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Biomedical subjects

J M Gutteridge

Publications and source records attributed to J M Gutteridge.

At least 37 records · Page 2Linked to original sources
PubMed1999

Plasma hypoxanthine levels during crystalloid and blood cardioplegias: warm blood cardioplegia increases hypoxanthine levels with a greater risk of oxidative stress.

BACKGROUND: PATIENTS undergoing cardiopulmonary bypass (CPB) are subjected to severe oxidative stress, and frequently show evidence of acute lung injury post surgery. Associations between acute lung injury, oxidative stress, and aberrant ATP catabolism have been made and prompted us to consider whether the purine metabolites xanthine and hypoxanthine alter significantly during CPB when different types of cardioplegia are used. METHODS EXPERIMENTAL DESIGN: retrospective follow up study on stored plasma samples from patients randomly selected to receive either warm blood, cold blood, or crystalloid cardioplegia. SETTING: adult intensive care unit of post graduate teaching hospital. PATIENTS: thirty-eight patients undergoing aortic valve replacement, with or without artery grafting. Operation was carried out by a single surgeon. INTERVENTIONS: all patients received either a homograft aortic valve or a stentless porcine valve. RESULTS: No significant differences in xanthine levels at any time points during CPB, or between the different cardioplegic groups. Hypoxanthine levels were, however, significantly higher in patients receiving warm blood cardioplegia (74.84+/-16.715 microM, p=0.0151), and was most marked at time point 3 when the aortic cross clamp was released. PATIENTS receiving crystalloid cardioplegia showed higher levels of hypoxanthine (44.56+/-10.16 microM) than those receiving cold blood cardioplegia (21.57+/-7.106 microM). CONCLUSIONS: Considering these data together, it suggests that aberrant ATP catabolism, characteristic of ischaemia/reperfusion, is further disturbed during warm blood cardioplegia leading to a marked increase in plasma hypoxanthine levels. This has the potential to further increase oxidative stress during CPB.

Aged↗
PubMed1998

Reactive iron species in biological fluids activate the iron-sulphur cluster of aconitase.

Low molecular mass iron (LMrFe) can appear in plasma when the transferrin becomes fully iron loaded. Such iron poses a risk factor for oxidative damage, and for microbial virulence. A previous novel approach to the detection and measurement of LMrFe in plasma was the use of the iron-binding properties of the glycopeptide antitumour antibiotic bleomycin and its ability to degrade DNA in the presence of oxygen, bound iron, and an iron reducing agent. Since bleomycin is a non-physiological ligand with iron-binding and redox cycling properties, it has been suggested that it may not be a valid biological model for detecting and measuring LMrFe. To address these concerns we have developed a biological approach to the detection and measurement of LMrFe based on the activation of iron-requiring aconitase. Parallel measurements, in a variety of clinical conditions in which there was a complete saturation of the plasma transferrin, showed that the bleomycin assay and the aconitase assay can give similar results for LMrFe.

Aconitate Hydratase↗
PubMed1998

Hypothesis: are fatty acid patterns characteristic of essential fatty acid deficiency indicative of oxidative stress?

Several unrelated diseases show plasma and tissue fatty acid patterns characteristic of those seen in Essential Fatty Acid Deficiency Disease (EFADD). A common feature occurring in all these diseases is oxidative stress. We hypothesize that reactive oxygen species or products of oxidative damage, particularly those derived from lipids, act as signal molecules to alter desaturase enzymes and induce the fatty acid patterns characteristic of EFADD.

Animals↗
PubMed1998

A marked increase in free copper levels in the plasma and liver of LEC rats: an animal model for Wilson disease and liver cancer.

Most of copper present in rat plasma and liver binds to caeruloplasmin and metallothionein, respectively, and is not redox active. However, free forms of copper including loosely bound forms to other molecules are redox active. We assessed the free copper in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease and liver cancer. Compared to those of control rats, the liver and plasma of LEC rats showed a marked elevation of free copper, especially at the stage of acute hepatitis, in parallel with an increase of total copper levels in the livers and a decrease of plasma caeruloplasmin (ferroxidase I) activity. At the onset of jaundice, the total copper levels, however, decreased in liver, but increased in plasma, while free copper levels in both liver and plasma remained higher. Free iron levels in both liver and plasma were also determined and did not change significantly, except for the case of plasma in jaundiced rats. The data are consistent with a proposal in which increased levels of redox active free copper in the liver of LEC rats catalyze Fenton-type reactions, producing a large flux of hydroxyl radicals that would play an important role in the observed liver dysfunction, leading to acute hepatitis, and finally, hepatocarcinoma. This is the first demonstration that the free copper may participate in the pathophysiology of the LEC rats and Wilson disease.

Animals↗
PubMed1998

Iron binding and autoreduction by citrate: are these involved in signalling by iron regulatory protein-1?

Ferric ions bind to citrate and undergo an autoreduction to form a ferrous-citrate complex, greatly increasing the redox activity of the iron complex. Ferrous ions and citrate are also essential for the enzymic activity of aconitase. Aconitase, with its iron-sulphur cluster has a versatile structure which allows it to act as an iron regulatory protein (IRP-1). The purpose of this study was to see whether iron binding, and its autoreduction by citrate, could play a physiological signalling role in iron regulation. Significant amounts of ferrous ions were associated with citrate, when measured using ferrozine, however, these did not appear to activate iron-requiring aconitase.

Aconitate Hydratase↗
PubMed1998

Phagomimetic action of antimicrobial agents.

A wide variety of extracted and synthesised drug molecules have electron transfer capabilities which allow them to generate reactive oxygen species (ROS). In particular, many antibiotics that kill or inhibit bacteria, yeasts and cancer cells readily transfer electrons to oxygen making superoxide and hydrogen peroxide in the process. When suitable redox active forms of iron are available, Fenton chemistry occurs generating the highly damaging hydroxyl radical. This type of chemistry is very similar to that which evolved within phagocytic cells as part of their microbial killing armoury. Many antibiotics, when used in model systems, have well defined pharmacological actions against key cellular functions, but their clinical usefulness is also often demonstrable at concentrations in vivo well below their in vitro minimum inhibitory concentrations. These observations have led us to propose that a common mechanism exists whereby phagocytic cells and antibiotics exploit the use of ROS for microbial killing.

Anti-Bacterial Agents↗
PubMed1998

Reactive oxygen species in acute lung injury.

The acute respiratory distress syndrome (ARDS) in adults is associated with a wide variety of precipitating factors, often not directly involving the lung, and has an associated mortality of 50-80%. ARDS is almost invariably associated with sepsis, either as an initiating factor or as a secondary complication, which increases the expression of a number of cytokines impacting upon several cellular systems. Specifically, activation of neutrophils sequestered in the pulmonary circulation by this process, causes the release of free radicals and reactive oxygen species (ROS), increasingly regarded as key substances modulating the endothelial dysfunction and disruption responsible for the principal clinical manifestations of the syndrome. Here we discuss briefly the pathophysiology of ARDS and its impact upon pulmonary vascular control; the biological origins of free radicals and other ROS involved, the mechanisms of their damaging effects, their contribution to the modification of pulmonary vascular control mechanisms in lung injury and possible therapeutic perspectives.

Adult↗
PubMed1998

Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion.

1. Albumin is often administered intravenously to critically ill patients as a volume expander, to combat hypoalbuminaemia, and to decrease hyperbilirubinaemia. There is, however, an ongoing debate concerning the therapeutic benefit of the former which is an expensive form of treatment.2. Albumin has several biological functions, in particular as a ligand binder. It also acts as an extracellular transition metal ion-binding and radical-scavenging antioxidant. These functions are influenced by the presence of an exposed thiol group (cys 34) on the surface of the albumin molecule. 3. The ability of infused albumin to influence the plasma thiol pool, and hence antioxidant potential, was investigated in patients with sepsis syndrome.4. Plasma thiol levels rose rapidly after albumin infusion and remained elevated even after plasma albumin levels had declined significantly, due to interstitial leakage. Data are suggestive of some form of thiol exchange in the plasma of these patients between albumin and molecules containing oxidized thiol groups.5. Administration of albumin to patients with sepsis syndrome leads to a sustained increase in plasma thiols. Thiols have several important antioxidant functions, and thiol repletion in these patients, who are known to suffer from oxidative stress, may have beneficial antioxidant effects. Antioxidant repletion may represent an important facet of clinically administered albumin.

Adult↗
PubMed1997

Is bleomycin-detectable iron present in the plasma of patients with septic shock?

OBJECTIVE: To assess plasma iron status in critically ill patients with septic shock. DESIGN: Observational, prospective study. SETTING: Adult intensive care units in teaching and tertiary referral hospitals. PATIENTS AND PARTICIPANTS: Fifteen adult patients with established septic shock. Normal control subjects (n = 10) were also investigated. Data from patients and controls were compared with previously published iron values in critical care patients. MEASUREMENTS AND RESULTS: The indices investigated and correlated with clinical scores of illness severity included bleomycin-detectable iron, non-haem iron; transferrin and its percentage iron saturation, and the iron binding (anti-oxidant) activity of transferrin. Bleomycin-detectable iron was not present in the plasma of patients with septic shock whilst the plasma transferrin remained unsaturated with iron. One patient in multi-organ failure displayed bleomycin-detectable iron in plasma (1.16 mumol/l) and had 100% iron-saturation of transferrin. The plasma non-haem iron levels (7.84 +/- 1.82 mumol/l) were the lowest of all critical care patient groups studied by us. The plasma transferrin levels were also low but resulted in a near normal percentage saturation of transferrin with iron (34.6 +/- 6.5%). The scores of clinical severity correlated with changes in plasma iron chemistry. CONCLUSIONS: Patients with septic shock rarely have iron saturated transferrin in their plasma leading to the presence of bleomycin-detectable iron.

APACHE↗
PubMed1997

Pulmonary vascular permeability after cardiopulmonary bypass and its relationship to oxidative stress.

OBJECTIVE: To assess the relationship between oxidative stress resulting from cardiopulmonary bypass and the onset of increased pulmonary vascular permeability. DESIGN: Prospective, controlled study. SETTING: Adult intensive care unit of a postgraduate teaching hospital. PATIENTS: Ten patients undergoing surgery requiring cardiopulmonary bypass, and seven normal subjects. INTERVENTIONS: Cardiopulmonary bypass in ten patients undergoing surgery. MEASUREMENTS AND MAIN RESULTS: Protein accumulation index was measured in patients after surgery and in normal subjects as a marker of increased pulmonary vascular permeability. Plasma markers of lipid peroxidation (lipid peroxides and thiobarbituric acid-reactivity), plasma chelatable iron, total non-heme iron, transferrin, and primary plasma proteinaceous antioxidant activities were measured before and after cardiopulmonary bypass, and compared with those values found in normal subjects. Protein accumulation index was significantly higher (1.79 +/- 0.54 [SEM]) in the postcardiopulmonary bypass patients compared with healthy subjects (0.33 +/- 0.07, p < .05). Concentrations of lipid peroxides precardiopulmonary bypass were similar to those concentrations in control patients (0.020 +/- 0.003 vs. 0.031 +/- 0.002 nmol/mg protein), but were significantly increased postcardiopulmonary bypass (0.114 +/- 0.010 nmol/mg protein, p < .01). Thiobarbituric acid-reactive substances were higher precardiopulmonary bypass than those in controls (0.052 +/- 0.01 vs. 0.019 +/- 0.01), and increased postcardiopulmonary bypass (0.072 +/- 0.012), although they did not reach significance. Bleomycin-chelatable iron, indicative of transient plasma iron-overload, was only found in one patient (6.5 mumol/L) postcardiopulmonary bypass. Total plasma non-heme iron concentrations before cardiopulmonary bypass were similar to those concentrations in normal control patients (0.19 +/- 0.03 vs. 0.22 +/- 0.015 nmol/mg of protein), and significantly increased postcardiopulmonary bypass (0.48 +/- 0.08, p < .01). Transferrin concentrations were lower in cardiopulmonary bypass patients (2.43 +/- 0.17 vs. 2.89 +/- 0.03 g/L) than in controls and significantly decreased postcardiopulmonary bypass (1.55 +/- 0.09 g/L, p < .01). High plasma iron concentrations with a lower level of transferrin, postcardiopulmonary bypass, gave significantly increased mean percentage iron-saturation of transferrin, increasing from 27.1% to 61.7% (p < .01). Proteinaceous primary antioxidant activities, measuring iron-binding and iron-oxidizing protection of peroxidizing lipid membranes, were both significantly decreased postcardiopulmonary bypass (83.7 +/- 3.71% pre and 26.6 +/- 8.42% post, p < .01, and 51.2 +/- 2.96% pre and 29.0 +/- 2.94% post, p < .01, respectively). In 90% of the cardiopulmonary bypass patients, there was a significant correlation between the percent increase in iron saturation of transferrin and the protein accumulation index. CONCLUSIONS: Pulmonary vascular permeability was significantly increased in patients postcardiopulmonary bypass compared with normal subjects. This patient population also had significantly increased plasma markers of lipid peroxidation compared with normal subjects. Cardiopulmonary bypass induced further increases in lipid peroxidation products but a substantial decrease in proteinaceous primary antioxidants. In the majority of patients, there was a significant correlation between the iron saturation of transferrin and the protein accumulation index.

Adult↗
PubMed1997

Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality.

Acute respiratory distress syndrome in adults (ARDS) carries a high mortality. Patients with ARDS experience severe oxidative stress from neutrophil activation, and from treatment with high inspired oxygen concentrations (F(I)O2). Oxidative stress arises from an increased generation of reactive oxygen species (ROS) which overwhelm existing antioxidant defenses. Patients who do not survive ARDS sustain much greater levels of oxidative molecular damage, suggesting that they are less able to protect themselves against increased oxidative stress. We measured plasma levels of pro-oxidant substrates for xanthine oxidase, namely hypoxanthine and xanthine, and correlated them with the loss of plasma protein thiol groups. All patients with ARDS had higher levels of hypoxanthine (37.48 +/- 3.1 microM in nonsurvivors, 15.24 +/- 2.09 microM in survivors) compared with patients undergoing pulmonary resection (9.22 +/- 1.89 microM), patients in intensive care with sepsis but no lung injury (1.12 +/- 0.69 microM) and normal healthy control subjects (1.43 +/- 0.38 microM). The difference in plasma hypoxanthine levels between survivors and nonsurvivors of ARDS was highly significant (p < 0.001) and showed a negative correlation with loss of protein thiol groups. Xanthine levels were also higher in patients with ARDS but were not significantly different between ARDS survivors and nonsurvivors. Nonsurvivors of ARDS appear to experience higher levels of oxidative stress and damage than do survivors.

APACHE↗
PubMed1996

"Free" iron in neonatal plasma activates aconitase: evidence for biologically reactive iron.

Plasma from certain preterm and term babies has recently been shown to contain low molecular mass iron (LMrFe) that can be chelated and measured in the bleomycin assay. The chemical nature of such iron, when detected in biological fluids, is still unclear with suggestions that it may not be a redox active form of iron until it becomes bound to bleomycin. Here we show that all plasma samples, from umbilical cord bloods, containing bleomycin-detectable iron, activated the enzyme aconitase in a cell-free system. It is, therefore, highly likely that LMrFe detected in the bleomycin assay is a biologically redox active form of iron.

Aconitate Hydratase↗
PubMed1996

Pro-oxidant iron is present in human pulmonary epithelial lining fluid: implications for oxidative stress in the lung.

Bronchoalveolar lavage (BAL) provides a sample of lung surface lining fluid. Several pulmonary diseases appear to involve tissue damage caused by reactive oxygen species generated by inhaled oxidants or by phagocytic cells activated within the lung. We show that BAL from normal healthy controls contain chelatable redox active iron that is pro-oxidant towards free radical reactions. Adult patients with the acute respiratory distress syndrome (ARDS) are known to he under severe oxidative stress and to have high mortality rates. Patients who survived ARDS were found to have chelatable redox active iron in their lung fluid, whereas nonsurvivors had no such iron present. Severe lung leak in nonsurvivors was paradoxically associated with increased levels of transferrin and iron-binding antioxidant activity. We suggest that the presence of pro-oxidant iron in normal lung fluid is an important factor which makes the lung vulnerable to oxidative stress.

Adolescent↗
PubMed1996

Ischaemia--reperfusion injury in the rat is modulated by superoxide generation and leads to an augmentation of the hypoxic pulmonary vascular response.

1. The effects of the scavengers of reactive oxygen species superoxide dismutase and catalase, the iron chelator desferrioxamine and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester and saline (control vehicle) on hypoxic pulmonary vasoconstriction, a measure of albumin flux and an index of lipid peroxidation (palmitic:linoleic acid ratio) were investigated after ischaemia-reperfusion in an isolated, blood-perfused rat lung model. 2. Lungs treated immediately before reperfusion with catalase (5,000 units), desferrioxamine (2 mg/kg), NG-nitro-L-arginine methyl ester (5 mmol/l) or saline showed a significant augmentation in pre-ischaemia-reperfusion hypoxic pulmonary vasoconstriction (57.7 +/- 6.0%, 82.7 +/- 28.8%, 95.2 +/- 36.6% and 45.95 +/- 10.53% respectively), an increase in albumin flux (0.35 +/- 0.04, 0.31 +/- 0.06, 0.29 +/- 0.04 and 0.33 +/- 0.02) and an increase in pre-ischaemia-reperfusion palmitic:linoleic acid ratio (0.64 +/- 0.08, 0.51 +/- 0.19, 0.5 +/- 0.04 and 0.17 +/- 0.07). Superoxide dismutase (2,750 i.u.) administered immediately before reperfusion prevented completely the changes in hypoxic pulmonary vasoconstriction (-0.3 +/- 5.4%), albumin flux (0.09 +/- 0.11) and palmitic:linoleic acid ratio (-0.06 +/- 0.12). In control lungs (2h of continuous perfusion), superoxide dismutase, catalase, desferrioxamine and saline did not affect hypoxic pulmonary vasoconstriction (5.5 +/- 4.9%, 1.0 +/- 3.1%, -5.1 +/- 1.8% and 3.0 +/- 6.6%). However, NG-nitro-L-arginine methyl ester significantly augmented hypoxic pulmonary vasoconstriction (275.1 +/- 39.3%). There was no effect of superoxide dismutase, catalase, desferrioxamine, NG-nitro-L-arginine methyl ester or saline in control lungs on albumin flux (0.10 +/- 0.04, 0.11 +/- 0.01, 0.1 +/- 0.01, 0.12 +/- 0.01 and 0.11 +/- 0.01 respectively) or palmitic:linoleic acid ratio (-0.08 +/- 0.08, 0.73 +/- 0.76, -0.03 +/- 0.12, 0.01 +/- 0.17 and 0.00 +/- 0.0 respectively). 3. We conclude that superoxide dismutase attenuates ischaemia-reperfusion-induced increases in albumin flux and hypoxic pulmonary vasoconstriction, and prevents consumption of linoleic acid in the isolated, blood-perfused rat lung.

Animals↗
PubMed1996

Iron, ascorbate and copper status of Sowetan Blacks with calcific chronic pancreatitis.

Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low-molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.

Adult↗
PubMed1996

Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome.

OBJECTIVE: There is a strong evidence that adult patients with acute respiratory distress syndrome (ARDS) are under severe oxidative stress, which leads to molecular damage. Using gas chromatography-mass spectrometry, our objective was to sequentially monitor changes, in intensive care unit (ICU) patients, characteristic of the oxidative loss of plasma unsaturated fatty acids and formation of the highly specific oxidation product of linoleic acid, 4-hydroxy-2-nonenal. DESIGN: Prospective, nonintervention, descriptive study. Limited statistics were applied to facilitate interpretation of the data. SETTING: ICU of a postgraduate teaching hospital. PATIENTS: Eighteen critically ill patients with an established diagnosis of ARDS requiring high FIO2 administered by mechanical ventilation were compared with ten normal, healthy controls and ten patients pre- and postcardiopulmonary bypass surgery at risk for developing ARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty percent of the patients with ARDS included in this study survived. Major changes in the plasma concentrations of fatty acids occurred in all patients during their stay in the ICU. Percentage decreases in plasma linoleic acid concentrations were accompanied by increases in plasma oleic and palmitoleic acid concentrations. Circulating linoleic acid concentrations were significantly (p = .0001) lower in patients with ARDS than in the two control groups. The patients with ARDS who did not survive had lower (p = .0056) plasma oleic acid values than normal healthy controls and patients at risk for ARDs as a consequence of undergoing cardiopulmonary bypass surgery. Changes in palmitoleic acid, however, did not reach significance within the different groups studied. Patients with ARDS showed higher plasma concentrations of 4-hydroxy-2-nonenal (0.433 +/- 0.048 vs. 0.523 +/- 0.069 nmol/mL plasma for survivors and nonsurvivors, respectively) when compared with normal healthy controls (0.205 +/- 0.03 nmol/mL, p = 0.0001) and cardiopulmonary bypass patients at risk for developing ARDS (0.279 +/- 0.027 nmol/mL, p = .034 prebypass). CONCLUSIONS: During intensive care treatment, patients with ARDS decrease their percentage plasma concentrations of total plasma linoleic acid, but increase their percentage concentrations of oleic and palmitoleic acids. As plasma linoleic acid concentrations decreased, there was usually an increase in plasma 4-hydroxy-2-nonenal values, one of its specific peroxidation products, suggestive of severe oxidative stress leading to molecular damage to lipids.

Adolescent↗
PubMed1996

Commentary: mannitol: molecule magnifique or a case of radical misinterpretation?

Reactive oxygen species are constantly formed in biological systems. When production exceeds antioxidant protection, oxidative stress leading to molecular damage occurs. The most reactive ROS in biological systems is the hydroxyl radical which damages adjacent molecules at diffusion controlled rates. The possibility of preventing such chemistry inside cells with therapeutic doses of mannitol at present seem remote.

Animals↗