UMLS:C0036690 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxinaemia stimulates the generation of cysteinyl leukotrienes (LT), potent mediators of inflammation which are preferentially eliminated into the bile. Nitric oxide (NO) is a mediator molecule that has a possible protective role in liver injury. As sepsis and shock often lead to the development of hypoxic regions in the liver, the influence of hypoxia on the metabolism of cysteinyl leukotrienes and the hepatic production of NO were investigated in the isolated perfused rat liver. Livers were perfused in a non-recirculating haemoglobin-free system from the portal to the caval vein. Perfusion medium was equilibrated with 95% O2/5% CO2. In hypoxia experiments, gassing was changed to 95% N2/5% CO2 for 20 min. Tritiated leukotrienes were infused to the portal vein and metabolites in effluent and bile were measured by HPLC. Hypoxia did not influence the uptake of 3H-LTC4 and 3H-LTE4 but biliary elimination was reduced by 50-60% compared to normoxic control experiments. In hypoxia, the metabolite pattern in bile was also significantly changed with a decrease of omega-oxidation products. Following reoxygenation larger amounts of leukotrienes were excreted from the liver into the bile. To induce NO synthase in the liver, rats were injected intraperitoneally with endotoxin 6 hours before livers were isolated for perfusion. In contrast to nontreated livers, nitrite and nitrate, the oxidation products of NO, were detectable in the effluent perfusate. Basal NO2(-)+NO3- release was 5.3 (1.2) nmol/g liver/min. NO2(-)+NO3- release was stimulated by L-arginine infusion, whereas hypoxia resulted in an almost complete inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:[Effect of hypoxia on nitric oxide formation and leukotriene metabolism in the perfused rat liver]. 751 4

Neutrophil accumulation in tissue is a hallmark of inflammation and is associated with a variety of pathological conditions. In bacterial infection neutrophils are selectively attracted in large numbers to phagocytose and kill invading microorganisms. However, activated neutrophils can also cause injury to tissues. To investigate functional alterations in liver recruited neutrophils (PMNs), we studied the functional characteristics of circulating blood and liver sequestered PMNs in terms of host defense mechanisms, such as nitric oxide (NO) and superoxide (SO) generation, beta 2 integrin expression, phagocytosis, and eicosanoid profile. Cells were isolated from rats infused with a nonlethal dose (320 micrograms/kg) of E. coli endotoxin (ET) or pyrogen-free saline for 90 min. Liver PMNs produced significantly more NO both in the absence and in the presence of an in vitro endotoxin challenge than did blood PMNs. No significant difference was observed in phorbol myristate acetate-stimulated SO generation. Endotoxin infusion significantly up-regulated the expression of CD11b/c in circulating and even more so in liver PMNs. Phagocytosis was significantly enhanced by in vivo ET treatment in blood PMNs, and liver PMNs showed even greater phagocytic activity than blood PMNs or Kupffer cells. The percent distribution of prostaglandins D2 and E2 of total 14C-eicosanoids was significantly higher and that of thromboxane B2 and 5-, 12-, and 15-HETEs was significantly lower in liver than in blood PMNs. Our study demonstrates several functional differences between liver-recruited and circulating PMNs in an acute endotoxic model. The implications of altered neutrophil function may extend to mechanisms of host defense and hepatotoxicity associated with sepsis and endotoxemia.
...
PMID:Functional characterization of peripheral circulating and liver recruited neutrophils in endotoxic rats. 752 Sep 27

The L-arginine:nitric oxide (NO) biosynthetic pathway has been proposed as an important mediator in host defense mechanisms and may therefore play a role in the acute allograft response. We have studied NO generation in liver allograft rejection and determined its value in immunological monitoring. Stable end products of this pathway have been determined serially in 50 primary liver recipients and compared with 2 known mediators and markers of acute allograft rejection (IL-2R positive lymphocytes and circulating TNF alpha). Plasma concentrations of acid-labile nitrosocompounds (NOx), which increased during acute allograft rejection (P < 0.0001), correlated with rejection severity and were reduced after administration of supplemental high dose glucocorticoids. Concentrations were significantly lower in nonrejection graft complications but were elevated during episodes of sepsis. Correlations between plasma NOx levels and circulating TNF-alpha (r = 0.451, P < 0.001) and IL-2R-positive lymphocytes in peripheral blood (r = 0.781, P < 0.001) were demonstrated. In a logistic analysis of these variables, plasma NOx was the most predictive parameter of an episode of acute cellular rejection. Nitric oxide generation in FK506-treated patients was lower compared with patients receiving a CsA-based immunosuppression regimen and was associated with a reduced frequency of acute rejection in the FK506 group. These data are consistent with a role for NO in the cellular alloantigen immune response and indicate that monitoring of plasma levels of NOx may be useful in the detection of acute allograft rejection.
...
PMID:Nitric oxide generation. A predictive parameter of acute allograft rejection. 752 65

We evaluated regional blood flows in a hyperdynamic sepsis model and the reversal of increased flows by blockade of nitric oxide (NO) synthase. Seven awake sheep were continuously infused with Escherichia coli endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1] for 48 h. The NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg) was injected after 24 h. Blood flows to systemic organs were determined with the radioactive microsphere technique. LPS induced elevation of cardiac index by 36% (P < 0.05) and a fall in systemic vascular resistance index by 37% (P < 0.05) at 0 h [time of L-NAME administration, 24 h after infusion of LPS had begun] L-NAME administration normalized cardiac index [6.1 +/- 0.5 at 4 h posttreatment, 6.1 +/- 0.5 l.min-1.m-2 at -24 h (baseline)] and systemic vascular resistance index (1,333 +/- 105 at 4 h posttreatment, 1,280 +/- 163 dyn.s.cm-5.m2 at -24 h) and reduced all regional blood flows to near-baseline levels for the remainder of the study period (24 h). O2 consumption was unaffected by treatment.
...
PMID:Increased organ blood flow in chronic endotoxemia is reversed by nitric oxide synthase inhibition. 752 59

To evaluate the role of nitric oxide (NO) in the attenuated vascular reactivity observed in sepsis, we utilized the specific NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Male Sprague-Dawley rats (n = 16) were randomized to either sepsis induced by cecal ligation and perforation (CLP; n = 8) or sham procedure (Sham; n = 8). Vascular reactivity was assessed by measuring the pulmonary pressor response to hypoxia (HPV) (fractional inspired O2 concentration = 0.08) and the pulmonary and systemic pressor response to an intravenous infusion of phenylephrine (1.5-6.0 micrograms.kg-1.min-1). Twenty-four hours after surgery, CLP animals had significantly attenuated HPV compared with Sham animals. In response to hypoxia the change in total pulmonary vascular resistance during hypoxia was 0.008 +/- 0.004 and 0.021 +/- 0.006 mmHg.min-ml-1 in CLP and Sham animals, respectively (P < 0.05). The pulmonary and systemic blood pressure response to phenylephrine was also attenuated in CLP compared with Sham animals. After L-NAME infusion (15 mg/kg), there was a significant augmentation of the HPV response in Sham animals. In contrast, the HPV response in CLP animals was unchanged after L-NAME. The attenuated pressor response to phenylephrine in neither the pulmonary nor the systemic circulation was changed after the administration of L-NAME. These data suggest that in rats, excess NO is not an important mediator of the attenuated vascular reactivity observed in sepsis.
...
PMID:Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis. 752 65

Hyperdynamic sepsis is associated with a redistribution of organ blood flow. We hypothesized that increased nitric oxide (NO) production could mediate this process. The objective of this study was to determine the effect of a NO synthesis inhibitor on systemic and organ blood flows in vivo in septic and in normal rats. Rats were instrumented for hemodynamic monitoring and randomized to undergo cecal ligation and perforation (CLP) or control laparotomy. Cardiac output and organ blood flow were measured by thermodilution and radioactive microspheres, respectively. Baseline values were obtained at 24 h after CLP or control laparotomy and after the administration of L-nitro-arginine methyl ester (L-NAME) at 2, 4, 8, and 16 mg/kg intravenously. All studies were performed in awake, unrestrained animals. Septic animals were normotensive and hyperdynamic. L-NAME decreased cardiac index and increased systemic vascular resistance and mean arterial blood pressure to an equivalent degree in control and in CLP animals. CLP was associated with significantly increased relative blood flow to the small bowel and portal circulation. Although cardiac output decreased with L-NAME, blood flow to the diaphragm, liver, and brain was relatively well preserved. Absolute blood flow to other organs, including small bowel, decreased in parallel to the cardiac output. The effect of L-NAME on organ blood flow was comparable in control and in CLP animals. We conclude that the influence of NO on organ blood flows appears to vary between organs, but that NO does not explain the redistribution of blood flow observed in hyperdynamic sepsis.
...
PMID:Modulation of hemodynamics and organ blood flow by nitric oxide synthase inhibition is not altered in normotensive, septic rats. 752 82

Treatment of rats with bacterial endotoxin resulted in a significant induction of hepatic nitric oxide synthase within 3 hours. The response was maximal at 12 hours and was maintained over 18 hours. The induction of nitric oxide synthase correlated well with the increase in plasma nitrate plus nitrite concentrations and also with the inhibition of glucose synthesis in subsequently isolated hepatocytes. The decline in the rate of gluconeogenesis also correlated with an inhibition of flux through phosphoenolpyruvate carboxykinase but not with alterations in flux through either pyruvate kinase or 6-phosphofructo-1-kinase, suggesting that a nitric oxide-induced inhibition of phosphoenolpyruvate carboxykinase may underlie the decreased glucose production in sepsis.
...
PMID:Endotoxin causes reciprocal changes in hepatic nitric oxide synthesis, gluconeogenesis, and flux through phosphoenolpyruvate carboxykinase. 752 53

We and others have proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. An effect of NO on cardiac sarcolemmal L-type calcium channels has also recently been proposed. The spontaneous beating rate of neonatal cardiac myocytes is regulated by the sarcolemmal L-type calcium channel. Accordingly, we sought to determine if cytokine-stimulated NO production could also regulate beating rates of neonatal cardiac myocytes. Treatment of neonatal rat cardiac myocytes with TNF, IL-1, IL-6, 10(-5)M NMA, or 10(-3)M NMA significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 hours (p < or = .01; n = 12 for each). Only IL-1 treatment resulted in significant nitrite levels vs. control over 48 hours (4.2 +/- 0.7 vs. 0.3 +/- 0.2 nmoles/1.25 x 10(-5) cells, respectively) (n = 12). Nitrite production by IL-1 was inhibited by 10(-3)M NMA but not 10(-5)M NMA (0.3 +/- 0.2 vs. 4.1 +/- 0.6 nmoles; p < .01; n = 12). The addition of 10(-5)M NMA to TNF, IL-1, and IL-6 did not alter the effect of the cytokines on the spontaneous beating rates of the cardiac cells (p < or = .01; n = 12 for each). These results strongly suggest that cytokines and NMA affect cardiac myocyte spontaneous beating rates through mechanisms independent of NO.
...
PMID:Chronotropic effects of cytokines and the nitric oxide synthase inhibitor, L-NMMA, on cardiac myocytes. 752 6

Nitric oxide (NO) has been reported to have a protective function in attenuating hepatic injury during endotoxemia or sepsis. As a result, the role of NO in attenuating the hepatic microcirculatory alterations associated with endotoxemia was investigated in mice by in vivo microscopy. The livers were examined 2 h after intravenous injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS) alone or in combination with inhibitors of the synthesis of NO, NG-nitro-L-arginine methyl ester or NG-monomethyl-L-arginine. In the animals treated with the combination of NO synthase inhibitors and LPS, leukocyte adherence was increased threefold above that in animals treated with LPS alone. This was accompanied by a 33% reduction in sinusoidal blood flow. Simultaneous administration of L-arginine, but not D-arginine, eliminated these microcirculatory disturbances. The results demonstrate that inhibition of LPS-stimulated NO production results in an early hepatic microvascular inflammatory response to a dose of endotoxin which by itself is scarcely inflammatory. This suggests that NO plays a significant role in stabilizing the hepatic microcirculation during endotoxemia, thereby helping to protect the liver from ischemia and leukocyte-induced oxidative injury.
...
PMID:Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia. 752 79

Tumor necrosis factor-alpha (TNF-alpha) inhibits release of nitric oxide (NO) in vitro by stimulating the degradation of constitutive NO synthase (cNOS III) mRNA. However, TNF-alpha is believed to be the cytokine mediator of the hypotension and upregulation of inducible NO synthase (iNOS II) produced by gram-negative bacterial endotoxin (LPS). Some in vivo effects of TNF-alpha are opposite to those which occur in vitro. This study tested the hypothesis that in vivo administration of exogenous TNF-alpha and endogenously released TNF-alpha induce iNOS II activity and inhibit cNOS III activity, and thereby mediate the acute phase effects of LPS on blood pressure and the NO system in the rat. We show that LPS produces acute phase hypotension in ketamine anesthetized rats. The hypotension was associated with elevation of biologically active TNF-alpha in plasma, increased production of RNI (NO2- and NO3- anion) in rat neutrophils (PMN) and suppression of RNI production by A23187 (1 microM) stimulated thoracic aorta (RTA) ex vivo. TNA-alpha (10(6) U/ml, iv) did not produce acute phase hypotension but initially raised arterial blood pressure and heart rate (HR), did not increase RNI production by PMN, and inhibited RNI production by A23187 stimulated RTA ex vivo. Pretreatment of rats with the immunex monomeric soluble P75 receptor binding protein for TNF-alpha (TNFsr, 0.5 mg/kg, iv) 15 min prior to LPS administration decreased circulating TNF-alpha from 92,137 +/- 12,456 U/ml to undetectable levels as determined by the L929 bioassay. However, LPS-induced increases in RNI in PMN was enhanced and LPS-induced decreases in RNI production by RTA was inhibited by TNFsr. Thus, in vivo administration of TNF-alpha does not mimic the hemodynamic and NO-inducing effects of LPS. However, TNF-alpha mediates in part LPS-induced inhibition of RNI production by RTA. Thus, endogenous TNF-alpha is not required for LPS-induced acute phase hypotension or iNOS II activity. The importance of TNF-alpha in sepsis resides in systems other than iNOSII and blood pressure.
...
PMID:In vivo administration of endotoxin and tumor necrosis factor-alpha produce different effects on constitutive and inducible nitric oxide synthase activity in rat neutrophils and aorta ex vivo. 753 Mar 65

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>