Search PubMed⌕ Search

Biomedical subjects

A H Jobe

Publications and source records attributed to A H Jobe.

At least 55 records · Page 3Linked to original sources
PubMed2000

Repetitive prenatal glucocorticoids increase lung endothelial nitric oxide synthase expression in ovine fetuses delivered at term.

Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant production and altered parenchymal lung structure. Whether steroid treatment also affects lung vascular function is unclear. Because nitric oxide contributes to the fall in pulmonary vascular resistance at birth, we hypothesized that the improvement of postnatal lung function of preterm lambs after treatment with prenatal glucocorticoids may be in part caused by an increase in endothelial nitric oxide synthase (eNOS) activity. To determine whether glucocorticoid treatment increases lung eNOS expression, we measured eNOS protein content by Western blot analysis of distal lung homogenates and immunostaining of formalin-fixed lungs from ovine fetuses delivered at preterm and term gestation after prenatal administration of glucocorticoids. Treatment protocols were followed in which ewes were treated with intramuscular betamethasone (0.5 mg/kg) at single or multiple doses at weekly intervals, and fetuses were delivered at 125, 135, or 145 d gestation. All groups were compared with saline-treated controls. Western blot analysis of whole lung homogenates demonstrated a 4-fold increase in eNOS protein content in lambs treated with repetitive doses of glucocorticoids and delivery at term (145 d; p < 0.002). In addition, a small increase in lung eNOS protein content was seen in lambs treated with a single dose of betamethasone at 128 d gestation with delivery at 135 d gestation. In comparison with control animals, there were no differences in lung eNOS content from the remaining lambs treated with glucocorticoids when delivery occurred at preterm ages (125 and 135 d). Immunostaining showed eNOS predominantly in the vascular endothelium in all vessel sizes. Pattern of staining was not altered by treatment with antenatal glucocorticoids. We conclude that maternal treatment with glucocorticoids increases lung eNOS content after multiple doses and delivery at term gestation. We speculate that antenatal glucocorticoids may up-regulate eNOS but that the timing and duration of steroid administration appears to be critical to this response.

Animals↗
PubMed2000

Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs.

In utero inflammation may accelerate fetal lung maturation but may also play a role in the pathogenesis of chronic lung disease. We examined the impact of endotoxin, a potent proinflammatory stimulus, on structural and functional maturation of preterm sheep lungs. Date bred ewes received 20 mg Escherichia coli endotoxin or saline by ultrasound guided intra-amniotic injection at 119 d gestation. A comparison group of animals received 0.5 mg/kg betamethasone, a known maturational agent, at 118 d gestation. Lambs were delivered by cesarean section at 125 d (term = 150 d) and ventilated for 40 min. Lung function data are reported elsewhere. Total and differential white cell counts were performed on amniotic fluid and fetal lung fluid samples. Morphometric analyses were performed on inflation fixed right upper lobes. Total cell count increased slightly but not significantly in both amniotic fluid and fetal lung fluid. Both endotoxin and betamethasone had similar effects on alveolarization: average alveolar volume increased by approximately 20% and total alveolar number decreased by almost 30%. Both treatments led to thinning of alveolar walls, although this was statistically significant in the betamethasone-treated group only. Although antenatal endotoxin leads to striking improvements in postnatal lung function, this may be at the expense of normal alveolar development.

Amniotic Fluid↗
PubMed1999

Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice.

Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabolic studies in GM-CSF-deficient [GM(-/-)] mice indicated that defects in surfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(-/-) mice were treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4-5 wk. Lung histology, alveolar macrophage differentiation, and surfactant protein B immunostaining returned toward normal levels in the GM-CSF aerosol-treated mice. Alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased after treatment with aerosolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in increased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(-/-) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(-/-) mice, demonstrating that surfactant homeostasis can be influenced by local administration of GM-CSF to the respiratory tract.

Administration, Inhalation↗
PubMed1999

CCSP deficiency does not alter surfactant homeostasis during adenoviral infection.

Clara cell secretory protein (CCSP) deficiency in mice is associated with increased susceptibility to pulmonary inflammation after hyperoxia or viral infection. Because adenoviral exposure perturbs pulmonary surfactant homeostasis in vivo, we hypothesized that CCSP deficiency would influence surfactant metabolism after pulmonary infection. Alveolar and total lung saturated phosphatidylcholine pool sizes were similar in CCSP-deficient [CCSP(-/-)] and wild-type [CCSP(+/+)] mice before and 7 days after intratracheal administration of adenovirus. Radiolabeled choline and palmitate incorporation into saturated phosphatidylcholine was similar, and there was no alteration by previous infection 7 days before the incorporation measurements. Furthermore, CCSP deficiency did not influence clearance of [(14)C]dipalmitoylphosphatidylcholine and (125)I-labeled recombinant surfactant protein C. Increased persistence of alveolar capillary leak was observed in CCSP(-/-) mice after adenoviral infection. Surfactant lipid homeostasis was not influenced by CCSP before or after administration of adenovirus to the lung. Persistence of alveolar capillary leak in CCSP(-/-) mice after adenovirus provides further evidence for the role of CCSP in the regulation of pulmonary inflammation.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1999

Surfactant protein C in fetal and ventilated preterm rabbit lungs.

The developing lung contains surfactant protein (SP) C mRNA levels comparable to term values before mature type II cells and alveolar surfactant lipids are detectable. Estimates of the amount of mature SP-C in the alveolar lavages of preterm lungs are not available. We used an antibody to a recombinant human SP-C to measure the amount of SP-C in alveolar lavages of preterm fetal rabbits, ventilated preterm rabbits, and term rabbits. The amounts of SP-C were compared with the amounts of saturated phosphatidylcholine (Sat PC). Median Sat PC amounts increased about 680-fold, and median SP-C values increased by over 5,000-fold in alveolar washes from 27 days gestation to term. There was no increase in Sat PC or SP-C with ventilation at 27 and 28 days gestation, but ventilation increased both Sat PC and SP-C at 29 days gestation. The molar percent of SP-C relative to Sat PC also increased with gestational age and with ventilation at 29 days gestation. proSP-C was abundant in a membrane fraction from lung tissue at 27 and 28 days gestation when minimal mature SP-C was detected in alveolar washes. At 29 days and at term, proSP-C decreased in membrane fractions. The preterm lung that is surfactant lipid deficient is also severely deficient in mature SP-C.

Animals↗
PubMed1999

Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs.

Glucocorticoid treatment increases content of surfactant protein (SP) A and SP-B in lung tissue and lavage fluid of preterm lambs. To investigate this process, we determined the ontogeny and glucocorticoid induction of SP mRNAs. In separate treatment protocols, each with its own controls, sheep were injected with betamethasone 15 h, 48 h, or weekly for 1-4 doses before preterm delivery. Using ovine SP cDNAs, we found an increase equal to or more than threefold in basal levels of all three SP mRNAs between 125 days and term. After betamethasone treatment, SP-B and SP-C mRNA levels increased by 15 h and all SP mRNAs were elevated after 24 h (>/=2-fold); mRNA levels in fetuses delivered 1-3 wk after betamethasone were not different from control. We conclude that in vivo betamethasone rapidly induces a coordinated increase in SP mRNAs, which is fully reversible within 7 days despite repetitive doses of betamethasone. Similar increases in mRNA and protein contents for SP-A and SP-B suggest that glucocorticoid regulation of these SPs in vivo is primarily pretranslational.

Animals↗
PubMed1999

Positive end-expiratory pressure preserves surfactant function in preterm lambs.

Ventilation style influences lung injury and the amount of large-aggregate biophysically active surfactant in adult lungs. We asked how positive end-expiratory pressures (PEEP) would influence clinical responses and surfactant pools in surfactant-treated preterm lambs ventilated for 7 h with tidal volumes (VT) of 10 ml/kg. The 126-d gestation preterms were delivered and treated with 100 mg/kg recombinant human surfactant protein C (rSP-C) containing surfactant and ventilated with zero, 4, or 7 cm H(2)O of PEEP. A comparison group was treated with natural sheep surfactant and ventilated with zero PEEP. Physiologic measurements were similar for lambs treated with rSP-C surfactant and natural surfactant. PEEP 4 and 7 improved oxygenation and compliance relative to either group of lambs ventilated with PEEP zero. The maximal lung volumes measured at 40 cm H(2)O pressure after 7 h ventilation for the PEEP 4 and 7 groups were more than double those measured for either PEEP zero group. Alveolar surfactant pools were larger for the PEEP 7 group, and the large-aggregate fraction was increased for the PEEP 4 and 7 groups, resulting in large-aggregate pool sizes that were 3-fold higher for the PEEP 4 and 4-fold higher for the PEEP 7 groups relative to the PEEP zero group treated with rSP-C surfactant. All large-aggregate surfactants lowered minimal surface tensions of a captive bubble to less than 5 mN/m. In preterm surfactant-treated lambs PEEP improved lung function and maintained more of an rSP-C surfactant in the biophysically active form.

Adult↗
PubMed1999

Metabolism of endogenous surfactant in premature baboons and effect of prenatal corticosteroids.

We studied the synthesis of surfactant and the effect of prenatal betamethasone treatment in vivo in very preterm baboons. Ten pregnant baboons were randomized to receive either betamethasone (beta) or saline (control) 48 and 24 h before preterm delivery. The newborn baboons were intubated, treated with surfactant, and ventilated for 6 d. They received a 24-h infusion with the stable isotope [U-(13)C]glucose as precursor for the synthesis of palmitic acid in surfactant phosphatidylcholine (PC). Palmitic acid in surfactant PC became enriched 27 +/- 2 h after the start of the isotope infusion and was maximally enriched at 100 +/- 4 h. The fractional synthesis rate of PC palmitate in the beta group (1.5 +/- 0.2%/d) was increased by 129% above control (0.7 +/- 0.1%/d) (p < 0.02, Mann- Whitney U test). The absolute synthesis rate of PC in the beta group [1.6 +/- 0.3 micromol/kg/d] was increased by 128% above controls [0.7 +/- 0.2 micromol/kg/d] (p < 0.02). These data show that the synthesis of endogenous surfactant from plasma glucose as precursor is a slow process. It is shown, for the first time in vivo, that prenatal glucocorticosteroids stimulate the synthesis of surfactant PC in the very premature baboon.

Animals↗
PubMed1999

Lung morphometry and collagen and elastin content: changes during normal development and after prenatal hormone exposure in sheep.

This study examined whether the improvement in lung function after prenatal hormone exposure coincided with changes in lung morphometry or in collagen and elastin content. Fetal lambs received a single intramuscular injection of betamethasone (0.5 mg/kg) plus L-thyroxine (T4) (15 micrograms/kg) or vehicle control 48 h before delivery at 121, 128, or 135 d gestational age (d 121, d 128, d 135, term = 150 d). T4 was administered in conjunction with betamethasone in an attempt to enhance the maturational response. The right-upper lobes were instillation fixed at 30 cm H2O by Karnovsky's fixative after a 40-min period of mechanical ventilation. A number of significant changes occurred between d 121 and d 135 in control animals: alveolar airspace volume increased by 270%; despite a 40% reduction in alveolar septal thickness, alveolar septal volume did not change appreciably, suggesting a "redistribution" of septal tissue into the formation of secondary alveolar septa, which doubled in number; and both parenchymal collagen and elastin volume increased significantly, whereas pleural collagen and elastin volume did not change. In contrast to the changes seen in control animals, exposure to betamethasone plus T4 led to alveolar septal thinning at each gestational age without an associated increase in secondary septal number, a 40% decrease in alveolar septal volume, and a proportionate reduction in parenchymal elastin at d 121. Although attenuation of alveolar septa coincides with redistribution of septal tissue into the formation of secondary septa during normal maturation, exposure to betamethasone plus T4 promotes thinning of alveolar septa in the absence of secondary septal formation, which results in a loss of alveolar septal tissue.

Aging↗
PubMed1998

Surfactant protein metabolism in vivo.

The surfactant components saturated phosphatidylcholine, SP-B and SP-C, are secreted together in lamellar bodies, and at least a part of the de novo synthesized SP-A is secreted independently. The surface film forms from tubular myelin and loose lipid arrays, and it generates unilamellar vesicles that lack surfactant proteins and are thought to represent catabolic forms. The half-life values for the clearance of surfactant proteins from lungs range from 6.5 to 28 h and vary with species. There is minimal information about the associations of the surfactant proteins with lipids or with each other after film formation, although all surfactant components seem to be recycled back into lamellar bodies in type II cells. The relative importance of type II cells or macrophages to the catabolism of the protein components of surfactant remains to be characterized, as do regulators of surfactant homeostasis.

Animals↗
PubMed1998

Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo.

Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (+/-) and SP-D (-/-) mice. Both SP-D (-/-) and SP-D (+/-) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (+/-) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (-/-) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (-/-) mice. Phospholipid composition was unaltered in SP-D (-/-) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (-/-) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (-/-) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.

Animals↗
PubMed1998

Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep.

OBJECTIVE: We evaluated the effects of single or three repeated doses of maternal betamethasone on fetal growth at preterm and term delivery in sheep. STUDY DESIGN: Pregnant ewes were randomly assigned to receive one dose of 0.5 mg/kg betamethasone at 104 days' gestational age; three doses of betamethasone at 104, 111, and 118 days' gestational age; or saline for controls. Lambs were delivered at 125 days' (preterm) or at 145 days' (term) gestational age for assessments of fetal growth. RESULTS: The single betamethasone exposure at 104 days' gestational age caused symmetric growth retardation of 11% at 125 days' gestational age and 14% at term. The three-dose exposures decreased body weights by 25% in preterm lambs and by 19% at term. Organ protein and deoxyribonucleic acid per kilogram of body weight were selectively decreased in preterm lambs. At term the decreases in organ weight, protein, and deoxyribonucleic acid were proportionate to the decreased birth weight. CONCLUSION: One or three doses of maternal glucocorticoids begun at an early gestational age caused symmetric growth retardation in lambs delivered prematurely, and the decreased fetal size persisted to term.

Animals↗
PubMed1998

Mechanisms initiating lung injury in the preterm.

Bronchopulmonary dysplasia (BPD)/chronic lung disease occurs primarily in very low birth weight infants (VLBW) often without antecedent severe respiratory distress syndrome. The BPD in these VLBW infants results in less fibrosis than the traditional BPD but the normal process of alveolarization seems to be disrupted. This review develops the thesis that BPD in VLBW infants results from inflammatory mediators interfering with the signaling required for normal late gestational lung development. Proinflammatory mediators may be elevated because of fetal exposure, postnatal infection or by release from preterm lungs ventilated at either low or high lung volumes. The preterm lung is highly susceptible to injury during resuscitation or more chronic mechanical ventilation because the gas volumes/kg body weight of the lungs are small. An understanding of what causes cytokine release and how cytokines influence lung development is necessary to develop targeted therapies to minimize BPD. However, care strategies that minimize inflammation and ventilator-induced lung injury should help decrease BPD.

Bronchopulmonary Dysplasia↗
PubMed1998

Clearance of SP-C and recombinant SP-C in vivo and in vitro.

Surfactant protein (SP) C metabolism was evaluated in vivo by measurements of the clearance of bovine native SP-C (nSP-C) and a recombinant SP-C (rSP-C) in rabbits and mice and in vitro by the uptake into MLE-12 cells. rSP-C is the 34-amino acid human sequence with phenylalanine instead of cysteine in positions 4 and 5 and isoleucine instead of methionine in position 32. Alveolar clearances of iodinated SP-C and rSP-C after tracheal instillation were similar and slower than those for dipalmitoyl phosphatidylcholine (DPC) in the rabbit. nSP-C and rSP-C were cleared from rabbit lungs similarly to DPC, each with a half-life (t1/2) of approximately 11 h. In mice, the clearance of rSP-C from the lungs was slower (t1/2 28 h) than the clearance of DPC (t1/2 12 h). Liposome-associated dinitrophenyl-labeled rSP-C was taken up by MLE-12 cells, and the uptake was inhibited by excess nSP-C. The pattern of inhibition of dinitrophenyl-rSP-C uptake by SP-B, but not by SP-A, was similar to that previously reported for nSP-C. Clearance kinetics of nSP-C were similar to previous measurements of pulmonary clearance of SP-B in rabbits and mice. rSP-C has clearance kinetics and uptake by cells similar to those of nSP-C.

Animals↗
PubMed1998

Characteristics of surfactant from SP-A-deficient mice.

Mice that are surfactant protein (SP) A deficient [SP-A(-/-)] have no apparent abnormalities in lung function. To understand the contributions of SP-A to surfactant, the biophysical properties and functional characteristics of surfactant from normal [SP-A(+/+)] and SP-A(-/-) mice were evaluated. SP-A-deficient surfactant had a lower buoyant density, a lower percentage of large-aggregate forms, an increased rate of conversion from large-aggregate to small-aggregate forms with surface area cycling, increased sensitivity to inhibition of minimum surface tension by plasma protein, and no tubular myelin by electron microscopy. Nevertheless, large-aggregate surfactants from SP-A(-/-) and SP-A(+/+) mice had similar adsorption rates and improved the lung volume of surfactant-deficient preterm rabbits similarly. Pulmonary edema and death caused by N-nitroso-N-methylurethane-induced lung injury were not different in SP-A(-/-) and SP-A(+/+) mice. The clearance of 125I-labeled SP-A from lungs of SP-A(-/-) mice was slightly slower than from SP-A(+/+) mice. Although the absence of SP-A changed the structure and in vitro properties of surfactant, the in vivo function of surfactant in SP-A(-/-) mice was not changed under the conditions of these experiments.

Adsorption↗
PubMed1998

Direct fetal glucocorticoid treatment alters postnatal adaptation in premature newborn baboons.

Abnormalities of premature newborn adaptation after preterm birth result in significant perinatal mortality and morbidity. We assessed the effects of short-term (24 h) fetal betamethasone exposure on preterm newborn baboon pulmonary and cardiovascular regulation and renal sodium handling during the first 24 h after birth. Male fetal baboons (Papio) (124-day gestation, term 185 days) received ultrasound-guided intramuscular injections of saline (n = 5) or betamethasone (0.5 mg/kg; n = 5). Fetuses were cesarean delivered 24 h later, treated with 100 mg/kg surfactant, and ventilated by adjusting peak inspiratory pressures to maintain PCO2 values of 35-50 mmHg for 24 h. Betamethasone- vs. saline-treated mean +/- SE newborn body weights (0.45 +/- 0.02 vs. 0.41 +/- 0.01 kg) were similar. Although prenatal betamethasone did not affect postnatal lung function (PCO2, arterial/alveolar O2 gradient, or dynamic compliance), plasma hormone (cortisol or thyroxine), or catecholamine levels, mean arterial pressure (25 +/- 1 vs. 32 +/- 1 mmHg), plasma sodium concentration (132 +/- 2 vs. 138 +/- 1 meq/l), glomerular filtration rate (0.07 +/- 0.02 vs. 0.16 +/- 0.02 ml.min-1.kg-1), and renal total sodium reabsorption (1.5 +/- 0.5 vs. 16.0 +/- 3.0 mu eq.min-1.kg-1) values were significantly lower in saline-treated than in betamethasone-treated newborns at 24 h. We conclude that despite the fact that there are no pulmonary and endocrine effects, antenatal glucocorticoid exposure alters premature newborn baboon vascular and renal glomerular function and improves sodium reabsorption after preterm delivery.

Adaptation, Physiological↗
PubMed1998

Repetitive prenatal glucocorticoid therapy reduces oxidative stress in the lungs of preterm lambs.

Repetitive courses of maternal prenatal glucocorticoids are often used in high-risk pregnancies with threatening preterm labor to induce lung maturation, but the effects on the cellular oxidant-antioxidant balance in the fetal lung have not been evaluated. We investigated the effect of repetitive treatment with glucocorticoids, beginning early in gestation, on oxidative stress in the preterm ovine lung. Pregnant ewes were randomized to receive one, two, three, or four doses of 0.5 mg/kg betamethasone or saline placebo at 7-day intervals on 104, 111, 118, and 124 days gestation (n = 11 for each group). All lambs were delivered preterm at 125 days gestation, and lung tissue was assayed for antioxidant enzymes, lipid hydroperoxides, and carbonyl proteins. Lung manganese superoxide dismutase, catalase, and glutathione peroxidase activity increased after 1 dose of betamethasone given at 104 days gestation, whereas copper-zinc superoxide dismutase activity increased after 2 doses given at 104 and 111 days gestation. The activity of all four antioxidant enzymes further increased with additional doses and was maximal after four doses of betamethasone. Lung lipid hydroperoxide levels and carbonyl protein content decreased stepwise after each dose of betamethasone and were lowest after four doses. Repetitive prenatal glucocorticoid therapy increases antioxidant enzyme activity and reduces oxidative stress in the lungs of preterm lambs, and these effects begin early in gestation and persist for 2-3 wk.

Animals↗