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Biomedical subjects

F J Kelly

Publications and source records attributed to F J Kelly.

At least 91 records · Page 5Linked to original sources
PubMed1994

Depletion of pulmonary glutathione using diethylmaleic acid accelerates the development of oxygen-induced lung injury in term and preterm guinea-pig neonates.

Dietary or chemical depletion of pulmonary glutathione in adult rats and mice, has been demonstrated to exacerbate the toxic effects of high oxygen concentrations. The present paper has examined this phenomenon in a guinea-pig model of prematurity, using the electrophilic agent diethylmaleic acid (DEM) to provide a transient (up to 12 h) pulmonary glutathione depletion. Full-term and 3-days preterm guinea-pig pups were studied to assess the possible role for glutathione deficiency as a mechanism mediating the increased susceptibility of the immature lung to oxygen free-radical damage. The administration of DEM to guinea-pig neonates depleted lung glutathione by 90% (term) or 68% (preterm) over 2 h. On exposure of pups to 95% oxygen for 48 h, DEM increased the incidence of oxygen-related death to 31% in term pups and 100% in preterm pups. Term pups exposed to hyperoxia and treated with DEM showed evidence of pulmonary injury, indicated by an influx of neutrophils into the lung airspaces, and elevated microvascular permeability. Control pups exposed to 95% oxygen were found to have uninjured lungs after 48 h. We conclude that glutathione is an essential component of the pulmonary antioxidant array in neonates. Glutathione may be of particular importance in the early phase of oxygen exposure. The deficiency of lung glutathione observed in preterm animals may account for their increased susceptibility to oxygen-induced pulmonary injury.

Animals↗
PubMed1994

Vitamin E supplementation in the critically ill patient: too narrow a view?

Oxidative stress plays an important contributory role in a number of diseases. In critically ill patients, oxidative stress is a major problem that results from a number of compounding factors such as supportive oxygen therapy, pulmonary inflammation, and the nutritional inadequacies of these patients. It has been known for some time that the circulating concentration of vitamin E, the primary lipid-soluble antioxidant, is low in critically ill patients. However, supplementation with vitamin E by oral loading has not been successful in improving clinical status. A better understanding of the bioavailability of vitamin E in these patients and of the synergistic action of other antioxidant nutrients such as vitamin C and glutathione with vitamin E has provided new opportunities to reexamine the use of antioxidant supplementation for the critically ill.

Ascorbic Acid↗
PubMed1994

Pulmonary protein synthesis response to ozone.

1. Exposure to either 800 or 1200 ppb ozone for 6 h did not influence the content or activity of mouse lung ribosomal RNA; in consequence pulmonary protein synthesis pathways were not altered. 2. Increasing the exposure period to 24 h had a marked effect on protein metabolism which depended on the dose of ozone employed. A dose of 800 ppb resulted in a 17% increase in lung protein content. Since both lung ribosomal capacity and fractional synthesis rates were unchanged at this time, it is concluded that both a lower ribosomal activity and an increased protein degradation rate were responsible for the decrease in content. 3. Exposure to 1200 ppb ozone for 24 h, paradoxically resulted in increases in both the fractional (33%) and total (19%) protein synthetic rates. These responses were due to an increased pulmonary ribosomal efficiency in the lung at this time. 4. We conclude that, in the short term, reduced pulmonary synthetic capacity is not a component of ozone-induced lung injury, but rather, this important component of the repair mechanism, can be up-regulated in response to lung injury.

Animals↗
PubMed1994

Evidence for increased oxidative damage in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) may be more susceptible to oxidative cell injury than normal healthy children due to both the impaired absorption of antioxidant nutrients and the increased oxidative stress caused by chronic pulmonary infections. The purpose of this study was to examine whether markers of oxidative damage to lipids (malondialdehyde-like substances and lipid hydroperoxides) and proteins (protein carbonyls) were present in the plasma of CF patients. Mean values (+/- SD) of thiobarbituric acid-reactive substances were significantly higher in patients (6.93 +/- 1.47 mumol/L; n = 25) than in controls (5.84 +/- 0.59 mumol/L; n = 10). FFA hydroperoxides were not detected in control subjects (the detection limit of the assay was 0.02 mumol/L), but in 11 of the 33 CF patients studied they were found in a range of 0.03-0.34 mumol/L. Plasma protein carbonyl concentrations did not differ significantly between the two groups (p = 0.076), although a much wider distribution was observed in the CF patients (range 0.17-5.64 nmol/mg protein) than in the control group (range 0.24-1.55 nmol/mg protein). No correlation was found between thiobarbituric acid-reactive substances and FFA hydroperoxides or between either of these markers and protein carbonyl content. Concentrations of plasma vitamin E, vitamin C, and protein sulfhydryls were within the normal ranges in both control subjects and CF patients. The concentration of uric acid was significantly reduced (p < 0.01) in the CF group (204 +/- 96.99 mumol/L) compared with that in control subjects (352 +/- 81.11 mumol/L), but reduction in plasma levels of this antioxidant did not correlate with increased markers of free radical damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Dexamethasone treatment fails to reduce oxygen-induced lung injury in the preterm guinea pig. Effects on pulmonary inflammation and antioxidant status.

Dexamethasone (10 mg/kg/day) or vehicle was administered in a randomized, controlled fashion to 3-day preterm guinea pigs exposed to either 21% oxygen or 95% oxygen for 72 hr and maintained in room air for a further 96 hr. Treatment with dexamethasone had no effect on survival of preterm pups maintained in either 21% or 95% O2. Dexamethasone treatment reduced the growth rate of pups, the effect occurring earlier (0-3 days) in 21% O2-treated pups than in 95% O2-treated pups (5-7 days). Exposure to 95% O2 reduced the survival rate of preterm animals (73% vs 100%, P < 0.05). Surviving pups developed acute lung injury, characterized by the accumulation of a protein-rich exudate in the alveoli and an infiltration of inflammatory cells, particularly neutrophils into the lung. Dexamethasone treatment attenuated the pulmonary inflammatory cell infiltration, in particular neutrophils, both during oxygen exposure (16.4 x 10(4) vs 9.4 x 10(4)/mL; P < 0.05) and following return to ambient conditions (28.0 x 10(4) vs 5.1 x 10(4)/mL; P < 0.05). Elastase activity in bronchoalveolar lavage fluid, which was primarily of neutrophil origin, was unchanged by dexamethasone treatment. Dexamethasone-treated pups had increased pulmonary antioxidant enzyme activities (Cu/Zn-superoxide dismutase; Mn-superoxide dismutase, catalase and glutathione peroxidase) during recovery from oxidative injury. Although there was both a marked reduction in numbers of neutrophils in the lung and elevated pulmonary antioxidant enzyme activities in dexamethasone-treated pups, the degree of microvascular permeability, as determined by both the lung wet weight/dry weight ratio and the presence of plasma proteins in the lavage fluid, was unchanged. Combined, these results imply that dexamethasone, although capable of blunting the influx of neutrophils to the hyperoxia-exposed lung and inducing antioxidant defences in the immature lung, cannot modify the progression of acute oxygen-induced injury of the immature lung.

Amino Acid Sequence↗
PubMed1993

Synthesis of phosphatidylcholine in guinea-pig fetal lung involves acyl remodelling and differential turnover of individual molecular species.

The mechanisms for accumulation of disaturated phosphatidylcholine (PC) molecular species in developing fetal guinea-pig lung during the period of surfactant synthesis, between day (d) 55 and term (d68), were determined by the incorporation of 50 mu Ci [methyl-14C]choline into lung PC in utero over 3 h. Comparison of the pattern of PC synthesis de novo with the composition of the total PC pool indicated that approx. 50% of the total PC16:0/16:0 was synthesized by acyl remodelling of PC16:0/18:2 by the actions of phospholipase A2 and acyltransferases. Acyl remodelling was established before the onset of surfactant synthesis (d55) and so was not specific for this process. Between d55 and term the concentration of lung PC increased significantly. Conversely, the incorporation of [14C]choline into lung tissue and the rate of PC synthesis decreased over this period. Calculation of turnover times of lung PC species suggested that the increase in lung disaturated PC concentration during surfactant production might be due to a differential decrease in catabolism rather than increased PC synthesis.

Animals↗
PubMed1993

N-acetylcysteine ameliorates hyperoxic lung injury in the preterm guinea pig.

The therapeutic efficacy of N-acetylcysteine (NAC) in the management of hyperoxia-induced lung injury was assessed using the preterm guinea pig model of prematurity. Preterm guinea pig pups were delivered by Caesarean section 3 days preterm, and exposed to either 21 or 95% oxygen for 72 hr. NAC (200 mg/kg body weight) or saline was injected twice daily. Bronchoalveolar lavage fluid (BALF) from hyperoxia-exposed pups contained significantly higher protein concentrations and an increased number of neutrophils. NAC partly ameliorated lung injury, preventing the increase in BALF protein concentration, which is generally associated with oedema. There was no effect on the movement of neutrophils into the lung airspaces in response to oxygen. Treatment with NAC had no effect on lung or liver glutathione (reduced) (GSH) concentrations either after 2 hr post-administration, or over the full 72 hr experimental period. An apparent resistance of the lung to increased synthesis or uptake of GSH was demonstrated by the lack of effect of direct administration of GSH, its isopropyl ester or 2-oxo-4-thiazolidine carboxylic acid. Oxygen exposure alone (95%) increased lung concentrations by 60-70%. It would, therefore, appear from this data that NAC may have potential as a future component of antioxidant therapy, although its effects are not mediated through increased GSH levels.

Acetylcysteine↗
PubMed1993

Mechanisms of hepatic phosphatidylcholine synthesis in the developing guinea pig: contributions of acyl remodelling and of N-methylation of phosphatidylethanolamine.

Hepatic phosphatidylcholine (PC) from the immature fetal guinea pig at day 55 of gestation comprised mainly unsaturated molecular species containing C18:2(n-6) and C22:6(n-3) at the sn-2 position, reflecting placental permeability to essential fatty acids. At both day 55 and term (day 68), [Me-14C]choline was incorporated in utero over 3 h largely into sn-1-C16:0 PC species, with incorporation into sn-1-C18:0 PC species increasing by 18 h of incubation. Comparison of specific radioactivities after 3 h and 18 h suggests PC acyl remodelling by phospholipase A1. No incorporation into C20:4(n-6)-containing PC species could be detected of either [Me-14C]choline in vivo or CDP-[Me-14C]choline in isolated microsomes. The major phosphatidylethanolamine (PE) species were 16:0/22:6 and 18:0/22:6. Although [14C]ethanolamine was initially incorporated mainly into sn-1-C16:0 species, specific-radioactivity analysis suggested differential turnover rather than acyl remodelling. [1,2-14C]Ethanolamine and [Me-14C]methionine incorporation into PC molecular species indicated that both newly synthesized and total PE pools were available for N-methylation. Since the PC pool synthesized from PE included C20:4- and C22:6-containing species, N-methylation may provide a mechanism for supplying essential long-chain fatty acids to developing tissues that can be regulated independently from bulk PC synthesis.

Animals↗
PubMed1993

Effects of the glucocorticoid agonist, RU28362, and the antagonist RU486 on lung phosphatidylcholine and antioxidant enzyme development in the genetically obese Zucker rat.

The biochemical maturation of the lung in late gestation and in the young animal is regulated by glucocorticoids. The present study was aimed at dissociating the different glucocorticoid receptor sites involved in these regulatory functions. The obese Zucker rat was selected as a model for this study as it exhibits hypersensitivity to glucocorticoid hormone action by virtue of its elevated receptor numbers and activity. Two synthetic steroid analogues were administered to obese animals; RU28362, a specific type II receptor agonist, and the type II antagonist RU486. RU28362 promoted a strong catabolic effect, which was associated with reduced food intake and the abolition of growth in the rats. The agonist, RU28362, attenuated developmental increases in antioxidant enzyme activities, and altered the growth of the tissue. At the age studied, development of the lung phosphatidylcholine (PC) system was almost complete, but RU28362 increased disaturated PC 16:0/16:0 concentrations by almost 2-fold, and altered the molecular composition of total pulmonary PC. RU486 attenuated the growth of the rats and reduced their food intake. Treatment with the type II antagonist attenuated lung growth and increased the activities of pulmonary copper zinc (Cu/Zn) and manganese (Mn) superoxide dismutases. RU486 had no effect on lung PC concentrations and molecular composition. The data suggest a role for type I glucocorticoid receptors in the regulation of the antioxidant enzyme system in the lung, as type II antagonism will channel endogenous glucocorticoid binding to the type I site. Type II receptor binding would appear to play a role in regulating the lung PC content.

Androstanols↗
PubMed1993

Distribution of vitamin E between tissues during periods of hyperoxic and nutritional stress in the preterm guinea pig.

1. Using a preterm guinea pig model we examined the impact of oxidative and nutritional stress on the vitamin E status of a number of immature tissues. 2. Liver, brain, lung, red blood cell and plasma alpha-tocopherol concentrations were measured in fed and fasted, preterm guinea pigs exposed to 21 or 95% oxygen for 48 hr. 3. Exposure to hyperoxia did not influence plasma, red blood cell, lung or brain vitamin E status of preterm pups. Liver alpha-tocopherol content was reduced 20% following 48 hr hyperoxic exposure (P < 0.05). 4. Food restriction (48 hr) alone reduced liver (41%) and red blood cell (32%) alpha-tocopherol concentrations in preterm animals while plasma, lung and brain vitamin E levels were unaffected. Combined with hyperoxic exposure, food restriction resulted in a (50%) fall in liver alpha-tocopherol concentration (P < 0.01). 5. The findings of this study suggest that the liver acts as a reservoir for vitamin E in the perinatal period, releasing increased quantities of this lipid soluble antioxidant for use by non-hepatic tissues during periods of hyperoxic and nutrient stress.

Analysis of Variance↗
PubMed1993

Ozone exposure inhibits cardiac protein synthesis in the mouse.

Ozone is a major environmental oxidant pollutant. Following ozone inhalation, there are a number of marked pulmonary responses depending on the extent and duration of exposure. Recently it has been established that ozone exposure may also result in cardiac injury. In this study we show that exposure of mice to 800 ppb ozone for as little as 6 h results in a 16% decrease in cardiac protein synthesis rates (p < .02). The fall in protein synthesis is due primarily to a reduced rate of ribosomal efficiency (40%) in the hearts of ozone-exposed mice. This change in cardiac protein metabolism is accompanied by increased levels of two markers of tissue injury: edema and protein carbonyl content. It is unlikely, however, that these observations represent a direct action of ozone on the heart, but rather an indirect effect, possibly mediated by lipid peroxidation products generated in the lung.

Animals↗
PubMed1993

Glutathione content of the small intestine: regulation and function.

In ad lib.-fed rats the epithelium of the small intestine, like the liver, contains large quantities of glutathione, 17.0 and 32.4 nmol/mg protein respectively. Following 24 h food restriction the glutathione content in both tissues fell 53 and 69% respectively. Unlike the liver, however, the glutathione content of the intestinal mucosa is not regulated to a diurnal rhythm, suggesting that the liver may provide glutathione or glutathione precursors to maintain intestinal glutathione levels. Intestinal epithelial cell preparations obtained from 24 h food-deprived rats had depleted glutathione stores (50%) and as a consequence were more susceptible to the oxidizing effects of cumene hydroperoxide. These results suggest that if glutathione plays a major role in the defence of the intestinal mucosa from ingested toxins then depletion of this defence during periods of food restriction could significantly increase the susceptibility of the individual to toxins present in the diet.

Animals↗
PubMed1993

Free radical disorders of preterm infants.

In recent years increasing experimental and clinical data have provided compelling evidence for the involvement of oxygen free radicals in the 3 main disorders of prematurity--chronic lung disease, retinopathy of prematurity and intraventricular haemorrhage. Infants born prior to 30 weeks gestation or weighing less than 1500 g at birth appear to be most at risk. They are very underdeveloped and as a consequence of the immaturity of their lungs often require intense respiratory support, including the provision of supplemental oxygen. The theoretical basis for free radical involvement in these disorders is that oxygen centred radicals and related reactive oxygen metabolites are formed too rapidly to be detoxified by the antioxidant defence mechanisms in specific tissues. In the case of chronic lung disease, the evidence currently favours excess oxygen (hyperoxia) as the cause of the greater oxygen free radical production, whereas in retinopathy of prematurity and intraventricular haemorrhage, it is proposed that low oxygen tensions (hypoxia) followed by periods of reoxygenation is the more likely stimulus for excess radical formation.

Bronchopulmonary Dysplasia↗
PubMed1993

Reduced free-radical-trapping capacity and altered plasma antioxidant status in cystic fibrosis.

Plasma antioxidant status and total radical-trapping antioxidant potential (TRAP) of children (n = 24) with cystic fibrosis (CF) were compared with those of children (n = 21) without the disease. Children with CF were found to have elevated plasma concentrations of ascorbic acid (94.6 +/- 58.2 mumol/L), with respect to normal children (65.6 +/- 18.8 mumol/L). Plasma uric acid (330.8 +/- 84 versus 198.0 +/- 31 mumol/L p < 0.01) and sulfhydryl group (518 +/- 43 versus 363 +/- 31 mumol/L p < 0.01) concentrations were also elevated in CF. Vitamin E levels (16.9 +/- 1.8 versus 18.4 +/- 1.3 mumol/L) were at the low end of the normal range. Despite an overall increased antioxidant array, CF patients had a reduced TRAP capacity (488 +/- 34 versus 580 +/- 79 mumol/L, p < 0.05). TRAP measurements in CF patients showed a strong negative correlation (r = 0.80, p < 0.001) with high ascorbic acid concentration, suggesting a prooxidant effect of ascorbic acid. Oral administration of ascorbic acid to adults was found to diminish TRAP activity. Concentrations of ascorbic acid similar to those seen in CF patients were attained in ascorbate-supplemented individuals, with substantial decreases in TRAP capacity. These studies suggest that high plasma ascorbic acid levels in children with CF may have a prooxidant effect. This appears to reduce the extracellular antioxidant defense of these children and may increase susceptibility to oxidative stress.

Adolescent↗
PubMed1993

Temporal association between pulmonary inflammation and antioxidant induction following hyperoxic exposure of the preterm guinea pig.

The time course and nature of the pulmonary inflammatory and antioxidant responses, both during and after hyperoxic-induced acute lung injury were studied in the preterm guinea pig. Three-day preterm (65 days gestation) guinea pigs were randomly exposed to either 21% O2 (control) or 95% O2 (hyperoxia) for 72 hours. All pups were then maintained in ambient conditions for up to a further 11 days, during which time lung damage was monitored. In animals exposed to hyperoxia, evidence of acute lung injury and inflammation was characterized by a marked increase in microvascular permeability and elevated numbers of neutrophils in bronchoalveolar lavage fluid. Protein concentration, elastase-like activity and elastase-inhibitory capacity in lavage fluid were at a maximum at the end of the 72 hours hyperoxic exposure. Four days later, all values had returned to control levels. In contrast, increased numbers of neutrophils, macrophages and lymphocytes were recovered in the lavage fluid during this early recovery period. Coinciding with the influx of inflammatory cells, there was a significant increase in glutathione peroxidase, manganese superoxide dismutase and catalase activities in immature lung. Lung copper/zinc superoxide dismutase activity remained unchanged during both experimental periods. The strong temporal relationship between the influx of inflammatory cells to the lung and the induction of pulmonary antioxidant enzyme defences suggests that a common mechanism underlies both responses. These findings have led us to regard inflammation in the hyperoxic-injured immature lung as a beneficial event and not, as previously suggested, as part of the injurious process.

Animals↗
PubMed1992

Differing response of the glutathione system to fasting in neonatal and adult guinea pigs.

Adult, term neonatal and 3 day preterm neonatal guinea pigs were fasted for 48 hr, and the glutathione concentrations of the liver and lung assessed. In adult animals, glutathione concentration decreased by 43% in the liver and 29% in the lung with respect to fed controls. The decrease in liver glutathione was associated with a 75% reduction in the hepatic activity of tau-glutamyltranspeptidase (tau GGT). Conversely, both liver and lung glutathione levels in preterm pups remained unchanged following 48 hr food restriction. Likewise, hepatic tau GGT, glutathione reductase (GRed) and glutathione peroxidase (GPx) activities were unchanged by fasting in preterm pups. Fasting increased pulmonary GPx activity by 27% in these pups. In fasted, term animals, substantial increases in both lung (65%) and liver (80%) glutathione concentrations were observed, with concomitant increases in GPx and GRed activities. Hepatic tau GGT activity was significantly reduced (57%) in term pups. These results may suggest that the neonatal guinea pig can maintain tissue glutathione status during periods of nutrient stress, through an increased capacity for recycling oxidized glutathione and a decrease in turnover of the tripeptide. Guinea pig neonates are therefore able to resist starvation-induced decreases in tissue glutathione levels seen in adult rodents. If this is a general neonatal response it may have important clinical implications in the treatment of preterm babies.

Aging↗
PubMed1992

Catalase, superoxide dismutase and glutathione peroxidase activities of lung and liver during human development.

The developmental expression of catalase, superoxide dismutase (both Mn-SOD and Cu/Zn-SOD) and glutathione peroxide activities were determined in human lung and liver from 10 wk gestation to 3 months following birth. Pulmonary superoxide dismutase and glutathione peroxidase activities did not change appreciably over this period. Catalase activity however, increased from 20.9 +/- 7.8 U/mg protein (n = 29) at 11-20 wk gestation to 73 +/- 27.5 U/mg protein (n = 30; P less than 0.001) following normal delivery (41-60 wk post-conceptual age). Lung catalase activity was temporally associated with the late gestational increase in the fractional content of lung DPPC (r = 0.79, P less than 0.01). In contrast with the lung, liver total superoxide dismutase activity increased from 2.5 +/- 0.6 U/mg protein (n = 27) between 11 and 20 wk gestation to 9.4 +/- 4.4 U/mg protein after term (n = 22; P less than 0.001). Since hepatic Mn-superoxide dismutase activity did not change over this period, the increase was attributed to elevated expression of Cu/Zn-superoxide dismutase. Liver glutathione peroxidase activities remained relatively constant during the same period, while hepatic catalase activity, although constant during gestation (60 +/- 15.6 microU/mg protein), increased significantly following birth (99.7 +/- 33.0 microU/mg protein; P less than 0.001). These results demonstrate that the developmental expression of antioxidant enzymes differs between tissues and that, unlike many commonly used laboratory species, only increased expression of catalase activity is associated with human lung development.

Aging↗