peroxidation products malondialdehyde and conjugated dienes. Because NAC has been widely used as a mucolytic drug for the treatment of lung diseases, the influence on tracheobronchial mucus was studied, too. METHODS. In a randomized, double-blind, placebo-controlled study, a total of 38 long-term ventilated patients of a surgical intensive care unit were investigated. Patients were treated for 5 days with either 3 g NAC/day or placebo. The plasma concentration of reduced glutathione, malondialdehyde, and conjugated dienes were measured on admission and on the 3rd and 5th days of treatment [8, 34, 48]. Additionally, the numbers of tracheobronchial suctionings were registered and chest radiographs were evaluated. A fibre-bronchoscopy was performed on admission and on the 3rd day of treatment. The amount and viscidity of tracheobronchial secretions were examined semiquantitatively, and glutathione levels were measured in the unconcentrated BAL. The study was approved by the ethics committee of the University of Ulm. RESULTS. The two groups were comparable with respect to age, sex, APACHE II score and diagnosis (Table 1). We found no significant differences in reduced glutathione levels in the plasma or in the BAL (Figs. 1, 2). Plasma concentrations of malondialdehyde were similar (Fig. 3). Only the levels of conjugated dienes were significantly higher on the 5th treatment day in the placebo group (Fig. 4). The organ function of the lung (FiO2, PEEP, PaO2), liver (SGOT, bilirubin), and kidney (creatinine) and coagulation parameters (PTT, prothrombin time, platelet count) were similar in the two groups during the time of investigation. We observed no clinically relevant differences in the tracheobronchial mucus (Table 2). CONCLUSION. The present data do not support routine use of NAC in ventilated patients, either as an antioxidant or as a mucolytic agent. Intravenous administration of 3 g NAC/day had no clinically relevant effect on glutathione levels, lipid peroxidation products, tracheobronchial mucus, and clinical condition.
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PMID:[The application of n-acetylcysteine as an antioxidant and mucolytic in mechanical ventilation in intensive care patients. A prospective, randomized, placebo-controlled, double-blind study]. 748 27

The effect of the antioxidant N-acetyl-L-cysteine was studied in a model of polymicrobial sepsis induced in CD-1 mice by cecal ligation and puncture. N-Acetyl-L-cysteine significantly improved survival during the 6 days following sepsis induction and caused lower liver toxicity. This effect was not related to free radicals generated by xanthine oxidase which was significantly induced in liver after cecal ligation and puncture. A specific inhibitor of xanthine oxidase, allopurinol, significantly reduced this enzyme and reduced the early survival rate. The effect of N-acetyl-L-cysteine was not related either to a reduction in tumor necrosis factor production or to a modulation of nitrites or to liver glutathione content. These results show that the induction of xanthine oxidase is not deleterious in this model of sepsis and suggest that N-acetyl-L-cysteine works as a direct antioxidant and scavenger of free radicals generated from other sources.
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PMID:Effect of N-acetyl-L-cysteine on sepsis in mice. 779 76

Hyperoxic ventilation, used to prevent hypoxemia during potential periods of hypoventilation, has been reported to paradoxically decrease whole body oxygen consumption (VO2). Reduction in nutritive blood flow due to oxygen radical production is one possible mechanism. We investigated whether pretreatment with the sulfhydryl group donor and O2 radical scavenger N-acetylcysteine (NAC) would preserve whole body VO2 and prevent deterioration of oxygenation in gastric mucosal tissue during hyperoxia. Thirty-eight patients, requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to sepsis syndrome, were included in this randomized experiment. All patients exhibited stable clinical conditions (hemodynamics, body temperature, hemoglobin, FIO2 < 0.5). A gastric tonometer was placed to measure the gastric intramucosal pH (pHi), which indirectly assesses nutritive blood flow to the mucosa. Cardiac output was determined by thermodilution and VO2 by cardiovascular Fick. After baseline measurements, patients randomly received either 150 mg.kg-1 NAC (n = 19) or placebo (n = 19) in 250 ml 5% dextrose intravenously over a period of 15 min. Measurements were repeated 30 min after starting NAC or placebo infusion, 30 min after starting hyperoxia (FIO2 = 1.0), and 60 min after resetting the original FIO2. There were no significant differences between groups in any of the measurements before treatment and after the return to baseline FIO2 at the end of the study. NAC, but not placebo infusion, caused a slight but significant increase in cardiac output and decrease in systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-acetylcysteine preserves oxygen consumption and gastric mucosal pH during hyperoxic ventilation. 788 69

We studied the effect of nitric oxide on LPS-induced TNF-alpha production by human neutrophils. Human neutrophils exposed to LPS and IFN-gamma did not show measurable increases in intracellular cyclic GMP (cGMP). However, cGMP increased upto 30-fold (p < 0.01) in neutrophils incubated with both sodium nitroprusside (SNP), an exogenous source of nitric oxide, and N-acetylcysteine (NAC), which increases the bioavailability of nitric oxide; this increase indicates that neutrophils contain a nitric oxide-sensitive guanylate cyclase. SNP, with or without NAC, did not increase TNF-alpha production in human neutrophils cultured in medium alone. However, LPS-dependent TNF-alpha production was increased by exposure to SNP (p < 0.05); this effect was further increased by the addition of NAC (p < 0.02). IFN-gamma greatly increased LPS-mediated TNF-alpha production by human neutrophils (p < 0.01), and SNP plus NAC was found to further augment this production (p < 0.01). The up-regulation of TNF-alpha production by nitric oxide was not associated with increased amounts of LPS-induced TNF-alpha mRNA, and was not reproduced by exposing neutrophils to cGMP analogues. These data suggest that nitric oxide released by endothelial and vascular smooth muscle cells may exert a paracrine effect on human neutrophils and augment the inflammatory response in sepsis by increasing the production of cytokines. Although the mechanism of this effect remains unknown, it does not seem to be dependent on cGMP or increased levels of TNF-alpha mRNA.
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PMID:Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils. 814 75

Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.
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PMID:Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells. 900 92

Activation of the resident macrophage populations of the reticuloendothelial system is a key component of the complex pathophysiology of sepsis. Macrophage activation leads to production and secretion of inflammatory mediators such as cytokines, vasoactive substances, free radicals, and chemokines, which have been associated with high morbidity and mortality in the septic patient. The goal of the present study was to determine whether antioxidants could suppress Kupffer cell activation at points beyond the initiation of activation. Kupffer cells were studied since they are central to the clearance of bacteria and endotoxins, and have been associated with hepatocellular dysfunction in sepsis. Cells were activated with 10 ng/ml LPS for various times whereupon N-acetylcysteine (30 mM) and alpha-tocopherol (50 microM) were added. Steady state levels of cytokine mRNA, activation of nuclear factor-kappaB, and TNF-alpha secretion were determined when expression was maximal in control cells. The results of this study show that antioxidants can be used to suppress Kupffer cell activation at points beyond the initiation of activation. Furthermore, we show that N-acetylcysteine-mediated inhibition of activation requires secondary protein synthesis, but does not modulate IkappaB-alpha mRNA expression. The inhibitory effect of these drugs occurs at the very earliest steps of the LPS signal transduction cascade as it is currently understood. The results of the present study suggest that the inflammatory response to sepsis may be controlled through appropriate antioxidant therapy.
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PMID:N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells. 916 63


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