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Biomedical subjects

F J Kelly

Publications and source records attributed to F J Kelly.

At least 109 records · Page 6Linked to original sources
PubMed1992

Characterization of a cell-free protein synthesizing system from rat lung.

1. A cell-free protein synthesizing system has been developed from a novel source, namely the rat lung. 2. The system translates endogenous mRNA at a linear rate for up to 10 min at approx 5% of the in vivo rate. 3. With the use of edeine and 7-methylguanosine-5'-triphosphate (m7GTP), specific blockers of peptide chain initiation, we have demonstrated that 40-60% of total amino acid incorporation is attributable to reinitiation on nascent polypeptide chains. 4. The lung cell-free system will be a valuable asset when investigating the mechanisms involved in the regulation of pulmonary protein synthesis.

Animals↗
PubMed1992

Dietary supplementation of vitamin E fails to prevent the development of hyperoxic lung injury in the premature guinea pig.

1. The benefit of dietary vitamin E supplementation in preventing oxidative-induced lung injury was investigated. Three day preterm guinea pig pups were exposed to hyperoxic (85% O2) or normoxic (21% O2) conditions. The animals were fed either a standard low birthweight human infant formula milk (6.4 mg/l vitamin E), or a vitamin E supplemented milk (100 mg/l) for up to 7 days. 2. After 3 days vitamin E supplementation, plasma but not erythrocyte vitamin E concentrations were elevated, while following 7 days both plasma and erythrocyte vitamin E concentrations were significantly increased. 3. Lung and liver vitamin E concentrations were elevated at both 3 and 7 days. At 3 days the increase in lung vitamin E was oxygen-dependent, suggesting that the lung increases uptake of vitamin E in response to oxidative stress. 4. Despite an increase in the vitamin E concentration of the lungs of preterm guinea pigs, no amelioration of the lung injury was observed. These results suggest that although vitamin E is a potent antioxidant, it is unable to protect adequately the lungs from reactive oxygen species in the absence of sufficient primary enzymatic antioxidant defences.

Animals↗
PubMed1992

Tissue alpha-tocopherol status during late fetal and early neonatal life of the guinea-pig.

The alpha-tocopherol content of a number of different fetal, neonatal and maternal guinea-pig tissues was determined and compared with plasma and erythrocyte alpha-tocopherol values. During late gestation, the fetal liver appears to act as a storage site for alpha-tocopherol, the majority of which is released immediately following birth. In contrast, lung and brain vitamin E levels are relatively constant over the final period of gestation and during early neonatal life. The ontogeny of alpha-tocopherol in brain and lung was similar to that for erythrocytes while plasma alpha-tocopherol content varied considerably and did not accurately reflect tissue alpha-tocopherol status. Surprisingly, fetal and maternal lung alpha-tocopherol concentrations were similar at all time-points considered, whereas fetal liver alpha-tocopherol status was always considerably greater than maternal liver alpha-tocopherol content. These results, if representative of the human fetus, suggest that preterm infants may not have tissue alpha-tocopherol concentrations as low as previously assumed and that during the perinatal period erythrocyte alpha-tocopherol content is a more accurate indicator of tissue alpha-tocopherol concentration than plasma alpha-tocopherol content.

Animals↗
PubMed1992

Phosphatidylcholine composition of endotracheal tube aspirates of neonates and subsequent respiratory disease.

The phosphatidylcholine (PC) content of the initial endotracheal tube aspirate was measured in 105 infants intubated for resuscitation or for ventilation for respiratory distress syndrome, using high performance liquid chromatography and postcolumn fluorescence derivitization with diphenyl-1,3,5-hexatriene. Sixty eight had measurable PC. Of the infants who developed respiratory distress syndrome, with or without subsequent chronic lung disease, neither the percentage of dipalmitoylphosphatidylcholine (DPPC) nor the ratio of DPPC to palmitoyloleoylphosphatidylcholine (POPC), showed any correlation with gestational age. However, both parameters were significantly lower overall in this group than in the group of infants who did not develop respiratory distress syndrome. Infants with a ratio of DPPC:POPC less than 3.0 developed respiratory distress syndrome irrespective of gestational age, but there was considerable overlap between groups for values greater than this. The infants with respiratory distress syndrome who went on to develop chronic lung disease had the same initial PC profile as those with respiratory distress syndrome who did not develop chronic lung disease, but differed as a group by being lighter and more premature. The development of chronic lung disease was not associated with a particular initial PC composition. Other factors related to increasing prematurity must therefore be involved in rendering infants vulnerable to developing chronic lung disease.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Effect of acute food restriction on pulmonary growth and protein turnover in preterm guinea pigs.

The effects of food restriction on the growth and protein turnover of the immature lung were investigated. Preterm guinea pigs, delivered by cesarean section at 65 days gestation (term = 68 days), were given free access to a lactating dam or restricted from feeding for 48 h. Food restriction resulted in significantly reduced body and lung (P less than 0.05) weight compared with fed controls. The rate of pulmonary protein synthesis determined in vivo was reduced by 33% in the food-restricted pups (28.9 +/- 10.2 vs. 19.4 +/- 4.5%, P less than 0.05 for control and food-restricted pups, respectively), whereas the calculated rate of protein breakdown remained unchanged. The inhibition of protein synthesis was accounted for by a 36% decrease in ribosomal efficiency (11.03 +/- 2.61 vs. 7.04 +/- 1.26%, P less than 0.01 for control and food-restricted pups, respectively), whereas ribosomal capacity was unaltered. Polyribosomal analysis indicated an increase in the proportion of RNA present in polysomes and a fall in the free monomer pool (26%), suggesting that food restriction blocked translation by reducing the rate of peptide chain elongation. This finding was confirmed by the analysis of ribosome transit times, which indicated a significant increase in the elongation rate in the lungs from food-restricted pups (0.51 +/- 0.11 vs. 0.94 +/- 0.19 min, P less than 0.05 for control and food-restricted pups, respectively). These results imply that nutrient supply plays an important role in protein deposition and hence growth and repair capacity of the immature lung.

Animals↗
PubMed1992

Effect of food restriction on hyperoxia-induced lung injury in preterm guinea pig.

Undernutrition may exacerbate hyperoxia-induced lung injury, a finding that may be of significance in the early clinical management of the premature human infant. Addressing this specific problem, we found that 72 h of food restriction in guinea pig pups delivered 3 days preterm increased mortality rates among pups exposed to 95% oxygen (8/18) and yet had no effect on 21% oxygen (air)-exposed pups (0/10). Reduced tolerance of hyperoxic conditions was not, however, associated with increased lung injury, assessed as pulmonary microvascular leakage. Pulmonary antioxidant enzyme activities [Cu,Zn superoxide dismutase (SOD), Mn SOD, glutathione peroxidase, and catalase] were unaltered by starvation or hyperoxia. Lung glutathione concentration was slightly decreased after food restriction, whereas hyperoxic exposure did not change either lung or bronchoalveolar lavage fluid glutathione concentrations or lung antioxidant enzyme activities. Increased susceptibility to the lethal effects of oxygen in the starved preterm guinea pig pup could not be attributed to a deficiency of pulmonary antioxidant defenses.

Animals↗
PubMed1992

Magnitude of hyperoxic stress and degree of lung maturity determine the nature of pulmonary antioxidant response in the guinea pig.

The ability of the immature lung to induce antioxidant defences in response to hyperoxic stress was examined. Preterm guinea pigs (65 days gestation, term = 68 d) were exposed to either 21% O2, 85% O2 or 95% O2 for 72 hours. Exposure to 85% O2 increased lung catalase, glutathione peroxidase and manganese superoxide dismutase activities in comparison to air controls. Exposure to 95% O2 resulted only in an increase in glutathione peroxidase activity. Bronchoalveolar lavage fluid GSH concentration was increased by a similar amount by both exposure regimes, while lung copper/zinc superoxide dismutase activity was unchanged by either treatment. Comparison of the antioxidant response of term and preterm animals exposed to 85% O2 for 72 hours indicated a greater response in the lung of the preterm animals. Manganese superoxide dismutase activity was elevated in both term and preterm animals, while catalase and glutathione peroxidase activities were elevated only in preterm animals. The extent of microvascular permeability as indicated by bronchoalveolar lavage fluid protein concentration, was lower in preterm animals than in term animals. We conclude that the immature lung can respond to hyperoxic stress by antioxidant induction and that the nature of the response is dependent, in part, both on the severity of the stress and on the maturity of the lung.

Animals↗
PubMed1991

Effects of dexamethasone on lung protein turnover.

Dexamethasone (2.5 mg/day per kg) treatment of young growing rats resulted in reduced food intake and rapidly inhibited whole-body and lung growth. Although the reduction in food intake partially explained the decrease in whole-body growth, it did not influence lung growth. After 24 h of dexamethasone treatment, ribosomal efficiency in the lung was reduced 44%, producing a 38% decrease in the rate of pulmonary protein synthesis. Extending dexamethasone treatment to 5 days resulted in decreases in both ribosomal efficiency (35%) and capacity (28%), explaining the 53% reduction in lung protein synthesis at this time. After both the acute and chronic steroid regimes, the decreased rates of pulmonary protein synthesis were accompanied by a loss of polyribosomes and an elevated ribosomal monomer pool, indicating that dexamethasone blocked translation at the site of peptide-chain initiation.

Animals↗
PubMed1991

Biochemical maturation of the guinea pig lung and survival following premature delivery.

1. Viable preterm guinea pigs were delivered by Caesarean section from 62 day gestation (term = 68 days). 2. Survival rates (24 hr) were greater than 90%, greater than 55% and greater than 35% respectively at 65, 63 and 62 days gestation. Guinea pig pups experienced increasing respiratory difficulty with progressive prematurity. 3. Lung phosphatidylcholine concentration increased steadily from 0.52 +/- 0.09 mumol/mg DNA at day 50 to 3.9 +/- 0.5 mumol/mg DNA at term. The relative contribution of the disaturated dipalmitoyl species increased over this time from 24.5 to 42.9%. 4. Pulmonary antioxidant capacity increased markedly over the final eight days of gestation, individual increases being manganese superoxide dismutase 68%, copper/zinc superoxide dismutase 48%, glutathione peroxide 37% and catalase 198%.

Animals↗
PubMed1991

The metabolic role of n-3 polyunsaturated fatty acids: relationship to human disease.

1. An increasing body of evidence suggests that certain types of fat have beneficial effects on human health. 2. Fish oils in particular have been shown to exert positive effects on atherosclerosis, heart disease and carcinogenesis. 3. These positive effects are thought to be mediated through eicosanoids derived from polyunsaturated fatty acids of the n-3 family which are present in large quantities in fish oils.

Arteriosclerosis↗
PubMed1991

Developmental variation in whole human lung phosphatidylcholine molecular species: a comparison with guinea pig and rat.

Detailed analysis of the pattern of human and rodent lung phosphatidylcholine (PC) species during fetal development revealed a progressive increase in two disaturated species. The rise in the fractional content of dipalmitoyl PC (PC16:0/16:0) and myristoylpalmitoyl PC (PC14:0/16:0) was accompanied at each time point by a fall of similar magnitude in palmitoyloleoyl PC (PC16:0/18:1). Up to 20% of term lung PC was PC14:0/16:0. The temporal increase in rodent lung PC saturation began later in gestation than the human, and in the rat a significant increase in PC saturation only occurred postnatally. In this respect the guinea pig more closely resembled the human. For each mammal, a ratio of whole lung PC16:0/16:0 to PC16:0/18:1 (the P/O ratio) provided a sensitive marker of fetal lung maturity. The PC composition of whole adult lung and its saturation enrichment in bronchoalveolar lavage samples were similar in human, guinea pig and rat. We propose that the guinea pig provides a useful model for human lung prematurity studies.

Adult↗
PubMed1991

The pre-term guinea-pig: a model for the study of neonatal lung disease.

1. Research into the pathogenesis of acute and chronic neonatal lung disease has been hampered by the lack of a suitable small-animal model of prematurity. We describe such a model that has been developed and validated in the guinea-pig. 2. Pre-term guinea-pigs delivered by Caesarian section at 65 days gestation (normal gestation 68 days) exhibited transient respiratory distress. The survival of pre-term animals was lower than that of term animals after exposure to 95% O2 (pre-term 42% versus term 79% at 96 h, P less than 0.05). 3. Pulmonary histology in pre-term animals exposed to both 21% O2 and 95% O2 revealed evidence of acute lung injury with atelectasis, pulmonary oedema, fibrin deposition and inflammatory cell infiltration. No evidence of lung injury was observed in term animals exposed to 21% O2, whereas those exposed to 95% O2 showed a similar, but less pronounced, injury to that seen in pre-term pups. 4. The protein concentration in bronchoalveolar lavage fluid was similar in pre-term and term animals exposed to 95% O2, but neutrophil numbers in bronchoalveolar lavage fluid tended to be greater in pre-term pups. 5. Elastase-like activity, measured against succinyl-1-trialanine p-nitroanilide, was higher in bronchoalveolar lavage fluid from control pre-term animals compared with that from control term animals. Exposure to 95% O2 increased the elastase-like activity significantly in both groups. The majority of the elastase-like activity was EDTA-sensitive and thus is possibly due to metallo-elastase. Fractionation of bronchoalveolar lavage fluid indicated that the elastase-like activity was associated with a high-molecular-mass complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Mechanisms of phosphatidylcholine acyl remodeling by human fetal lung.

The molecular specificity of phosphatidylcholine (PC) synthesis by the de novo pathway in postmortem samples of human fetal lung (15 to 20 wk of gestation) was determined from the incorporation pattern in isolated microsomal preparations of CDP:[14C]choline into individual molecular species of PC. These analyses are based on the assumption that the molecular species composition of the pool of endogenous diacylglycerol used for PC synthesis by isolated microsomes reflects that of the authentic pool of diacylglycerol converted to PC by intact cells. Comparison of this microsomal incorporation pattern of radiolabel into PC with tissue PC composition suggested that even at this early stage of gestation 50% of lung dipalmitoyl PC was derived from synthesis de novo, with the remainder coming from acyl remodeling mechanisms. Analysis of PC synthesis de novo by organ cultures of human fetal lung showed that these acyl remodeling mechanisms were lost in culture. Despite evidence for differentiation of type II alveolar epithelial cells in culture, equilibrium labeling of PC with [14C]choline over 18 h resulted in a progressive decline in fractional incorporation into dipalmitoyl PC with time in culture. By 4 days in culture, this value was no different from the fractional incorporation of CDP:[14C]choline into microsomal PC in vitro over 3 h. The pattern of PC synthesized was not altered when total PC synthesis was stimulated by exposure of cultures to dexamethasone and tri-iodothyronine but was readily manipulated by exposure to exogenous fatty acids. These results demonstrate for the first time the activity of PC acyl remodeling mechanisms in human fetal lung, well before the initiation of surfactant production.(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed1990

Effect of starvation and diabetes on the activity of the eukaryotic initiation factor eIF-2 in rat skeletal muscle.

The ability of the initiation factor eIF-2 in skeletal muscle extracts to form ternary initiation complexes ([Met-tRNA(f).eIF-2.GDP]) is decreased by either starvation or diabetes. These conditions also impair the ability of muscle extracts to dissociate [eIF-2.GDP], suggesting inhibition of the guanine nucleotide exchange reaction essential for eIF-2 recycling. We could not, however, detect any change in the phosphorylation state of the alpha subunit of eIF-2. This suggests that eIF-2 activity may be regulated in this system by a mechanism not involving its phosphorylation.

Animals↗