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)

Sepsis is a common complication of cirrhosis with a high mortality. In this study, we have investigated some of the pathways that may be involved in tissue injury and death. Bile duct-ligated (BDL) cirrhotic and control rats were challenged with lipopolysaccharide (LPS). Sensitivity to LPS was markedly enhanced in the BDL group, and was associated with increased liver injury and mortality. There was a 5-fold constitutive activation of nuclear factor kappa B (NFkappaB) in the liver of BDL rat controls (P <.001), and this was activated further, but to a similar extent, in the liver of both sham and BDL rats after injection of LPS. Plasma tumor necrosis factor alpha (TNF-alpha) increased more markedly in the BDL cirrhotic rats (2,463 +/- 697 pg/mL in BDL rats versus 401 +/- 160 pg/mL in the controls at 3 hours; P <.01). Plasma nitrite/nitrate concentrations were increased in the BDL controls at baseline, and increased further after LPS (P <.05), but did not differ from sham controls at 6 hours. Plasma F(2)-isoprostanes increased 6-fold in the cirrhotic rats and 2-fold in the controls (P <.01) indicative of lipid peroxidation. Esterified F(2)-isoprostanes in the liver increased 2- to 3-fold at 1 hour in control and BDL rats, but returned to baseline levels by 3 hours. Esterified F(2)-isoprostanes in the kidney increased by 2-fold in the BDL rats after LPS administration, but remained unchanged in sham controls. We conclude that there is a marked increase in sensitivity to LPS in BDL cirrhotic rats. This is associated with an enhanced TNF-alpha response and increased lipid peroxidation. These may be directly and causally related to mortality.
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PMID:Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic Rat. 1053 41

Previous investigations have shown that sepsis, while causing cardiac dysfunction, can protect the heart from ischemia-reperfusion injury. Sepsis-induced protection may be due to nitric oxide produced by an inducible form of nitric oxide synthase generated in response to cytokines released during sepsis. The glucocorticoid dexamethasone has been shown to inhibit the synthesis of the inducible form of nitric oxide synthase (iNOS). The goals of this study were to determine if dexamethasone would prevent sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In this experiment, rats were made septic by injecting Escherichia coli into the dorsal subcutaneous space. Control rats were injected with sterile saline. At the time of surgery, some of the control and septic animals were injected intraperitoneally with dexamethasone (3 mg/kg). The next day, 24-26 hr after injection of the first dose of E. coli, animals were anesthetized, and hearts were removed and studied in the isovolumic beating-heart preparation. Left ventricular end diastolic pressure was set to 5 mmHg, and left ventricular pressure was measured continuously throughout the protocol. Left ventricular developed pressure (LVDP) was used as an index of LV function. After stabilization, hearts were made globally ischemic for 35 min and then reperfused for 25 min. As has been shown previously, sepsis depressed LVDP but also protected the heart from further depression of LVDP by ischemia and reperfusion. Dexamethasone prevented both sepsis-induced cardiac dysfunction and sepsis-induced protection of the heart from ischemia-reperfusion injury. In addition plasma nitrite/nitrate levels were not different from control levels in the dexamethasone-treated septic rats whereas levels were elevated in the septic animals. The dexamethasone mediated abrogation of sepsis-induced cardiac dysfunction and protection during ischemia-reperfusion injury may be due to suppression of nitric oxide production.
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PMID:Dexamethasone blocks sepsis-induced protection of the heart from ischemia reperfusion injury. 1063 65

Polymicrobial sepsis is characterized by an early, hyperdynamic phase (i.e., 2-10 h after cecal ligation and puncture [CLP]) followed by a late, hypodynamic phase (16 h after CLP or later). Although nitric oxide (NO) plays an important role in the pathophysiologic response during sepsis, it remains unknown how early NO is upregulated after the onset of sepsis and which organs are responsible for producing the increased amount of NO. To study this, male rats were subjected to sepsis by CLP followed by fluid resuscitation. Blood samples were then taken at 2, 5, 10, or 20 h after CLP or sham operation. In additional groups of animals, the kidneys, small intestine, heart, liver, and lungs were harvested at 5 or 10 h after CLP. Plasma and tissue levels of nitrate and nitrite (NO3-/NO2-, stable products of NO) were determined by using a colorimetric assay. Inducible NO synthase (iNOS) mRNA was examined in various tissues harvested at 10 h after CLP by reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicate that plasma levels of NO3-/NO2- (mainly reflecting iNOS activity) did not increase at 2-5 h but were significantly elevated at 10-20 h after CLP. Tissue levels of NO3-/NO2- increased significantly in the kidneys, small intestines, heart, and liver at 10 h but not at 5 h after CLP. Similarly, iNOS gene expression was upregulated in the kidneys, small intestines, and liver. Thus, the above organs appear to be important sites responsible for producing the increased NO during sepsis. Because we previously showed that the hyperdynamic response occurs as early as 2 h after CLP and because iNOS-derived NO production is not upregulated earlier than 10 h after the onset of Sepsis, it appears that factors other than NO are responsible for producing the hyperdynamic response during sepsis.
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PMID:Upregulation of inducible nitric oxide synthase and nitric oxide occurs later than the onset of the hyperdynamic response during sepsis. 1077 23

Nitric oxide (NO) is produced in excess in various pathological states, including sepsis and hepatic cirrhosis, and appears to be related to inflammatory status. In uremia, one would expect the levels of NO to increase. We aimed to determine whether hemodialysis (HD) would remove NO from the systemic circulation of uremic patients. Blood was collected before, after, and 1 day after HD from 12 uremic patients. Plasma nitrite and nitrate (NOx-) levels were measured by colorimetric Greiss reaction and cGMP was measured by an enzyme immunoassay kit. Our study demonstrated that uremic patients have high plasma NO levels, and HD led to a significant drop in plasma NOx- level (63 +/- 15% reduction). The level rose back to the pre-HD level on the following day. Plasma cGMP in the patients also decreased significantly after HD (27 +/- 14% reduction). In conclusion, we hypothesized that HD might be a possible approach for the removal of excess NO in pathological conditions such as sepsis and hepatic cirrhosis.
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PMID:Effect of hemodialysis on plasma nitric oxide levels. 1084 81

Development of severe sepsis is thought to result from the overproduction of cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and nitric oxide. Recently, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, which are antihypercholesterolemic agents, have been reported to inhibit lipopolysaccharide (LPS)-induced production of cytokines and nitric oxide in vitro. In this study, we tested these effects in vivo. After LPS administration (15 mg/kg i.p.) to CD-1 mice, serum levels of both TNF-alpha and IL-1beta transiently increased, and peaked at 2 h. After the peak responses of TNF-alpha and IL-1beta, serum levels of nitrite and nitrate increased until at least 8 h. Pretreatment of the mice with cerivastatin (20 mg/kg i.p. 12 and 1 h before LPS injection) reduced serum levels of TNF-alpha and IL-1beta at 2 h, and nitrite and nitrate at 8 h, by 93, 60, and 44%, respectively. In this model of sepsis, cerivastatin significantly (P =.016) improved the rate of 7-day survival from 26.7 to 73.3%. These results cast new light on the usefulness of cerivastatin in preventing severe sepsis.
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PMID:Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis. 1094 57

Carbon monoxide (CO) has been implicated as a new endogenously produced mediator similar to nitric oxide (NO). CO was measured in plasma samples from 7 term newborn infants with sepsis and from 30 healthy neonates. Plasma CO levels were significantly higher in the group with sepsis at the time of admission to the neonatal intensive care unit than in the healthy controls (p < 0.05). Moreover, the elevated plasma CO levels were significantly related to increased NO production, as indicated by plasma nitrite/nitrate levels (p < 0.05). The present study suggests that, in addition to NO, CO might be another important mediator taking part in the pathogenesis of neonatal sepsis.
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PMID:Plasma carbon monoxide levels in term newborn infants with sepsis. 1104 73

Erythrocyte deformability has been recognized as a determinant of microvascular perfusion. Because nitric oxide (NO) is implicated in the modulation of red blood cell (RBC) deformability and NO levels increase during sepsis, we tested the hypothesis that a NO-mediated decrease in RBC deformability contributes to decreased functional capillary density (CD) in remote organs. With the use of a peritonitis model of sepsis in the rat [cecal ligation and perforation (CLP)] and aminoguanidine (AG) to prevent increases in NO, we measured CD in skeletal muscle (intravital microscopy), mean erythrocyte membrane deformability (; micropipette aspiration), systemic NO production [plasma nitrite/nitrate (NO(x)) chemiluminescence], and NO accumulation in RBC [NO bound to hemoglobin (HbNO) detected by electron paramagnetic resonance spectroscopy]. In untreated CLP animals relative to sham, NO(x) increased 254% (P < 0.05), stopped flow capillaries increased 149% (P < 0.05), and decreased 12.7% (P < 0.05), with a subpopulation (5%) of RBC with deformabilities below the normal range. AG prevented increases in NO(x), accumulation of HbNO, and decreases in both and functional CD. We found no evidence of leukocyte plugging postcapillary venules. Our findings suggest that decreased functional CD during sepsis resulted from a NO-mediated decrease in erythrocyte deformability.
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PMID:Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. 1135 44

Carbon monoxide is thought to serve as a new endogenous mediator in the pathogenesis of sepsis and septic shock. In newborn rat endotoxicosis, carbon monoxide levels in the circulation as well as liver, kidney and lung were found to be significantly increased (P < 0.05). Moreover, the elevations of carbon monoxide correlated with enhanced nitric oxide production as indicated by nitrite/nitrate levels (P < 0.05). Our present data showed for the first time that endogenously produced carbon monoxide was increased during the course of shock-like states, which suggested that the role of carbon monoxide in sepsis and septic shock might worth further study.
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PMID:Evidence of increased endogenous carbon monoxide production in newborn rat endotoxicosis. 1136 May 52

To elucidate the possible roles of nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) in the pathophysiology of serogroup A streptococcal (GAS) peritoneal sepsis, we investigated the effects of aminoethylisothiourea (AE-ITU), an inducible NO synthase (iNOS) inhibitor, and a ROS scavenger, and the ET-1 receptor antagonist bosentan. In rats, live GAS inocula, 3 x 10(8) and 1 x 10(9) cfu/kg, entailed a 24-h mortality of 10% and 90%, respectively. GAS caused increases in tissue iNOS activity (9 h), in serum nitrite/nitrate (9-24 h), and in intracellular leukocyte ROS levels (3-6 h). These changes were all prevented by the pre-treatment with AE-ITU. A novel finding was that AE-ITU also prevented the GAS-induced marked increase in plasma ET-1 at 6 h. Short-term (7-h) survival was improved by both AE-ITU and by bosentan. The mechanism(s) for the beneficial effects of AE-ITU may possibly be a combined mode of action; iNOS inhibition, ROS scavenging, and inhibition of the increase in plasma ET-1 caused by GAS.
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PMID:Aminoethyl-isothiourea inhibits the increase in plasma endothelin-1 caused by serogroup A streptococci and prolongs survival in rat peritoneal sepsis. 1138 17

Nitric oxide synthase requires tetrahydrobiopterin for its activity. In animal models of sepsis, changes in circulating tetrahydrobiopterin concentrations precede increases in nitrate. We measured plasma tetrahydrobiopterin and nitrate concentrations on three consecutive days in 10 patients with septic shock and 10 critically ill control patients. Total nitrate concentration was measured after reduction of nitrite to nitrate. Tetrahydrobiopterin concentrations were measured using HPLC. The median (range) APACHE II score was 22 (13-27) in the patients with septic shock and 25 (7-28) in the control group. The nitrate concentration was significantly higher in patients with septic shock than in controls (P = 0.01) on all days but did not change with time. Tetrahydrobiopterin concentrations were highest in the patients with septic shock on day 1 only (P = 0.037). In the seven patients with renal failure, both nitrate and tetrahydrobiopterin concentrations tended to be higher than in the 13 patients without renal failure. The nitrate concentration correlated with tetrahydrobiopterin concentration on day 1 only (P = 0.05). In patients with septic shock, both tetrahydrobiopterin and total nitrate concentrations were higher than those in critically ill controls but were increased mainly in patients with renal failure. In summary, tetrahydrobiopterin concentration increases during septic shock, in line with increases in nitrate concentration. However, as for nitrate, concentrations
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PMID:Circulating tetrahydrobiopterin concentrations in patients with septic shock. 1157 38


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