Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrotoxicity caused by cyclosporin A (CSA) is the result of vasoconstriction of the renal microcirculation. The endothelium-derived relaxing factor nitric oxide (NO) regulates microvascular blood flow in various tissues, and mediates the microcirculatory response during hypertension and sepsis. This study investigated the role of NO in CSA-induced renal vasoconstriction. Hydronephrotic kidneys in rats were suspended in an environmentally controlled tissue bath, and interlobular, afferent and efferent arteriolar diameters and blood flow were measured by in vivo videomicroscopy. CSA was administered alone, with the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) or with exogenous NOS substrate L-arginine. CSA significantly constricted the whole of the renal microvasculature whereas L-NAME alone preferentially constricted the preglomerular vessels. L-Arginine reversed the vasoconstriction induced by CSA whereas L-NAME had no further effect. Preglomerular basal vascular tone is dependent on continuous production of NO and alterations in the L-arginine-NO pathway contribute to CSA-induced renal vasoconstriction.
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PMID:An experimental study of altered nitric oxide metabolism as a mechanism of cyclosporin-induced renal vasoconstriction. 774 87

Two cases of adult respiratory distress syndrome (ARDS) treated successfully with nitric oxide (NO) inhalation are described. One patient had severe sepsis and the other had trauma induced ARDS. The slow entry criteria for extracorporeal membrane oxygenation (ECMO) was fulfilled in both cases. NO inhalation substantially improved oxygenation, reduced pulmonary arterial pressure and peak inspiratory pressure. Treatment with NO inhalation was without side effects and easy to administer through the ventilator. Both patients survived without sequelae. We suggest that inhalation with NO should be tried before ECMO treatment is considered in severe ARDS.
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PMID:[Nitrogen oxide inhalation in acute pulmonary failure]. 778 4

In recent studies, production of interleukin-6 (IL-6) in cultured enterocytes was stimulated by lipolysaccharide (LPS). In other cell types, IL-6 production was inhibited by nitric oxide (NO). We tested the hypothesis that LPS-induced IL-6 production in the enterocyte is regulated, at least in part, by NO. IEC-6 cells (a rat intestinal epithelial cell line) were cultured for 3 days with different combinations of LPS (1-10 micrograms/ml), the NO synthase inhibitor N-omega-nitro-L-arginine (NNA, 3-300 microM), L-arginine (10 mM), the NO donor sodium nitroprusside (SNP, 0.5-1 microM), or medium alone as control. IL-6 levels in the culture medium were determined by the B9 murine hybridoma bioassay. Nitrite, a stable end product of NO metabolism, was measured by HPLC. PCR was performed to determine inducible NO synthase (iNOS) mRNA expression in the IEC-6 cells. Treatment of IEC-6 cells with LPS stimulated IL-6 production. LPS-induced IL-6 production was further increased by NNA in a dose-dependent fashion. This effect of NNA was abolished by the addition of L-arginine. SNP caused a dose-dependent decrease in IL-6 production. Nitrite production was increased in a dose-dependent fashion after LPS treatment. PCR revealed an increase in iNOS mRNA expression in IEC-6 cells after administration of 1 microgram/ml LPS. The results suggest that NO inhibits LPS-induced IL-6 production in the enterocyte. NO may be an important regulator of intestinal cytokine response during sepsis and endotoxemia.
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PMID:Nitric oxide inhibits LPS-induced IL-6 production in enterocytes. 779 30

Multiple organ failure is the most common cause of death in critically ill patients in the United States. Acute respiratory failure is the most important single component of this clinical scenario, with a mortality risk > 50%. Key pathophysiologic events occur in the pulmonary microvasculature at the interface between circulating elements and the external environment. In particular, the response of the alveolar capillary endothelial cell is of fundamental importance in this injury process. A variety of clinical stimuli initiate a systemic inflammatory response that contributes to acute microvascular lung injury. Sepsis, trauma, thermal injury, acute pancreatitis, and ischemia-reperfusion injury are among these stimuli. The particular emphasis of this review is on events associated with intestinal ischemia-reperfusion, a common and important clinical event. The pathogenic mechanisms that lead to acute lung injury in this setting are not completely understood, although it is clear that neutrophil-endothelial interactions regulated by both humoral and local mediators are crucial. Oxygen-derived free radicals, proteases, cytokines, eicosanoids, endotoxin, complement activation products, and probably platelet activating factor and nitric oxide are involved as either signalling or effector molecules. The key cellular participants during the acute phase of injury are the polymorphonuclear neutrophil (PMN) and the microvascular endothelial cell. Each of these participants is considered with regard to phlogistic behavior and the potential for therapeutic intervention. Adherence of the neutrophil to the endothelium creates a microenvironment in which PMN-derived oxidants, proteases, and cationic proteins are discharged under conditions that lead to cellular injury. Loss of microvascular integrity results and pulmonary dysfunction follows. At present, we offer only nonspecific supportive care for patients with this problem. However, investigations into relevant molecular and cellular regulatory events offer important opportunities for directed therapy. We are now approaching the threshold for utilization of several new and specific approaches. While no single pharmacologic therapy is likely to be curative for this complex problem, it is probable that certain approaches will be of clinical benefit in the near future. This review is designed to provide a basis for understanding this evolution.
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PMID:Pulmonary microvascular injury following intestinal reperfusion. 780 96

Nitric oxide (NO) is an important physiological mediator of vascular tone and is thought to be involved in the pathogenesis of septic shock. Plasma nitrate is the stable end product of NO oxidation and in part reflects endogenous NO production. We measured plasma nitrate levels in 47 episodes of suspected septicaemia in 43 in-patients (16 male and 27 female, age 15-63 years). Nitrate concentrations were significantly higher (P < 0.01) compared to healthy controls. Further analysis revealed that significantly elevated levels occurred only in the septic patients who had normal or elevated numbers of neutrophils in the peripheral blood and were hypotensive on presentation. Failure of plasma nitrate concentrations to rise significantly in patients with neutropenia suggests that this cell type may be important in the activation of the arginine-NO system in severe sepsis in man.
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PMID:Plasma nitrate concentrations in neutropenic and non-neutropenic patients with suspected septicaemia. 783 64

Inflammatory stimulation of the liver is known to induce nitric oxide (NO) biosynthesis. NO can interfere with the activity of a number of enzymes important to cellular metabolism. This study was carried out to investigate the influence of NO on rat hepatocyte glucose output and urea production. Induction of NO synthesis by incubation with a combination of cytokines and lipopolysaccharide led to a 48.8 +/- 2.4% inhibition of glucose output and to a 45.0 +/- 6.4% suppression of urea production. Inhibition of NO synthesis with NG-monomethyl-L-arginine was able to totally prevent these effects. High concentrations of L-arginine overcame the inhibition of urea production caused by endogenous NO synthesis. Exposure of HC to NO donors resulted in a concentration-dependent inhibition of glucose output, without having any effect on urea production. Hepatocellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was also found to be inhibited by endogenously produced NO (33.5 +/- 5.2%), as well as by exogenously applied NO. However, an exact correlation between GAPDH activity and glucose output could not be established. These data indicate that NO biosynthesis may contribute to the development of hepatic dysfunction in chronic sepsis.
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PMID:Hepatocyte nitric oxide biosynthesis inhibits glucose output and competes with urea synthesis for L-arginine. 784 Feb 3

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator in sepsis and septic shock. Kupffer cells (KCs) are the resident macrophages of the liver and are potent producers of TNF-alpha in response to inflammatory stimuli such as bacterial endotoxin or lipopolysaccharide (LPS). Although the effects of exogenous cytokines such as interferon-gamma on TNF-alpha production by macrophages have been fairly well studied, the intracellular pathways regulating KC TNF-alpha synthesis are largely unknown. We investigated the role of guanylate cyclase and cGMP in LPS-induced KC TNF-alpha synthesis. Exogenous 8-BrcGMP and dbcGMP increased LPS-stimulated TNF-alpha synthesis but had no effect on KC TNF-alpha in the absence of LPS. Sodium nitroprusside (SNP), a nitric oxide-releasing substance that stimulates guanylate cyclase, increased TNF-alpha synthesis in response to LPS, whereas methylene blue and LY83583, guanylate cyclase inhibitors, decreased KC TNF-alpha synthesis. The inhibitory effect of methylene blue could be overcome with exogenous dbcGMP or SNP. Our results demonstrate that guanylate cyclase and cGMP mediate LPS-induced KC TNF-alpha synthesis and suggest that agents that alter cyclic nucleotide metabolism in KCs may affect the response of these cells to inflammation and inflammatory stimuli.
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PMID:Cyclic GMP and guanylate cyclase mediate lipopolysaccharide-induced Kupffer cell tumor necrosis factor-alpha synthesis. 785 45

We have previously reported differential impairment of pulmonary and systemic vascular contractility in hyperdynamic sepsis. The objectives of this study were (1) to determine whether the magnitude of this phenomenon depends on the control group chosen for comparison, and (2) to examine the role of nitric oxide (NO) in this altered vascular contractility. Rats were randomized to sepsis induced by cecal ligation and perforation (CLP) or to one of two control procedures. The Sepsis group had a jugular venous line for fluid administration, laparotomy, and CLP. Control group 1 (Control) had only a jugular venous line inserted, while group 2 (Sham) had a jugular venous line inserted and an abdominal incision. All rats were killed 24 h after surgery. Vascular contractility of small pulmonary arterial and thoracic aortic rings was assessed in vitro by obtaining cumulative dose-response curves to the contractile agonists potassium chloride (KCl), phenylephrine (PE), and prostaglandin F2 alpha (PGF2 alpha). Pulmonary vessels from animals in the Sepsis and Sham groups exhibited significant attenuation of the contractile responses to KCl, PE, and PGF2 alpha compared with the Control group. In contrast, contractility of the aortic rings to KCl, PE, and PGF2 alpha was not significantly different in the three groups studied. Incubation of pulmonary and aortic vessels with NG-nitro-L-argine methyl ester (L-NAME, 10 microM) caused an increase in the response to KCl, PE, and PGF2 alpha in pulmonary vessels in Sepsis and Sham rats but not in Control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular reactivity in sepsis: importance of controls and role of nitric oxide. 788 60

Among the important pathophysiologic alterations in the brain in bacterial meningitis are abnormalities of cerebral circulation and metabolism; however, the precise mechanisms by which these disturbances occur are not completely delineated. It has been recently recognized that cytokines are produced by tissues in the central nervous system in meningitis and play a critical role in the host inflammatory response. Because these mediators are involved in circulatory and metabolic disturbances in other tissues in sepsis, we investigated the role of tumor necrosis factor-alpha in the central nervous system in a rabbit model. We found that injection of recombinant human TNF into the cisterna magna in the rabbit led to an acute reduction in cerebral oxygen uptake and a more prolonged reduction in cerebral blood flow. This was accompanied by an increase in intracranial pressure and an increase in cerebrospinal fluid lactate. Reduction in oxygen uptake and increases in intracranial pressure and CSF lactate were blocked by pretreatment with L-NAME, an inhibitor of nitric oxide synthase. Reduction in cerebral blood flow was not affected by L-NAME treatment and was due to increased cerebrovascular resistance and reduced oxygen demand. These results suggest that TNF may be a critical mediator of changes in cerebral circulation and metabolism and that some of these changes occur via the nitric oxide pathway.
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PMID:Effect of recombinant human tumor necrosis factor-alpha on cerebral oxygen uptake, cerebrospinal fluid lactate, and cerebral blood flow in the rabbit: role of nitric oxide. 788 56

Accumulation and stimulation of PMN-leukocytes, enhanced prostaglandin metabolism and tissue hypoxia lead to high concentrations of oxygen radicals and their metabolites in septic shock. Synchroneously, excessive high concentrations of nitric oxide are found, most likely due to the stimulation of its inducible synthetase. Oxygen radicals seem to be attributable for the irreversible tissue damage leading to multiple organ failure in sepsis. High concentrations of nitric oxide induce the typical macro- and microcirculatory derangements normally seen in sepsis. Both mediators are present in the early phase of sepsis and seem to influence the course of disease. Therapeutic interventions such as scavenger therapy or inhibition of the inducible NO-synthetase are promising. The results of the first clinical therapeutic studies, however, were not always conclusive. It is still unclear which scavenger and which inhibitor should be given when and in which dosage in order to improve the outcome of sepsis and septic shock. Furthermore, it remains unclear to which extend oxygen radicals and nitric oxide react with each other, thus possibly potentiating their effects. The open questions still warrant further research and may lead to new therapeutic options improving the morbidity and mortality of this severe disease.
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PMID:[Oxygen radicals and nitrogen monoxide in sepsis]. 788 85


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