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Biomedical subjects

A D Postle

Publications and source records attributed to A D Postle.

At least 55 records · Page 3Linked to original sources
PubMed1994

Hepatic phospholipid molecular species in the guinea pig. Adaptations to pregnancy.

Incorporation of polyunsaturated fatty acids (PUFA), particularly 22:6n-3, into fetal brain at specific gestational ages is critical for development of normal brain function. We have studied adaptations to maternal liver phospholipid molecular species compositions that may be related to the supply of PUFA to fetal brain. The increment of 22:6n-3 in brain phosphatidylethanolamine (PE) was maximal at day 25 to day 35 of gestation, consistent with early prenatal development of guinea pig brain. At the same gestational ages, there was a transient increase in maternal liver concentration of 16:0/22:6 phosphatidylcholine (PC), which preceded the progressive increase in total PC concentration toward term (day 68). This effect was specific for the sn-1 16:0 species, as there was no significant increase in 18:0/22:6 PC concentration. These results are consistent with a specific role for 16:0/22:6 PC in the directed supply of 22:6n-3 from maternal liver to the fetus. Concentrations of all PE species in maternal liver decreased at day 25 and day 35 of gestation. The gradual accumulation of 22:6n-3 in fetal liver throughout gestation did not correlate with the pattern of acquisition of 22:6n-3 into fetal brain PE. Maternal plasma PC and cholesterol concentrations decreased dramatically by day 25 of gestation, and remained low until term. This hypolipidemia of pregnancy in the guinea pig may be due to increased lipase-mediated turnover of plasma lipoproteins and contrasts strongly with the well-characterized hyperlipidemia in human and rat gestation.

Animals↗
PubMed1994

Plasma lipid concentrations in children with cystic fibrosis: the value of a high-fat diet and pancreatic supplementation.

Impaired digestion of dietary fat is an almost universal feature of cystic fibrosis (CF) which results in low concentrations of essential fatty acids in plasma lipids. We have evaluated the effect of a high-lipid diet and pancreatic enzyme supplementation, using enteric-coated microsphere preparations, on plasma lipid concentrations in paediatric CF patients. Absorption of dietary lipid was comparable between control and CF subjects. This resulted in plasma cholesterol, triacylglycerol, total phosphatidylcholine and individual phosphatidylcholine molecular species concentrations in CF patients which were in the same range as those in controls. Normal values for these variables were also found in patients with clinically detectable liver disease. These results show that present dietary management of CF patients supports normal plasma lipid concentrations.

Adolescent↗
PubMed1994

Surfactant phosphatidylcholine composition during dexamethasone treatment in chronic lung disease.

OBJECTIVES: To determine whether dexamethasone 'matures' the phosphatidylcholine (PC) composition of broncheoalveolar fluid in infants at high risk of neonatal chronic lung disease (CLD), either by increasing the proportion of dipalmitoylphosphatidylcholine (DPPC), expressed as a percentage of total PC (%DPPC), or by increasing the ratio of DPPC to palmitoyloleoylphosphatidylcholine (DPPC:POPC ratio). DESIGN: Double blind, placebo controlled. SETTING AND PATIENTS: Sixteen infants < 32 weeks' gestation, < 1250 g birth weight who were dependent on mechanical ventilation and requiring a fractional inspired oxygen of > 0.30 at 12 days of chronological age. INTERVENTION: Randomisation to receive a two week reducing course of dexamethasone base at an initial dose of 0.2 mg/kg three times a day, or equivalent volumes of normal saline, starting at 14 days. Eight infants were randomised into each group. Broncheoalveolar lavage was performed serially throughout the study period or until extubation. PC composition of the fluid was analysed by high performance liquid chromatography. OUTCOME MEASURES: The %DPPC and the DPPC:POPC ratios were calculated for individual infants for days -1 and 0 combined, days 1 and 3 combined, and days 5 and 7 combined. Analysis of covariance was used to analyse the results. RESULTS: The DPPC:POPC ratio was significantly less in the treated group than the placebo group on days 1 and 3, and not greater as the hypothesis stated. Three out of five infants treated with dexamethasone and for whom data were available showed a substantial rise in DPPC:POPC ratio on days 5/7, compared with the placebo group, but overall these changes were not statistically significant. CONCLUSIONS: The data do not support the hypothesis that dexamethasone's action in producing a clinical improvement within the first 72 hours of treatment for neonatal CLD is by the 'maturation' of pulmonary surfactant PC.

1,2-Dipalmitoylphosphatidylcholine↗
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

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↗
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↗
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

Turnover of exogenous artificial surfactant.

The turnover of the artificial surfactant Exosurf after its administration to infants with respiratory distress syndrome was studied. High performance liquid chromatography was used to compare the phosphatidylcholine (PC) composition of serial endotracheal tube secretions from three groups of infants. There were 22 infants who received two doses of Exosurf in 24 hours (group 1), 10 infants who received four doses in 36 hours (group 2), and 41 control infants who did not receive Exosurf. Two parameters were studied: (i) dipalmitoylphosphatidylcholine (DPPC), which is present in both Exosurf and endogenous surfactant, expressed as a percentage of total PC (% DPPC) and (ii) the ratio of DPPC to the entirely endogenous palmitoyloleoylphosphatidylcholine (DPPC:POPC ratio). The administration of Exosurf produced changes in endotracheal tube aspirate PC composition that were detectable for over one week. Four doses of Exosurf in 36 hours prolonged the persistence of these changes compared with two doses in 24 hours, but the numbers of infants were small, and should not be over-interpreted. We conclude that after giving two doses of Exosurf, further doses might best be delayed until after two days, and that further clinical evaluation of dosage regimens is required.

1,2-Dipalmitoylphosphatidylcholine↗
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↗