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Biomedical subjects

N R Webster

Publications and source records attributed to N R Webster.

At least 55 records · Page 3Linked to original sources
PubMed1999

Effect of the nitric oxide inhibitor, L-N(G)-monomethylarginine, on accumulation of interleukin-6 and interleukin-8, and nuclear factor-kappaB activity in a human endothelial cell line.

OBJECTIVE: To determine the effect of the nitric oxide synthase inhibitor, L-N(G)-monomethylarginine, on interleukin-6 and interleukin-8 accumulation, and nuclear factor-kappaB expression in an endothelial cell model of sepsis. DESIGN: Controlled cell culture experiments examining the immunomodulatory effects of nitric oxide synthase inhibition. SUBJECTS: A human endothelial cell line (EA.hy926). MEASUREMENTS AND RESULTS: Cells were incubated with tumor necrosis factor-alpha and interleukin (IL)-1beta in the presence of L-N(G)-monomethylarginine (L-NMMA). IL-6 and IL-8 were measured in culture supernatants using enzyme immunoassay. Nuclear factor-kappaB was measured using electrophoretic mobility shift assay and was quantified using phosphorimaging. IL-6 accumulation was decreased (p < .05) and IL-8 accumulation increased (p < .01) with L-NMMA. Increased nuclear factor-kappaB expression in stimulated cells was unaltered on exposure to L-NMMA. Cell viability was unaffected. CONCLUSIONS: Excessive production of nitric oxide has been implicated in septic shock, and the use of nitric oxide synthase inhibitors has been suggested. The immunoregulatory actions of nitric oxide synthase inhibitors affects the profile of cytokine release. This effect is not mediated through modulation of nuclear factor-kappaB. These findings have implications for the use of nitric oxide synthase inhibiting agents in septic shock.

Cell Line↗
PubMed1999

The role of the intensive care unit in the management of the critically ill surgical patient.

Surgical patients make up 60-70% of the work load of intensive care units in the UK. There is a recognised short fall in the resource allocation for high dependency units (HDUs) and intensive care units (ICUs) in this country, despite repeated national audits urging that this resource be increased. British ICUs admit patients later and with higher severity of illness scores than elsewhere and this leads to higher ICU mortality. How can this situation be improved? Scoring systems that allow selection of appropriate patients for admission to ICU and avoid inappropriate admission are still in development. Pre-operative admission and optimisation in ICU is rare in this country despite increasing evidence to support this practice in high risk surgical patients. Early admission to ICU, with potential improvement in outcomes, could also be achieved using multi-disciplinary medical emergency teams. These teams would be alerted by ward staff in response to set specific conditions and physiological criteria. These proposals are still under trial but may offer benefit by reducing mortality in critically ill surgical patients.

Critical Illness↗
PubMed1999

Monitoring the critically ill patient.

It has long been recognised that the physiological response of the patient to a stress or disease process will very largely determine the outcome. It is important, therefore, to monitor the physiological responses of patients since this not only allows the assessment of physiological reserve but will also give a baseline against which the effectiveness of any applied treatment can be judged. Basic knowledge of the principles of monitoring and correct interpretation of data is important since a failure to do so can result in misdirected therapy. Much of what will be discussed in this review revolves around the maintenance of normal aerobic metabolism and thus maintenance of viable cell function and measurement of the degree of tissue oxygenation. Reduced supply of oxygen over demand for oxygen results in cell injury and organ dysfunction. Only by assessing this dysfunction can appropriate modifications of therapy be undertaken.

Critical Care↗
PubMed1998

The effect of nitric oxide and peroxynitrite on apoptosis in human polymorphonuclear leukocytes.

In acute lung injury, neutrophil apoptosis may be important in regulating the inflammatory process by controlling neutrophil numbers and thus activity. Exogenous inhaled nitric oxide is now a widely used therapy in patients with acute lung injury, and its effects on apoptosis may be important. We investigated the effect of nitric oxide and peroxynitrite on apoptosis in lipopolysaccharide stimulated polymorphonuclear leukocytes as a model of nitric oxide-treated lung injury. Cells were incubated for up to 16 h with and without 1.7 microg/ml lipopolysaccharide and the nitric oxide donor GEA-3162 or the peroxynitrite donor SIN-1. Apoptosis was assessed using flow cytometry following annexin-V staining, after 4, 6, 8, and 16 h. Data were assessed using Kruskal-Wallis analysis of variance or Mann-Whitney U-test as appropriate. Annexin-V staining increased spontaneously over 16 h in untreated cells (p = .0002) and incubation with either 1000 microM SIN-1 or 10 microM GEA-3162 increased annexin staining at early time points in nonactivated cells. Apoptosis was attenuated when cells were exposed to lipopolysaccharide and both nitric oxide and peroxynitrite dose dependently inhibited this suppression at all time points and was most apparent at 16 h (p = .004 and .001, respectively). Exposure of activated neutrophils to exogenous nitric oxide or peroxynitrite has marked influences on apoptosis. This work has implications for the modulation of neutrophil function within the lung in patients with lung injury who receive inhaled nitric oxide therapy.

Annexin A5↗
PubMed1998

The effects of nitric oxide and peroxynitrite on interleukin-8 and elastase from lipopolysaccharide-stimulated whole blood.

UNLABELLED: Inhaled nitric oxide is now widely used in the treatment of hypoxemia and pulmonary hypertension in critically ill patients. Interleukin-8 (IL-8) and neutrophil elastase are important markers of the onset and severity of acute lung injury. We studied the effects of nitric oxide and peroxynitrite on IL-8) and elastase accumulation in lipopolysaccharide-activated whole blood. The nitric oxide donor (GEA-3162) did not affect IL-8 accumulation (P = 0.195) but did cause an increase in elastase accumulation (P = 0.007). The peroxynitrite donor (SIN-1) caused an increase in both IL-8 accumulation (P = 0.0004) and elastase accumulation (P = 0.007). The lack of effect of nitric oxide could be explained by the scavenging of nitric oxide by hemoglobin. These results suggest that modulation of the inflammatory response may occur during inhaled nitric oxide therapy in the critically ill. IMPLICATIONS: Inhaled nitric oxide, used in lung injury, reacts within the lung, forming peroxynitrite. We investigated the effect of nitric oxide and peroxynitrite on interleukin-8 and elastase release by white cells during inflammation. Nitric oxide and peroxynitrite had marked effects on elastase and interleukin-8, which suggests modulation of the inflammatory response.

Free Radical Scavengers↗
PubMed1998

The effect of midazolam and propofol on interleukin-8 from human polymorphonuclear leukocytes.

UNLABELLED: Anesthetics and sedatives contribute to postoperative immunosuppression. Interleukin-8 (IL-8) is a chemotactic and activating factor that mediates neutrophil adhesion and margination and is essential for host defense. We investigated the effect of anesthetics on isolated human polymorphonuclear leukocyte production of IL-8. Healthy human polymorphonuclear leukocytes were isolated using a single-step density gradient and stimulated with lipopolysaccharide in the presence of varying concentrations of propofol or midazolam for up to 20 h. IL-8 was measured in both culture supernatants and cell lysates using enzyme immunoassay, and IL-8 mRNA in cells was measured using Northern blotting and phosphorimaging. Data were analyzed using Kruskal-Wallis analysis of variance or the Mann-Whitney U-test as appropriate. Lipopolysaccharide increased extracellular accumulation of interleukin-8, which was suppressed by both propofol (P = 0.025) and midazolam (P = 0.028). However, intracellular IL-8 increased with exposure to lipopolysaccharide (P = 0.028) and remained increased with both anesthetics. Northern blot analysis also revealed increased IL-8 mRNA levels in the presence of both midazolam and propofol, which was confirmed by molecular imaging. These data strongly suggest that the anesthetics modulate transport or secretion of IL-8 protein from the cell. Suppression of IL-8 by anesthetics and sedatives may predispose postoperative and intensive care patients to infection. IMPLICATIONS: Anesthesia causes immune suppression and alters neutrophil function. We investigated the effect of propofol and midazolam on interleukin-8, a neutrophil chemotactic agent in human neutrophils. Both anesthetics decreased extracellular interleukin-8 accumulation, but intracellular levels and mRNA remained high. This suggests that propofol and midazolam alter interleukin-8 secretion from cells.

Analysis of Variance↗
PubMed1998

Spinal but not general anesthesia increases the ratio of T helper 1 to T helper 2 cell subsets in patients undergoing transurethral resection of the prostate.

UNLABELLED: Surgical stress and anesthesia cause immunosuppression that may predispose patients to postoperative infections. T helper lymphocytes play a major role in the immune response by controlling cell-mediated and humoral immunity. The type of immune response generated is determined by the differentiation of precursor T helper cells into Th1 or Th2 cells. Each cell subset secretes a particular array of cytokines that further augment the differentiation into that subset. Th1 cells produce interferon gamma and are responsible for cell-mediated immunity. Th2 cells produce interleukin-4 and are more effective in inducing humoral immunity. Cytokine concentrations are altered during surgery and anesthesia, which may effect Th cell predominance and, therefore, subsequent immune responses. We determined Th1 to Th2 cell ratios in patients undergoing transurethral resection of the prostate (TURP) using either spinal or general anesthesia. Mononuclear cells were isolated before anesthesia, immediately after surgery, and after 24 h from patients undergoing TURP, 10 under general anesthesia and 9 under spinal anesthesia. T helper cell subsets were quantified by using flow cytometry, and the ratio of Th1 to Th2 cells was calculated. Th1 to Th2 ratios in patients receiving spinal anesthesia increased over the three time points studied (P = 0.029) but did not change in patients who had general anesthesia (P = 0.11). At 24 h, Th1 to Th2 ratios were significantly higher in the spinal group than in patients who received general anesthesia (P = 0.0157). Total T helper cell numbers remained constant. These data suggest that, from an immunological viewpoint, spinal anesthesia, but not general anesthesia, benefits the patient by maintaining Th1 cell numbers, thereby promoting cellular immunity. IMPLICATIONS: Spinal anesthesia may result in less immunosuppression after surgery. We found that the ratio of T helper 1 to T helper 2 cells was higher in patients undergoing prostate surgery by spinal rather than general anesthesia. Th1 cells promote protective immune responses that may result in fewer postoperative infections.

Aged↗
PubMed1998

Nitric oxide synthase activity is increased in relation to the severity of liver dysfunction.

1. Nitric oxide is a potent vasodilator which plays a major role in the control of blood pressure. The hyperdynamic circulation of cirrhosis has been linked to nitric oxide.2. We measured neutrophil nitric oxide synthase activity in relation to the level of hepatic dysfunction in patients with liver disease of varying aetiology and severity.3. Neutrophils were isolated from 21 patients (7 Child-Pugh score A, 6 grade B and 8 grade C) aged 28-76 (median 49) years. Nitric oxide synthase activity was measured using the conversion of oxyhaemoglobin to methaemoglobin by nitric oxide and expressed in terms of cell protein. Blood pressure and biochemical indices were recorded. Data were assessed using Kruskal-Wallis one-way analysis of variance, Mann-Whitney U-test or Pearson correlation as appropriate.4.Systolic, mean arterial and diastolic blood pressures decreased with increasing hepatic damage (P=0.031, P=0.01 and P=0. 038 respectively). Nitric oxide synthase activity increased with the degree of liver dysfunction (P=0.033) and was highest in patients with Child-Pugh score C. Systolic blood pressure correlated with nitric oxide synthase activity in patients with Child-Pugh score C (P=0.029).5. Our results show that nitric oxide synthase activity increases with increasing Child-Pugh score and is associated with the development of systemic hypotension. These data may support the involvement of nitric oxide in the haemodynamic disturbances seen in liver disease.

Adult↗
PubMed1997

UK guidelines for the use of inhaled nitric oxide therapy in adult ICUs. American-European Consensus Conference on ALI/ARDS.

OBJECTIVE: Although unlicensed, inhaled nitric oxide (NO) therapy is now widely used in the United Kingdom. Our aim was to produce guidelines for the clinical application of inhaled NO in adult intensive care practice, based upon the current level of published information. METHODS: The published data regarding the use of inhaled NO in the acute respiratory distress syndrome and right-sided cardiac failure was presented, analysed and discussed. Recommendations based on these data as well as on current experience in the United Kingdom were formulated. DESIGN: An expert group comprising intensive care specialists from within the United Kingdom, representatives from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine and individuals from the Departments of Health and Industry related to the field was assembled. RESULTS: United Kingdom guidelines for the indications, contraindications, dose, delivery, monitoring and scavenging of inhaled NO therapy were produced. CONCLUSIONS: The need for additional quality research to establish evidence of efficacy and safety was emphasized. The guidelines are designed to act within the context of current practice and knowledge and should be revised as further data emerge.

Acute Disease↗
PubMed1997

The effects of intravenous antioxidants in patients with septic shock.

Oxidative stress is implicated in septic shock. We investigated the effect of intravenous antioxidant therapy on antioxidant status, lipid peroxidation, hemodynamics and nitrite in patients with septic shock. Thirty patients randomly received either antioxidants (n-acetylcysteine 150 mg/kg for 30 min then 20 mg/kg/h plus bolus doses of 1 g ascorbic acid and 400 mg alpha-tocopherol) or 5% dextrose. Basal vitamin C was low and redox-reactive iron was elevated in all patients. In the 16 patients receiving antioxidants, vitamin C increased (p = .0002) but total antioxidant capacity was unaffected. Lipid peroxides were elevated in all patients but did not increase further in the patients receiving antioxidants. Plasma total nitrite also increased (p = .007) in the antioxidant group. Heart rate increased in patients receiving antioxidants at 60 min (p = .018) and 120 min (p = .004). Cardiac index also increased at 60 min (p = .007) and 120 min (p = .05). Systemic vascular resistance index decreased at 120 min in the antioxidant treated patients (p = .003). The effect of antioxidants on hemodynamic variables has not previously been reported. Antioxidant administration may be a useful adjunct to conventional approaches in the management of septic shock.

Acetylcysteine↗
PubMed1997

Combination oral antioxidant supplementation reduces blood pressure.

1. Hypertension affects 30% of adults and low intakes of antioxidants have been associated with increased risk of hypertension and cardiovascular disease. To investigate the effect of short-term high-dose antioxidant supplementation on blood pressure in hypertensive and normotensive outpatients, we undertook a randomized, double-blind, crossover design placebo-controlled study. 2. Forty subjects were recruited from medical outpatient clinics, of whom 38 completed the study. Twenty-one were attending for treatment of hypertension and 17 were normotensive, attending for minor gastrointestinal complaints. Subjects were randomly assigned to receive either 8 weeks placebo followed by 2 weeks washout then 8 weeks antioxidants or vice versa. The combination of antioxidants consisted of 200 mg of zinc sulphate, 500 mg of ascorbic acid, 600 mg of alpha-tocopherol (sodium succinate salt) and 30 mg of beta-carotene daily. 3. Systolic blood pressure fell at the end of the antioxidant phase compared with the placebo phase both in subjects receiving anti-hypertensive therapy (P < 0.01) and those who were normotensive (P = 0.067). Circulating levels of beta-carotene and alpha-tocopherol increased in all subjects during supplementation (P < 0.01) and urine nitrite increased in hypertensive patients (P < 0.05). 4. Short-term oral high-dose combination antioxidant therapy reduces blood pressure, possibly via increased availability of nitric oxide. This study may have implications for the innovative use of antioxidants as an adjunct to anti-hypertensive therapy.

Administration, Oral↗
PubMed1997

Flow cytometry.

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Anesthetics, Intravenous↗
PubMed1997

Use of inhaled nitric oxide in British intensive therapy units.

The use of inhaled nitric oxide in the critically ill has increased significantly over the past few years but little published information exists on standards for current practice. Sixty-four intensive therapy units in the UK were surveyed by questionnaire from which 54 (84.4%) satisfactory replies were received. We present the survey results and put forward recommendations based on current literature and our own clinical experience for the safe use of inhaled nitric oxide.

Administration, Inhalation↗
PubMed1997

Effect of exogenous nitric oxide and superoxide on interleukin-8 from human polymorphonuclear leucocytes.

Patients with acute inflammatory lung injury are commonly treated with inhaled nitric oxide. Nitric oxide has profound immunoregulatory effects. Increased concentrations of the cytokine interleukin-8 (IL-8) in bronchoalveolar lavage fluid has been associated with disease severity. We have investigated the effects of a nitric oxide donor and a combined nitric oxide-superoxide donor on lipopolysaccharide-mediated accumulation of IL-8 from cultured human neutrophils. Interleukin-8 was measured in culture supernatant after 20 h using enzyme immunoassay. The combined nitric oxide-superoxide donor, 3-morpholinosydnonimine (SIN-1), dose-dependently decreased lipopolysaccharide-mediated IL-8 accumulation (P < 0.01). SIN-1 also decreased IL-8 accumulation from unstimulated neutrophils (P < 0.001). In contrast, the pure nitric oxide donor, 1,2,3,4-oxatriazolium 5-amino chloride (GEA-3162), increased stimulated IL-8 accumulation (P < 0.01) and also increased IL-8 accumulation in unstimulated cells (P < 0.002). Nitric oxide and superoxide have profound effects on IL-8. These results have important implications for the treatment of patients with acute lung injury with inhaled nitric oxide.

Cell Culture Techniques↗