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)

Nitric oxide (NO) is normally produced in the endothelium by the constitutive isoform of the NO synthase. This physiological production of NO is important for blood pressure regulation and blood flow distribution. Several lines of evidence suggest that a hyperproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Lipopolysaccarides and cytokines, such as tumor necrosis factor, interleukin-1 and interferon-gamma, have been shown to induce iNOS in the endothelium, vascular smooth muscle cells, macrophages and different parenchymal cells. Treatment with inhibitors of NO synthesis has been shown to improve hemodynamic variables and survival in several animal models of septic shock. In human septic shock, inhibition of NO synthesis has been shown to alter hemodynamic variables in short-term studies, but it is uncertain whether this treatment has beneficial long-term effects. The aim of this review is to give an overview of the physiological role of NO and to discuss the role of NO in sepsis and the potential therapeutic implications of NO as a target in treatment of human septic shock. A main new aspect of this review is a critical discussion of previous reports measuring plasma nitrite/nitrate during septic shock and an evaluation of the validity of interpreting these data as evidence for a hyperproduction of NO. This review also emphasizes that many septic patients have preexisting endothelial dysfunction and lung diseases, which may contribute to adverse effects by systemic inhibition of NO synthesis. Another new aspect of the present review is a focus on the lack of direct evidence of iNOS expression in human septic shock.
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PMID:The role of nitric oxide in sepsis--an overview. 1008 33

The host response to Gram-negative infection includes the elaboration of numerous proinflammatory agents, including tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). A component of the hepatic response to infection is an elevation in serum lipids, the so-called "lipemia of sepsis," which results from the increased production of triglyceride (TG)-rich lipoproteins by the liver. We have postulated that these lipoproteins are components of a nonadaptive, innate immune response to endotoxin [lipopolysaccharide (LPS)] and have previously demonstrated the capacity of TG-rich lipoproteins to protect against endotoxicity in rodent models of sepsis. Herein we report the capacity of a high-fructose diet to protect against LPS, most likely by inducing high circulating levels of endogenous TG-rich lipoproteins. The protective phenotype included the increased production of NO by hepatic endothelial cells. Rats, made hypertriglyceridemic by fructose feeding, experienced decreased LPS-induced mortality (P < 0.03) and systemic TNFalpha levels (P < 0.05) as compared with normolipidemic (chow-fed) controls. The increased survival was associated with elevated levels of inducible NO synthase (NOS2) mRNA levels and NO production (82 +/- 26 vs 3 +/- 3 nmol nitrite/10(6) cells, P < 0.001) by hepatic endothelial cells. Nonselective NOS inhibitors reversed the protective phenotype in vivo and readily decreased NO production by cultured endothelial cells from hypertriglyceridemic rats in vitro. This study suggests that a high-fructose diet can protect against endotoxicity in part through induction of endogenous TG-rich lipoproteins and hepatic endothelial cell NO production. This is the first report of diet-induced hyperlipoproteinemia and subsequent protection against endotoxemia.
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PMID:Diet-induced protection against lipopolysaccharide includes increased hepatic NO production. 1009 Aug 49

Elevated production of nitric oxide (NO) by the inducible NO synthase (type II, iNOS) may contribute to the vascular hyporesponsiveness and hemodynamic alterations associated with sepsis. Selective inhibition of this isoenzyme is a possible therapeutic intervention to correct these pathophysiological alterations. Aminoguanidine has been shown to be a selective iNOS inhibitor and to correct the endotoxin-mediated vascular hypocontractility in vitro. However, to date aminoguanidine has not been shown to selectively block iNOS activity in vivo. The in vivo effects of aminoguanidine were assessed in the cecal ligation and perforation model of sepsis in rats. Aminoguanidine (1.75-175 mg/kg) was administered to septic and sham-operated rats for 3 h before euthanasia and harvest of tissues. NOS activities were determined in the thoracic aorta and lung from these animals. Aminoguanidine (17.5 mg/kg) did not alter the mean arterial pressure; however, it did inhibit induced iNOS (but not constitutive NOS) activity in the lung and thoracic aorta from septic animals. Only the higher dose of aminoguanidine (175 mg/kg) was able to increase the mean arterial pressure in septic and sham-operated animals. Thus selective inhibition of iNOS in vivo with aminoguanidine is possible, but our data suggest that other mechanisms, in addition to iNOS induction, are responsible for the loss of vascular tone characteristic of sepsis.
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PMID:Selective in vivo inhibition of inducible nitric oxide synthase in a rat model of sepsis. 1023 42

Experimental sepsis induces disturbances in microcirculatory flow and nutrient exchange that may result in impaired tissue oxygenation. Volume resuscitation is a principal clinical intervention in patients with sepsis. Nitric oxide (NO) has been implicated in the pathophysiology of endotoxemia, but few data exist concerning the effects of either NO synthase inhibition (NOSi) or volume resuscitation on microvascular regulation and tissue oxygenation. Amperometric measurements were made of skeletal muscle (tissue) oxygen tension (PtO2) and its response to changes in fraction of inspired oxygen (FIO2) in rats rendered endotoxemic. Simultaneous measurements were made of systemic hemodynamic indices and arterial blood gas tensions. At normal PaO2, PtO2 in endotoxemic animals was significantly lower than in control animals, with marked attenuation of the response to increasing FIO2. These changes were associated with significant metabolic acidemia. In volume-resuscitated endotoxemic rats, PtO2 and blood pH were unchanged. A significant reduction in the PtO2 response to hyperoxia was observed in animals treated with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), an effect not reversed by fluid resuscitation. These data suggest that significant tissue hypoxia and abnormal microvascular control occur in endotoxemia. Volume resuscitation can reverse the changes in PtO2, whereas nitric oxide synthase (NOS) inhibition has deleterious effects on muscle PtO2 in both control and endotoxemic animals.
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PMID:Abnormal tissue oxygenation and cardiovascular changes in endotoxemia. 1035 8

Acute tubular injury in sepsis is associated with proximal tubular epithelial cell (PTEC) detachment into the lumen leading to back-leakage of glomerular ultrafiltrate and tubule obstruction. Inflammatory cytokines, such as IL-1alpha, IFNgamma and TNFalpha, are important mediators in sepsis-induced acute renal failure, although their precise role is unclear. We used primary cultures of human PTEC to investigate the hypothesis that inflammatory cytokines exert cytotoxic effects and cause detachment of cells from adherent monolayers, possibly through the intermediate nitric oxide (NO). At 5 days post-confluence, PTEC monolayers were stimulated for 24 hours with IL-1alpha (10 ng/ml), IFNgamma (200 u/ml) and TNFalpha (10 ng/ml). Monolayer viability was assessed by a live/dead dual fluorescence labeling technique. Apoptosis within monolayers was determined by morphological examination and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). PTEC in supernatants were counted and then analyzed by flow cytometry, using propidium iodide to assess cell viability and annexin V labeling to determine apoptosis. Results (mean +/- SEM; monolayers, n = 4; cell counts, n = 3; flow cytometry, n = 2) are shown below (at test, p < 0.05). Monolayers Supernatants Viable necrotic% of cells apoptotic countsx104/ml viable necrotic% of cells apoptotic Unstimulated 99.0+/-0.5 1.0+/-0.5 0 8.0+/-0.6a 64.6+/-2.5a 26.7+/-1.9a 6.2+/-0.6a Stimulated 92.4+/-3.2 7.6+/-3.2 0 14.7+/-0.6a 37.9+/-0.05a 48.0+/-0.3a 14.1+/-0.35a Following cytokine stimulation, there were significantly increased numbers of shed cells in supernatants. This cell population demonstrated significant loss of viability with increased numbers of both necrotic and apoptotic cells, as compared to unstimulated PTEC supernatants. Cytokine-stimulated monolayers maintained viability with no significant cell necrosis and no evidence of apoptosis. Preliminary experiments with the NO synthase inhibitor L-NMMA show that it reduces the number of cytokine-induced shed cells to the levels found in unstimulated cells (8.0 +/- 1.0 x 104/ml), although the percentages of necrotic and apoptotic cells are unchanged from cytokine-stimulated PTEC (44% and 15%, respectively). In conclusion, inflammatory cytokines induce necrotic and apoptotic cell shedding from PTEC monolayers with maintenance of monolayer viability. Preliminary data suggest that NO plays a cytotoxic role in this process.
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PMID:Inflammatory cytokines induce apoptotic and necrotic cell shedding from human proximal tubular epithelial cell monolayers 1035 8

Pentoxifylline, a methylxanthine derivative, has been widely used to improve erythrocyte deformability and capillary blood circulation in patients with claudication and cerebrovascular disorders as well as in animals with sepsis. Here, we investigate the effects of pentoxifylline on the hypotension, vascular hyporeactivity to noradrenaline, release of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), and inducible NO synthase protein expression in a rat model of circulatory shock induced by bacterial endotoxin (Escherichia coli lipopolysaccharide). In addition, we have evaluated the effect of pentoxifylline on the 36-h survival rate in a murine model of endotoxaemia. Male Wistar-Kyoto rats were anaesthetised and instrumented for the measurement of mean arterial pressure and heart rate. Injection of lipopolysaccharide (10 mg/kg, i.v.) resulted in a significant fall in mean arterial pressure and an increase of heart rate. In contrast, animals pretreated with pentoxifylline (3 mg/kg, i.v., at 30 min prior to lipopolysaccharide) maintained a significantly higher mean arterial pressure but showed no effect on the tachycardia when compared to rats given only lipopolysaccharide (lipopolysaccharide-rats). The pressor effect of noradrenaline (1 microg/kg, i.v.) was also significantly reduced after the treatment of rats with lipopolysaccharide. Similarly, rings of thoracic aorta obtained from lipopolysaccharide-rats showed a significant reduction in the contractile responses elicited by noradrenaline (1 microM). Pretreatment of lipopolysaccharide-rats with pentoxifylline partially, but significantly, prevented this lipopolysaccharide-induced hyporeactivity to noradrenaline in vivo and ex vivo. The injection of lipopolysaccharide resulted in bell-shape changes in plasma TNF-alpha level which reached a peak at 60 min, whereas the effect of lipopolysaccharide on the plasma level of nitrate (an indicator of NO formation) was increased in a time-dependent manner. This increase of both TNF-alpha and nitrate levels induced by lipopolysaccharide was significantly reduced in lipopolysaccharide-rats pretreated with pentoxifylline. Endotoxaemia for 240 min caused a significantly increased protein expression of inducible NO synthase in the lung. In lipopolysaccharide-rats pretreated with pentoxifylline, inducible NO synthase protein expression in lung homogenates was attenuated by 48 +/- 5%. Treatment of conscious mice with a high dose of endotoxin (60 mg/kg, i.p.) resulted in a survival rate of only 10% at 36 h (n = 20). However, therapeutic application of pentoxifylline (3 mg/kg, i.p. at 0, 6, 15 and 24 h after lipopolysaccharide) increased the 36-h survival to 35% (n = 20). Thus, pentoxifylline protects against circulatory failure and improves survival in rodents with severe endotoxaemia. These effects may be due to inhibition of the release of TNF-alpha and of the induction of inducible NO synthase.
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PMID:Pentoxifylline improves circulatory failure and survival in murine models of endotoxaemia. 1040 50

Nitric oxide (NO) production by inducible NO synthase (iNOS) during inflammation is an essential element of antimicrobial immunity but can also contribute to host-induced tissue damage. Under conditions of bacterial sepsis, large amounts of NO are produced, causing hypotension, a critical pathological feature of septic shock. In sepsis caused by gram-positive organisms, the bacterial factors contributing to host NO production are poorly characterized. We show that a soluble toxin of Streptococcus pneumoniae, pneumolysin (Pln), is a key component initiating NO production from macrophages. In contrast to wild-type bacteria, a mutant of S. pneumoniae lacking Pln failed to elicit NO production from murine macrophages. Purified recombinant Pln induced NO production at low concentrations and independently of exogenous gamma interferon (IFN-gamma) priming of RAW 264.7 macrophages. However, IFN-gamma was essential for Pln-induced NO production, since primary macrophages from mice lacking the IFN-gamma receptor or interferon regulatory factor 1, a transcription factor essential for iNOS expression, failed to produce NO when stimulated with Pln. In addition, Pln acts as an agonist of tumor necrosis factor alpha and interleukin 6 production in macrophages. The properties of Pln, previously identified as a pore-forming hemolysin, also include a role as a general inflammatory agonist.
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PMID:Pneumolysin, a protein toxin of Streptococcus pneumoniae, induces nitric oxide production from macrophages. 1041 33

Cellular mechanisms of sepsis-induced ileus remain an enigma. The study aim was to determine the role of nitric oxide (NO) in mediating the suppression of rat jejunal circular smooth muscle activity during endotoxemia. Isolated muscularis inducible NO synthase (iNOS) mRNA was measured by RT-PCR, immunohistochemistry was employed to localize iNOS protein, and contractile activity was measured in an organ bath. The low basal expression of muscularis iNOS mRNA expression was increased in a time-dependent fashion after lipopolysaccharide (LPS), resulting in a 20-fold increase over controls 3 h after injection. Immunohistochemistry of muscularis whole mounts and dissociated muscularis cells for iNOS revealed staining only in the muscularis macrophages 12 h after LPS. LPS caused a 68% reduction in spontaneous muscle activity 12 h after injection, which improved by 53% after the in vitro application of the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine. Similar results were obtained in C57BL/6 mice but not in iNOS knockout mice. These data demonstrate that macrophage iNOS plays an important role in mediating LPS-induced intestinal circular muscle suppression.
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PMID:LPS-induced muscularis macrophage nitric oxide suppresses rat jejunal circular muscle activity. 1044 63

Hyporeactivity to vasoconstrictors in aortae from portal vein-stenosed rats is associated with an increased activity of endothelial NO synthase (NOS3). In contrast, during sepsis, which is common in cirrhosis, vascular hyporeactivity is associated with an induction of inducible NOS2. The aim of this study was to investigate the in vitro reactivity to phenylephrine and the regulation of NOS2 and NOS3 in aortae from portal vein-stenosed rats after lipopolysaccharide (LPS) administration. Aortic vascular reactivity for phenylephrine, aortic NOS activity, and NOS2 and NOS3 protein expression were determined 5 hours after intravenous LPS or saline administration. Moreover, aortic NOS activity was measured after 5-hour in vitro incubation in LPS. LPS induced a significantly smaller decrease in aortic tension in portal vein-stenosed than in sham-operated rats. Under baseline conditions, aortic NOS activity and NOS3 protein expression were higher in portal vein-stenosed than in sham-operated rats, and NOS2 protein expression was not detected in aortae from either group. After LPS administration, NOS activity and NOS2 protein expression increased significantly less in portal vein-stenosed than in sham-operated rat aortae. Similar results were obtained after in vitro incubation with LPS. Endothelium removal or NOS3 inhibition with the calmodulin inhibitor, W7, increased NOS activity in the aortae of portal vein-stenosed rats after LPS incubation. In conclusion, in aortae of portal vein-stenosed rats exposed to LPS, no further decrease in aortic reactivity to phenylephrine was observed, and the induction of NOS2 was down-regulated. Endothelium removal or calmodulin inhibition inhibits NOS3 overactivity and leads to normalized NOS2 activation after LPS in aortae from portal vein-stenosed rats.
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PMID:Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration. 1046 76

Effects of excessive nitric oxide (NO) produced in vivo by an i.p. injection of bacterial lipopolysaccharide (LPS) on hepatic microsomal drug oxidation catalyzed by flavin-containing monooxygenase (FMO) were determined. At 6 and 24 h after the LPS injection, liver microsomes were isolated and FMO activities were determined by using FMO substrates like thiobenzamide, trimethylamine, N,N-dimethylaniline, and imipramine. Liver microsomal FMO activities of LPS-treated rats were decreased significantly for all these substrates. Microsomal content of FMO1 (the major form in rat liver) in LPS-treated rats as determined by immunoblotting, was severely decreased as well. In support of this, hepatic content of FMO1 mRNA was decreased by 43.6 to 67.3%. However, the hepatic content of inducible NO synthase (iNOS) mRNA was increased by 2.6- to 5.4-fold and the plasma nitrite/nitrate concentration was increased by about 30-fold in the LPS-treated rats. When this overproduction of NO in the LPS-treated rats was inhibited in vivo by a single or repeat doses of either a general NOS inhibitor N(G)-nitro-L-arginine or a specific iNOS inhibitor aminoguanidine, the FMO1 mRNA levels were not severely depressed (70-85% of the control level). Attendant with the reduction of plasma nitrite/nitrate concentration by single and repeated doses of NOS inhibitors, activity and content of FMO1 in liver microsomes isolated from these NOS inhibitor cotreated rats were restored partially (in single-dose inhibitors) or completely (in repeat doses). In contrast to these NO-mediated in vivo suppressive effects on the mRNA and enzyme contents of FMO1 as well as the FMO activity, the NO generated in vitro from sodium nitroprusside did not inhibit the FMO activities present in microsomes of rat and rabbit liver as well as those present in rabbit kidney and lung. Combined, the excessive NO produced in vivo (caused by the LPS-dependent induction of iNOS) suppresses the FMO1 mRNA and enzyme contents as well as the FMO activities without any direct in vitro effect on the activities of premade FMO enzyme. These findings suggest that NO is an important mediator involved in the suppression of FMO1 activity in vivo. Thus, together with the previously reported suppression on the cytochrome P-450 activities, the overproduced NO in the liver caused by induction of iNOS under conditions of endotoxemia or sepsis suppresses FMO and appears to be responsible for the decreased drug oxidation function observed generally under conditions of systemic bacterial or viral infections.
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PMID:Suppression of flavin-containing monooxygenase by overproduced nitric oxide in rat liver. 1046 38


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