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Biomedical subjects

A H Jobe

Publications and source records attributed to A H Jobe.

At least 91 records · Page 5Linked to original sources
PubMed1997

Combined effects of fetal beta agonist stimulation and glucocorticoids on lung function of preterm lambs.

We asked whether a single-dose fetal treatment strategy using betamethasone plus either a long-acting beta 2 agonist (formoterol) or betamethasone plus agents that elevate intracellular cyclic adenosine monophosphate (isobutyl methylxanthine and dibutyryl-cyclic adenosine monophosphate) would augment the effects of prenatal betamethasone on postnatal lung function. Preterm lambs were treated with 0.5 mg/kg beta-methasone or betamethasone plus the other agents and delivered 48 h after treatment. The postnatal lung function as assessed by compliance, ventilatory efficiency, and lung volumes at 40 min of age was improved by prenatal betamethasone and improved further by combination treatment, although the augmented responses were not significantly greater than with betamethasone alone. Fatty acid synthase protein and enzymatic activity were not increased by betamethasone or combined treatments, in contrast to responses reported for other animal models. There were no effects of glucocorticoids or the combined treatments on surfactant. Stimulation of the beta 2 agonist system did not augment postnatal lung function significantly above that noted for betamethasone alone with the agents, doses, and duration of exposures tested.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Intra-amniotic interleukin-1 alpha treatment alters postnatal adaptation in premature lambs.

We measured the physiological and biochemical responses of preterm lambs to intra-amniotic injection of interleukin-1 alpha (IL-1 alpha). Singleton lamb fetuses at 126 days of gestation were randomized to receive 125 micrograms IL-1 alpha or vehicle control via ultrasound-guided intra-amniotic injection. Each lamb was delivered 48 h later by caesarian section and ventilated for 120 min. Relative to controls, IL-1 alpha-treated lambs had higher dynamic compliance, ventilatory efficiency indices, and saturated phosphatidylcholine levels (all p < 0.05). Umbilical cord plasma cortisol and catecholamine levels, white blood cells and differentials, cardiac output, regional blood flow, and kidney function did not differ between the groups. However, at 120 min after delivery, the cortisol levels for IL-1 alpha-treated animal were higher than for controls. Single intra-amniotic IL-1 alpha treatment increases surfactant pool size and improves dynamic compliance in the absence of an inflammatory response or differences in other indicators of fetal or newborn organ function.

Adaptation, Physiological↗
PubMed1997

Keratinocyte growth factor increases surfactant pool sizes in premature rabbits.

Keratinocyte growth factor (KGF) is a recently described 19-kD glycoprotein that is a mitogen for epithelial-derived tissue and is expressed during embryonic tissue differentiation. We investigated whether human recombinant KGF (rKGF) could increase alveolar and lung-tissue saturated phosphatidyl-choline (Sat PC) in preterm rabbits delivered at 28.5 d gestation. Preterm rabbits were given 1, 5, or 10 mg/kg rKGF by tracheal injection at 30 min of age. Lung tissue and total lung (alveolar plus lung tissue) Sat PC increased by 48 h (5 and 10 mg/kg) (p < 0.01) and 72 h (1 and 10 mg/kg) (p < 0.05). A single intravascular or intramuscular dose of 10 mg/kg rKGF also increased long tissue and total-lung Sat PC by 48 h (p < 0.01). A single dose of rKGF given shortly after birth to preterm rabbits increased lung Sat PC in the preterm rabbits.

Animals↗
PubMed1997

Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs.

We evaluated the effects of multiple fetal exposures to glucocorticoids on postnatal lung function and growth. Ewes were randomized to receive 1 to 4 doses of 0.5 mg/kg betamethasone or saline placebo at 7 d intervals from 104 d to 118 d and at 124 d gestation. All lambs were delivered preterm at 125 d gestation, and postnatal lung function was evaluated. There were sequential improvements in compliance, ventilation efficiency, and lung volumes for two, three, and four doses of betamethasone. The maximal effect was a 150% increase in compliance and a 4-fold increase in lung volume after fetal exposure to four doses of betamethasone. However, birth weights decreased (15% after one dose, 19% after two doses, and 27% after three and four doses). There were no changes in lung to body weight ratios, lung dry to wet weight ratios, lung protein to body weight ratios, or lung hyaluronan content. Prenatal glucocorticoid exposure also altered postnatal cortisol, thyroid, and catecholamine plasma levels. Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.

Animals↗
PubMed1997

Prenatal glucocorticoid and T4 effects on lung morphology in preterm lambs.

Prenatal glucocorticoid plus T4 treatment of fetal sheep results in improvements in oxygenation, gas exchange, lung mechanics, and lung volumes after preterm delivery. We have evaluated the morphometric changes in the lungs of lambs exposed to betamethasone and T4 48 h before preterm delivery at 121 and 135 d gestation and related those changes to the physiologic improvements in lung function. The lungs used for the morphometric studies were from lambs with postnatal physiologic responses similar to those of the entire group of lambs reported previously (16). At both 121 and 135 d gestation, lung gas volumes and fixed tissue volumes increased, the percent of collapsed (nonaerated) parenchyma decreased, and the percent of perilobular connective tissue decreased with both gestational age and prenatal hormone exposure. Alveolar size, as estimated by mean linear intercept length, did not change with gestation or hormone exposure, but there was a decrease in alveolar wall thickness with advancing gestation and at each gestation with hormone exposure. The major anatomic effect of prenatal hormone exposure was a decrease in alveolar wall thickness and an increase in aerated parenchyma, effects that were consistent with the physiologic improvements in postnatal lung function.

Animals↗
PubMed1997

Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice.

Genetic ablation of the murine SP-B gene in transgenic mice caused lethal perinatal respiratory distress in homozygous offspring, whereas heterozygous SP-B (+/-) mice survived postnatally. In adult SP-B(+/-) mice, surfactant protein B mRNA and the alveolar lavage SP-B protein were reduced by 50% compared with wild-type littermates, consistent with the inactivation of a single SP-B allele. Expression of SP-A, SP-C, and SP-D proteins was not affected in SP-B(+/-) mice. Heterozygous SP-B(+/-) mice reached maturity in numbers expected by Mendelian inheritance of a recessive gene. Lung morphology and both intracellular and extracellular phospholipid pool size and composition were unaltered in the SP-B(+/-) mice. Despite normal survival, pulmonary function studies demonstrated a consistent decrease in lung compliance in SP-B(+/-) mice. Abnormalities of inflation/deflation curves demonstrated airway collapse at low deflation pressures. Residual volumes were increased in the SP-B(+/-) mice. In summary, SP-B mRNA and SP-B protein were reduced by 50% in SP-B(+/-) mice, resulting in abnormalities of lung compliance and air trapping, suggesting a potential susceptibility to pulmonary dysfunction associated with SP-B deficiency.

Animals↗
PubMed1997

Postnatal lung function after prenatal steroid treatment in sheep: effect of gender.

The effect of fetal gender on postnatal lung function and response to prenatal steroid exposure were examined retrospectively in a group of 115 preterm lambs. Fetuses received a single intramuscular injection of 0.5 mg/kg betamethasone alone or in conjunction with L-thyroxine 48 h before delivery at 128-d gestational age. Control animals received an equivalent volume of saline. After delivery, respiratory mechanics and blood gas parameters were recorded for 40 min. Deflation pressure volume curves were constructed in excised lungs. Right upper lobes from a randomly selected subgroup of control animals were examined morphometrically. Control (saline-treated) females were able to be ventilated at lower ventilatory pressures with equivalent tidal volumes and more efficient gas exchange. There were no gender differences in compliance, conductance, or excised lung volumes for saline-treated animals. More efficient gas exchange in females could not be explained by thinner alveolar septa or greater alveolar surface area. After hormone treatment, both males and females exhibited significant improvements in respiratory mechanics, gas exchange, and an increase in alveolar surfactant concentration. However, female exhibited a significantly greater improvement than males for compliance, conductance, excised lung volume, and arterial oxygen partial pressure. These data provide a comprehensive description of gender differences in postnatal lung function and response to steroid treatment in preterm animals, and support clinical findings of sexual dimorphism.

Animals↗
PubMed1996

Altered surfactant function and structure in SP-A gene targeted mice.

The surfactant protein A (SP-A) gene was disrupted by homologous recombination in embryonic stem cells that were used to generate homozygous SP-A-deficient mice. SP-A mRNA and protein were not detectable in the lungs of SP-A(-/-) mice, and perinatal survival of SP-A(-/-) mice was not altered compared with wild-type mice. Lung morphology, surfactant proteins B-D, lung tissue, alveolar phospholipid pool sizes and composition, and lung compliance in SP-A(-/-) mice were unaltered. At the highest concentration tested, surfactant from SP-A(-/-) mice produced the same surface tension as (+/+) mice. At lower concentrations, minimum surface tensions were higher for SP-A(-/-) mice. At the ultrastructural level, type II cell morphology was the same in SP-A(+/+) and (-/-) mice. While alveolar phospholipid pool sizes were unperturbed, tubular myelin figures were decreased in the lungs of SP-A(-/-) mice. A null mutation of the murine SP-A gene interferes with the formation of tubular myelin without detectably altering postnatal survival or pulmonary function.

Animals↗
PubMed1996

Surfactant effects on aerosolized and instilled adenoviral-mediated gene transfer.

The effects of surfactant on aerosolization of adenovirus and the distribution of aerosolized and instilled adenovirus in rabbit lungs were measured. Using 99Tc sulfur colloid as a marker for the aerosol, 33P-adenovirus with and without 3H-surfactant, we found that the aerosol had the same particle size distribution independent of surfactant and the 33P-adenovirus distributed proportionately to the other radiolabels in the aerosol. Rabbits received aerosolized or instilled suspensions of adenovirus and 99Tc-sulfur colloid with or without 10 mg/ml surfactant. Rabbit lungs were separated into large airways (trachea, carina, and primary bronchi) and more distal lung parenchyma either immediately after treatment for measurement of 99Tc distribution or 3 days after treatment for luciferase transgene expression. More instillate (94 +/- 1%) than aerosol (68 +/- 2%) was recovered in the parenchyma immediately after treatment (p < 0.01). Transgene expression in the parenchyma as a percent of total lung expression was lower for both instillation (72 +/- 8%) and aerosolization (30 +/- 8%) than for the initial distributions (p < 0.01). Surfactant did not change the distributions of 99Tc sulfur colloid or transgene expression. The adenovirus was aerosolized successfully but the distribution of the aerosol did not favor transgene expression in the lung parenchyma.

Adenoviruses, Human↗
PubMed1996

Differing patterns of mechanical response to direct fetal hormone treatment.

A single combined intramuscular dose of betamethasone and l-thyroxine (T4) or placebo was injected into the shoulder of fetal lambs 48 hours prior to delivery at days 121 (n = 14), 128 (n = 25) or 135 (n = 20) of gestation. Respiratory mechanics were calculated using multiple linear regression analysis. Both respiratory system resistance (RRS) and elastance (ERS) decreased approximately 4 fold between gestational days 121 (D121) and 135 (D135). Both variables were also reduced by hormone treatment. Reduction in ERS was due to a reduction in both lung (EL) and chest wall (EW) components. In absolute terms EW decreased with gestational age; however, EW as a proportion of total elastance (% EW) increased. Inclusion of a volume-dependent elastance term in the multiple linear regression model enabled us to separate total elastance into volume-independent (E1) and volume-dependent (E2V) components. E1 decreased almost 8-fold compared with only a 2.5-fold fall in E2V between D121 and D135. %E2, the proportion of ERS which is volume-dependent and which provides an index of overventilation, doubled over this time period. Hormone treatment affected E1 and E2V components equally hence %E2 was not altered. Both excised lung volume and end expiratory alveolar volume increased with gestational age and with treatment. The response to treatment was qualitatively similar at each of the gestational ages examined, however, for all mechanics variables, except resistance and E1, the magnitude of response to treatment was significantly smaller in D135 animals compared with other age groups.

Airway Resistance↗
PubMed1996

Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation.

Mice made granulocyte macrophage-colony stimulating factor (GM-CSF)-deficient by homologous recombination maintain normal steady-state hematopoiesis but have an alveolar accumulation of surfactant lipids and protein that is similar to pulmonary alveolar proteinosis in humans. We asked how GM-CSF deficiency alters surfactant metabolism and function in mice. Alveolar and lung tissue saturated phosphatidylcholine (Sat PC) were increased six- to eightfold in 7- to 9-wk-old GM-CSF-deficient mice relative to controls. Incorporation of radiolabeled palmitate and choline into Sat PC was higher in GM-CSF deficient mice than control mice, and no loss of labeled Sat PC occurred from the lungs of GM-CSF-deficient mice. Secretion of radiolabeled Sat PC to the alveolus was similar in GM-CSF-deficient and control mice. Labeled Sat PC and surfactant protein A (SP-A) given by tracheal instillation were cleared rapidly in control mice, but there was no measurable loss from the lungs of GM-CSF-deficient mice. The function of the surfactant from GM-CSF-deficient mice was normal when tested in preterm surfactant-deficient rabbits. GM-CSF deficiency results in a catabolic defect for Sat PC and SP-A.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1996

Higher lung antioxidant enzyme activity persists after single dose of corticosteroids in preterm lambs.

Although administration of exogenous corticosteroids accelerates the late gestational rise in fetal rat and lamb lung antioxidant enzyme activity, the effect of dosing intervals on these responses remains uncertain. We studied the persistence and efficacy of the antioxidant response in fetal lamb lung to a single fetal dose of corticosteroids injected between 121 and 127 days gestational age. Fetal lambs received 0.5 mg/kg of betamethasone (n = 35) or saline (n = 26) by fetal intramuscular injection 24 h, 48 h, 4 days, or 7 days before preterm delivery at 128 days gestation (term = 150 days). After delivery, the lambs were ventilated for 40 min and killed. Total superoxide dismutase, catalase, glutathione peroxidase activities, and lipid hydroperoxide levels were measured, using homogenized lung. The saline-injected controls were similar at all time points. Lung antioxidant enzyme activity was consistently higher and lipid hydroperoxide presence was lower in the betamethasone-treated groups. We conclude that the positive effect of a single fetal dose of betamethasone on lung antioxidant enzyme activity occurs within 24 h after exposure, persists over a period of 7 days without a major change in the magnitude of the response, and leads to a reduction in lipid hydroperoxide formation during immediate postdelivery oxygen exposure.

Animals↗
PubMed1996

Effect of interval from fetal corticosteriod treatment to delivery on postnatal lung function of preterm lambs.

The effect of altering the interval from treatment to delivery on postnatal lung function of the preterm lamb is unknown. We treated groups of 8-10 singleton fetal sheep with 0.5 mg/kg betamethasone by fetal injection and evaluated postnatal lung function 40 min after preterm delivery at 123 days gestation 2 days after treatment or at 128 days gestation 2, 4, and 7 days after treatment relative to groups of 4-8 saline-injected control animals. At 123 days, betamethasone significantly improved arterial PCO2, dynamic thoracic compliance, and ventilatory efficiency index and doubled lung gas volume relative to a control group. Fetal treatment with betamethasone 2, 4, or 7 days before delivery at 128 days also improved these same indicators of lung function relative to controls, and the magnitude of the improvements was the same for all indicators and independent of treatment-to-delivery interval. Betamethasone suppressed the normal postnatal increase in plasma cortisol after 2 and 4 days of exposure but not after 7 days of exposure. Betamethasone also increased fetal and postnatal triiodothyronine concentrations after 2 days of exposure but not at 4 or 7 days of exposure. Although the hormone effects were transient, postnatal lung functional responses to betamethasone persisted over the 2- to 7-day interval from treatment to delivery.

Adrenal Cortex Hormones↗
PubMed1996

Postnatal lung responses and surfactant function after fetal or maternal corticosteroid treatment.

To evaluate the effect of dose and route of administration of betamethasone on subsequent postnatal lung function, pregnant ewes were randomized at 127 days gestation to receive maternal or fetal intramuscular doses of 0.2 or 0.5 mg/kg body wt betamethasone or saline. At delivery 24 h later, preterm lambs were treated with surfactant and ventilated for 4 h. The lambs exposed to 0.5 mg/kg betamethasone by either the maternal or fetal route had higher Po2 values, lung volumes, dynamic compliances, and ventilatory efficiency indexes, as well as lower ventilatory pressure requirements, than did control animals (P < 0.05). There were no consistent improvements in postnatal lung function for the 0.2 mg/kg dose given to the fetus or ewe. However, measurements of radiolabeled protein in the total lung were decreased in all treatment groups (P < 0.01). Surfactant that was recovered from all groups of lambs and fractionated to isolate the large-aggregate fraction improved lung volumes in preterm rabbits to a greater degree than the surfactant used to treat the lambs (P < 0.05). Surfactant recovered from both groups treated with 0.5 mg/kg betamethasone was less sensitive to inactivation by plasma than was surfactant from the 0.2 mg/kg groups or the controls (P < 0.01). Fetal or maternal treatment with 0.5 mg/kg betamethasone improved postnatal lung function and increased the resistance of surfactant to inactivation.

Adrenal Cortex Hormones↗
PubMed1996

Surfactant inhibition by plasma: gestational age and surfactant treatment effects in preterm lambs.

The preterm infant with respiratory distress syndrome has edematous lungs and small amounts of surfactant that do not function normally. We reported that surfactant recovered from preterm lambs after surfactant treatment can have decreased sensitivity to inhibition of surface tension by plasma. We asked whether this augmented resistance to inhibition was dependent on lung development (gestational age) by testing sensitivity to plasma inhibition of 1) endogenous surfactant from preterm lambs and 2) surfactant from preterm lambs after treatment with an organic solvent-extracted natural sheep surfactant. Surfactant recovered after surfactant treatment of 121- or 128-days-gestation lambs had the same sensitivity to plasma inhibition as did the surfactant used to treat the lambs. Surfactant recovered from 134-days-gestation lambs had decreased sensitivity to inhibition. Lung maturation is a variable influencing surfactant inhibition by plasma.

Animals↗
PubMed1996

Ultrasonic nebulized in comparison with instilled surfactant treatment of preterm lambs.

To evaluate the efficiency and distribution of ultrasonic nebulized versus instilled surfactant in the treatment of surfactant deficiency at varying degrees of maturation, twin or triplet lamb fetuses were delivered at 125 to 137 d gestational age and received nebulized natural surfactant (Neb Only), instilled surfactant followed by a second instilled dose (Inst/Inst), instilled surfactant followed by nebulized surfactant (Inst/Neb), or no surfactant (Control). The lambs were ventilated for 6 h. Twenty-eight lambs were categorized into two groups (low compliance versus moderate compliance) based on initial physiologic lung characteristics. Efficiency of deposition of nebulized surfactant directly correlated with the compliances and ventilatory efficiency indices measured at 15 min of age. The low-compliance group (Low Comp) had significantly lower efficiency of surfactant deposition (7.6 +/- 1.6%) than did the moderate-compliance group (Mod Comp) (23.4 +/- 2.5%) (p < 0.01). Overall, instilled surfactant had a reasonably homogeneous distribution, whereas nebulized surfactant had a less homogeneous distribution, except for the Low Comp, Inst/Neb group, which had a distribution pattern similar to that for instilled surfactant. The potential for nebulized surfactant therapy for respiratory distress syndrome (RDS) may be limited by the nonhomogeneous nature of ventilation in the preterm lung.

Administration, Inhalation↗
PubMed1996

Alveolar and tissue surfactant pool sizes in humans.

The amounts of surfactant in human lung tissue and in the alveolar pool have not been extensively reported. We used 24 human lungs from persons over the age range of 13 mo to 80 yr to investigate whether the amount of saturated phosphatidylcholine (Sat-PC) in the human lung changed with age. Lung lavages also were obtained from 10 lungs at autopsy for measurements of the alveolar Sat-PC and surfactant protein-A (SP-A) concentrations. We found that (mean +/- SEM) lung Sat-PC/body weight (28.4 +/- 2.2 mumol/kg), Sat-PC/lung protein (0.060 +/- 0.005 mumol/mg), and Sat-PC/lung deoxyribonucleic acid (DNA) (0.23 +/- 0.01 mumol/mg) did not vary significantly with age. The amounts of alveolar Sat-PC (1.9 +/- 0.2 mumol/kg) and SP-A (105 +/- 15 micrograms/kg) were lower than previous estimates in other species. The relatively small surfactant pools in the human may make the lung more susceptible to injuries that interfere with surfactant function.

Adolescent↗