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Biomedical subjects

A H Jobe

Publications and source records attributed to A H Jobe.

At least 109 records · Page 6Linked to original sources
PubMed1996

Single dose fetal betamethasone administration stabilizes postnatal glomerular filtration rate and alters endocrine function in premature lambs.

UNLABELLED: These studies determined the effects of fetal treatment with betamethasone alone, or in combination with thyroid hormone (thyroxine; T4), on postnatal renal and endocrine adaptations in preterm newborn lambs. Ovine fetuses (126 d of gestation; term = 150 d) received single, ultrasound-guided intramuscular injections of saline, 0.5 mg/kg betamethasone (Celestone Soluspan, or 0.5 mg/kg betamethasone plus 60 micrograms/kg T4. After 48 h, lambs were delivered, treated with surfactant (Survanta, 100 mg/kg), and ventilated for 3 h. Due to maintained urine flow in the betamethasone-treated animals and a significant decrease in the saline group, betamethasone versus saline urine flow values (0.11 +/- 0.03 versus 0.03 +/- 0.004 mL.min-1.kg-1) were significantly elevated by the end of studies. GFR (1.5 +/- 0.3 versus 0.8 +/- 0.2 mL.min-1.kg-1) and mean blood pressure (61 +/- 4 versus 42 +/- 3 mm Hg) values also were higher in the betamethasone-treated animals. Although renal blood flow, renal plasma flow, and fractional sodium excretion rates did not differ, betamethasone versus saline values for the filtration fraction (11.9 +/- 1.5 versus 7.4 +/- 1.5%) and total sodium reabsorption (196 +/- 38 versus 81 +/- 16 microEq.min-1.kg-1) were increased. Betamethasone versus saline treatment also was associated with significant reductions in plasma angiotensin II (125 +/- 23 versus 550 +/- 140 pg/mL) and AVP (116 +/- 19 versus 230 +/- 77 pg/mL) levels. Overall, the effects of combined betamethasone + T4 treatment were similar to the effects of betamethasone alone. CONCLUSIONS: 1) fetal betamethasone injection 48 h before delivery stabilizes GFR and significantly alters endocrine function in preterm newborn lambs, and 2) the addition of T4 does not augment betamethasone-induced renal and endocrine responses.

Angiotensin II↗
PubMed1996

Surfactant enhances adenovirus-mediated gene expression in rabbit lungs.

The efficiency and localization of gene transfer for gene therapy in the lung will depend on vector selection and technique used to deliver the vector. We hypothesized that surfactant might facilitate gene transfer because of its biophysical properties that enhance spreading of saline suspensions in the airways. We used a replication defective adenovirus directing the expression of the luciferase reporter gene at different virus doses and surfactant concentrations and instilled 4 ml suspensions into the lungs of adult rabbits. Transgene expression measured as luciferase-dependent light units in tissue homogenates 3 days after instillation had similar lobar distributions for surfactant-viral suspensions and for phosphate-buffered saline viral suspensions. However, total light units were four- to six-fold increased for viral doses of < 10(10) plaque forming units in 10 mg/ml or 25 mg/ml surfactant suspensions. The percentage of total transgene expression in the tracheacarina-bronchus decreased from over 50% to about 10% for virus instilled with surfactant concentrations of 2 mg/ml or greater, indicating preferential expression in airway epithelial cells located more distally in the lung. Surfactant did not enhance persistence of transgene expression 7 or 14 days after instillation. Surfactant facilitates adenovirally mediated gene transfer in the peripheral lung and enhances transgene expression.

Adenoviruses, Human↗
PubMed1995

Postnatal lung function in preterm lambs: effects of a single exposure to betamethasone and thyroid hormones.

OBJECTIVE: We determined the effect of a single direct fetal injection of corticosteroid and thyroid hormones on postnatal pulmonary function in preterm lambs. STUDY DESIGN: Initially fetal sheep (126 days' gestation) randomly received saline solution, betamethasone (Celestone Soluspan, 0.5 mg/kg), betamethasone plus triiodothyronine (5 micrograms/kg), or betamethasone plus thyroxine (15 micrograms/kg) as a single injection. Forty-eight hours later (128 days' gestation) the fetuses were delivered and ventilated for 50 minutes. In a second protocol fetuses were delivered at 128 days' gestation, after only 24 hours of hormone exposure. RESULTS: Betamethasone treatment improved compliance nearly twofold after 24 or 48 hours of exposure. Efficiency of ventilation also improved after steroid therapy; this effect was augmented 48 hours after thyroxine exposure (but not triiodothyronine). No thyroxine effect was noted after 24 hours of exposure. Maximal lung volume increased by 80% after steroid treatment and doubled in response to combination betamethasone and thyroxine therapy. Alveolar pool sizes of saturated phosphatidylcholine and surfactant protein A were comparable for all groups exposed for 48 hours. CONCLUSIONS: A single fetal exposure to betamethasone improves postnatal pulmonary function after 24 or 48 hours. Addition of thyroxine (but not triiodothyronine) augments this effect at 48 hours.

Animals↗
PubMed1995

Clearance of surfactant protein B from rabbit lungs.

To characterize the metabolism of surfactant protein B (SP-B) in vivo, we measured the clearance of SP-B from adult rabbit lungs. Purified rabbit SP-B was radiolabeled with 125I by the Bolton-Hunter method. Trace amounts of 125I-labeled SP-B mixed with [14C]dipalmitoylphosphatidylcholine (DPPC) were given intratracheally via a bronchoscope to rabbits 0-16 h before collection of alveolar washes (AW). Macrophages were recovered from AW, and lamellar bodies (LB) were isolated from lung tissue by differential centrifugation. 125I-SP-B was cleared more rapidly from the airspaces and the total lung (half-life 7 h) than was DPPC (half-life 11 h in the total lung). There was an approximately threefold accumulation of SP-B relative to saturated phosphatidylcholine in macrophages at all times. The proportion of 125I and 14C radioactivities in lamellar bodies was similar at 2 and 4 h, but there was 14-fold less 125I-SP-B than [14C]DPPC in lamellar bodies by 16 h. This loss of SP-B from the lamellar body fraction is consistent with less recycling of SP-B. The results demonstrate different clearance kinetics of these two components of surfactant and indicate a significant role of macrophages in the clearance of SP-B.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Surfactant treatment and ventilation effects on surfactant SP-A, SP-B, and SP-C mRNA levels in preterm lamb lungs.

The effects of exogenous surfactant treatment combined with postnatal ventilation on surfactant protein (SP)-A, SP-B, and SP-C steady-state mRNA levels were evaluated in preterm sheep at 120, 132, and 139 days gestation. Three groups were studied at each gestation period: animals ventilated and treated with 100 mg/kg natural sheep surfactant, animals ventilated and not treated with surfactant, and a comparison group of lambs that were neither ventilated nor treated with surfactant. In unventilated lambs, SP-A and SP-C mRNA levels measured by densitometry from Northern blots increased between 120 and 132 days gestation (P < 0.05). At 120 days gestation, no differences in SP-A, SP-B, or SP-C mRNA levels were noted among the three groups. At 132 days gestation, SP-A mRNA levels increased in both ventilated groups (P < 0.01), but no additional surfactant effect on SP-A mRNA expression was detected. There were no changes in SP-B or SP-C mRNA levels among the groups at 132 days gestation. At 139 days gestation, mRNA levels for both SP-A and SP-B increased after ventilation, compared with the unventilated groups (P < 0.05). Furthermore, an additional effect of surfactant treatment to increase SP-A mRNA levels relative to animals undergoing ventilation alone was noted (P < 0.05). We conclude that postnatal changes in mRNA levels for the surfactant proteins are gestationally regulated and protein specific.

Animals↗
PubMed1995

Exogenous surfactant function in very preterm lambs with and without fetal corticosteroid treatment.

We have asked whether the function of a bovine source surfactant frequently used clinically (Survanta) could be enhanced after exposure to the very preterm lung when the surfactant was subsequently tested in vivo in preterm surfactant-deficient rabbits. We also evaluated whether there would be effects resulting from fetal treatment with 0.5 mg/kg betamethasone given 48 h before delivery of lambs at 121 days gestational age. The fetal corticosteroid treatment significantly improved gas exchange, increased compliance, increased functional residual capacity, decreased vascular-to-alveolar protein leak, and increased static lung volumes. However, surfactant from both groups of lambs, recovered by alveolar wash and subsequently fractionated to recover the large-aggregate functional surfactant, was equivalent in function to the Survants given to the lambs when tested in preterm surfactant-deficient rabbits. Addition of plasma to Survanta resulted in high minimum surface tensions in vitro, and this inhibition could be prevented by supplementation of the Survanta with 5 or 10% sheep surfactant. No activation occurred with treatment of the very preterm lung, a result consistent with the lung being too immature to contribute components to the surfactant used for treatment. Fetal corticosteroid treatment had no effect on surfactant function at this gestational age.

Adrenal Cortex Hormones↗
PubMed1995

Fetal corticosteroid and T4 treatment effects on lung function of surfactant-treated preterm lambs.

Three groups of sheep fetuses at 125 or 126 d gestational age randomly received a single ultrasound-guided intramuscular injection of saline, 0.5 mg/kg betamethasone, or 0.5 mg/kg betamethasone plus 50 micrograms/kg thyroxine (T4). Forty-eight hours later the fetuses were delivered, treated with a pulmonary surfactant preparation, and ventilated for 3 h. Corticosteroids alone and in combination with T4 increased FRC, compliance, and lung volumes, and decreased the protein leak into the airspace. Saturated phosphatidylcholine pool sizes recovered by alveolar washing were not changed after hormone treatment. To evaluate the function of surfactant recovered from the lambs in vivo, we treated preterm rabbits at 27 d gestational age with the large-aggregate surfactant from alveolar washes. Large-aggregate surfactants and the pulmonary surfactant preparation increased compliances and maximal lung volumes relative to those in untreated preterm rabbits. Large-aggregate surfactants improved compliance more than did the pulmonary surfactant preparation. We conclude that ultrasound-guided single fetal corticosteroid treatment followed by postnatal surfactant improved postnatal lung function in preterm lambs. Addition of T4 did not augment corticosteroid effects. The function of the exogenous surfactant was improved in premature lamb lungs independently of the fetal treatment modality.

Animals↗
PubMed1995

Decreased surfactant dose-response after delayed administration to preterm rabbits.

Preterm rabbits from 14 litters were delivered at 27 d gestation, anesthetized, and treated with surfactant at birth, 15 min, or 30 min after the onset of mechanical ventilation. Doses of surfactant ranging from 0 to 100 mg/kg body weight were given intratracheally and the rabbits were ventilated for 45 min after birth. Pressure-volume curves and dynamic compliances demonstrated that the dose response to surfactant progressively decreased with delayed treatment. Following surfactant treatments of 50 mg/kg at birth, 15 min, and 30 min, peak lung volumes at 35 cm H2O were increased by 49, 30, and 8.4%, respectively over those of untreated controls. Lung lavages from rabbits receiving surfactant at 30 min had significantly higher protein contents and minimum surface tensions on the Wilhelmy balance than those from rabbits treated at birth (23.1 +/- 1.1 versus 16.0 +/- 2.7 dynes/cm), and lung sections from rabbits treated at 30 min had a significantly less uniform distribution of surfactant than those from rabbits treated at birth. While increasing phospholipid concentrations may reverse the inhibition of surfactant by serum proteins in vitro, there was a progressive inability of exogenous surfactant to overcome this inhibition in vivo following delayed administration to very immature rabbits. This inability to overcome inhibition with increasing surfactant dose was associated with a less uniform distribution of surfactant following its delayed administration.

Animals↗
PubMed1995

Postnatal lung function in lambs after fetal hormone treatment. Effects of gestational age.

We previously found that a single dose of betamethasone in combination with thyroxine given by intramuscular injection to fetal sheep 48 h before preterm delivery at 128 d gestation improved postnatal lung function. We have now asked how the combination of 0.5 mg/kg betamethasone and 15 micrograms/kg T4 given by a single fetal intramuscular injection changes lung response 48 h after treatment at 121 and 135 d gestation. At 121 d gestation the fetal hormone treatment significantly improved postnatal lung function. Compliance increased by 55%, arterial PO2 increased from 39 to 215 mm Hg, PCO2 decreased from 109 to 79 mm Hg, and maximal lung volumes increased by 112%. The hormone treatment decreased the severity of the respiratory failure, although these very preterm lambs still had severe respiratory failure. At 135 d gestation, the fetal hormone treatment decreased the ventilatory pressure requirements that were needed to normalize PCO2 values from 30 to 21 cm H2O. Compliance increased by 40%, and maximal lung volumes increased by 33%. Alveolar or lung tissue, saturated phosphatidylcholine, or alveolar SP-A pool sizes did not change with hormone treatment at 135 d gestation. We conclude that fetal hormone treatment significantly improved postnatal lung function at both gestational ages, although the characteristics of the responses were different.

Animals↗
PubMed1995

Clearance of surfactant protein A from rabbit lungs.

Surfactant protein A (SP-A) is a major surfactant protein with multiple biophysical, metabolic, and host defense functions. To further characterize its metabolism in vivo, we measured clearance of SP-A from adult rabbit lungs. Trace amounts of [125I]SP-A radiolabeled by the Bolton-Hunter method and mixed with [3H]dipalmitoylphosphatidylcholine (DPPC) were given intratracheally via a bronchoscope to rabbits. Groups of five to six animals were studied 10 min to 16 h after labeled surfactant administration. After collection of alveolar washes, lamellar bodies were isolated from lung tissue. Macrophages also were isolated from alveolar washes. [125I]SP-A was cleared more rapidly than DPPC from the airspaces. Both [125I]SP-A and [3H]DPPC were lost exponentially from the total lungs, with half-life values of 6.5 h for SP-A and 12 h for DPPC (P < 0.01). In macrophages, the highest radioactivities for SP-A and DPPC were at 10 to 45 min and the radiolabels subsequently disappeared similarly. In lamellar bodies, 125I and 3H radioactivities per mumol saturated phosphatidylcholine (Sat PC) increased in parallel and were highest at 2 h. Whereas radiolabeled lipids were recovered in lamellar bodies for up to 16 h, iodinated SP-A was lost, indicating less recycling of SP-A than DPPC. We previously showed independent pathways of SP-A and Sat PC secretion in rabbits. These results demonstrate the different clearance kinetics of these two principle components of surfactant.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Surfactant protein-B supplementation improves in vivo function of a modified natural surfactant.

The effect of the addition of surfactant protein (SP)-B or SP-B plus SP-C (SP-BC) to a surfactant made from bovine lung (Survanta) was evaluated in 27-d-gestation preterm rabbits. The animals were treated with Survanta, Survanta + 2% SP-B, Survanta + 3% SP-BC, or sheep surfactant. They were then ventilated with 3 cm H2O positive end-expiratory pressure and tidal volumes of 8 mL/kg. Survanta + 2% SP-B was prepared by adding SP-B in water to Survanta or by adding SP-B in chloroform [SP-B(Chl)] to lipid-extracted Survanta. Dynamic compliances of the Survanta + 2% SP-B(Chl)- and Survanta + 3% SP-BC-treated rabbits were greater (p < 0.05) than those treated with Survanta or Survanta + 2% SP-B in water and were comparable to sheep surfactant. Postventilation pressure-volume curves for the groups treated with Survanta supplemented with SP-B had significantly larger retained volumes on deflation compared with those treated only with Survanta (p < 0.01). The effects of ventilation style on the responses were assessed by ventilating other groups of rabbits treated with Survanta, Survanta + 0.5% SP-B(Chl), Survanta + 2% SP-B(Chl), or sheep surfactant with tidal volumes of 10 mL/kg and 0 cm H2O positive end-expiratory pressure. SP-B (2%) augmented the in vivo function of Survanta without positive end-expiratory pressure, and 0.5% SP-B had no effect. Infasurf, a surfactant with more SP-B, was more effective than Survanta when tested in the preterm rabbits. SP-B is a critical factor for optimum immediate surfactant function.

Animals↗
PubMed1995

Postnatal cardiovascular and metabolic responses to a single intramuscular dose of betamethasone in fetal sheep born prematurely by cesarean section.

Although the benefits of antenatal hormone treatment are well accepted, most studies have reported only pulmonary effects. There is evidence of beneficial cardiovascular and metabolic effects in studies using chronically catheterized animals; however because of the route of administration, the results are not directly applicable to clinical strategies. We previously demonstrated significant pulmonary effects in animals treated antenatally with a single, direct fetal, intramuscular injection of glucocorticoids. This study was performed to determine the effects of a single fetal injection of betamethasone (BETA) alone or in combination with thyroxine (T4) on cardiovascular and metabolic responses after preterm birth. Hemodynamic and metabolic responses at birth were determined in fetuses (126-d gestation; term = 150 d) treated with ultrasound-guided intramuscular injections of 0.5 mg/kg BETA (n = 7), BETA plus 60 g/kg T4 (n = 7), or saline (SAL, n = 9). After 48 h, lambs were delivered by cesarean section and studied for 3 h. BETA treatment increased mean arterial blood pressure [56 +/- 6 (SEM) versus 42 +/- 3 mm Hg], heart rate (152 +/- 5 versus 123 +/- 4 beats/min), and cardiac output (467 +/- 17 versus 349 +/- 36 mL/min/kg) versus SAL. Responses of BETA+T4-treated animals were not different from animals treated with BETA alone. Glucose and FFA were similar among all groups. The increase in catecholamine levels normally seen at birth was significantly attenuated in both the BETA and BETA+T4-treated animals. A single, intramuscular injection of glucocorticoids 48 h before delivery improves cardiovascular responses to preterm birth. This effect is not augmented by concomitant administration of T4.

Animals↗
PubMed1994

Catecholamine response to ultrasonographically guided percutaneous blood sampling in fetal sheep.

OBJECTIVE: The purpose of this study was to investigate the fetal catecholamine and arterial blood gas responses to ultrasonographically guided percutaneous needle aspiration of blood from a fetal cardiac ventricle. STUDY DESIGN: A crossover trial design was used. Nine pregnant sheep of 120 to 130 days' gestation were stratified to either percutaneous fetal blood sampling or a sham experiment performed on the first day, and the alternative study on the following day. Arterial blood samples were withdrawn from chronically implanted catheters. RESULTS: Percutaneous fetal blood sampling caused small but statistically significant increases in mean plasma epinephrine and norepinephrine levels 5 seconds after the procedure. Levels thereafter were similar to baseline values. Arterial pH and PCO2 values were unaltered except in one fetus, where blood sampling was followed by bradycardia with acidosis and elevated catecholamine levels. CONCLUSIONS: Ultrasonographically guided percutaneous fetal blood sampling from a cardiac ventricle in sheep produces a rise in catecholamine levels that return to baseline values within 5 minutes. This technique provides an alternative to chronic catheterization for some experiments in which blood sampling or drug injection is required. The results also indicate that needle insertion produces only a modest and transient stress response in the fetus.

Animals↗
PubMed1994

Distribution of surfactant and ventilation in surfactant-treated preterm lambs.

Surfactant-deficient ventilated preterm lambs were treated with 100 mg/kg of surfactant radiolabeled with microspheres at 30 min and 2.5 h of age to evaluate the effect of treatment technique on surfactant distribution. The treatments were four positions with four boluses (bolus 4), two lateral positions with two boluses (bolus 2), or a 30-min infusion (infusion). The bolus groups had uniform surfactant distributions to the > 100 pieces analyzed for each lung. Infusion resulted in a very nonuniform surfactant distribution (P < 0.01). Surfactant was recovered equivalently in all lobes of the bolus groups, whereas infusion lungs contained surfactant preferentially in upper lobes (P < 0.01). The second dose of surfactant localized into the same lung doses as the first dose (P < 0.001). Blood flow increased proportionately to surfactant content in the bolus groups. With infusion, blood flow decreased and ventilation measured with 99Tc-labeled aerosol increased to pieces of lung receiving large amounts of the infusion surfactant, suggesting that localized overinflation was likely. Physiological measurements indicated better responses to bolus treatments, although the infusion lambs did improve. These results indicate that different treatment techniques can have large effects on surfactant distributions.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Developmental changes of sheep surfactant: in vivo function and in vitro subtype conversion.

Developmental differences in the intrinsic characteristics of surfactant have not been evaluated. Therefore, heavy-subtype surfactant was recovered from alveolar washes of 132-, 139-, and 148-day preterm lambs, 2- to 3-day-old newborn ventilated lambs, and adult sheep. The density of heavy-subtype surfactant and surfactant protein-A-to-saturated phosphatidylcholine ratios increased significantly with developmental age. In contrast, percent conversion from heavy to light surfactant forms was more rapid for surfactant from preterm animals than for surfactant from mature or adult animals. The function of the heavy-subtype surfactant was tested by treating ventilated 27-day gestational age preterm rabbits. The surfactant from the most immature animals was less effective at improving compliance or maintaining lung volumes on deflation than was surfactant from newborn or adult animals. These results demonstrate intrinsic and functional differences in surfactant from developing compared with mature sheep that correlated with the surfactant protein-A-content. The pattern of changes indicates that the preterm animal is at a disadvantage, because the surfactant is intrinsically abnormal relative to that of the adult.

Aging↗
PubMed1994

Lung parenchyma and type II cell morphometrics: effect of surfactant treatment on preterm ventilated lamb lungs.

The effect of exogenous surfactant treatment on lung and type II cell structure of ventilated lambs of 137-138 days gestational age was studied. Thirty-four lambs were delivered and randomized to control or 100 mg/kg of natural sheep surfactant treatment groups. Lungs from one group of lambs not treated with surfactant were fixed before ventilation, and the other animals were ventilated to maintain normal blood gas values for 3, 24, or 48 h. Morphometric assessment of the inflation-fixed lung parenchyma of ventilated lungs was compared with the architectural appearance of alveoli and alveolar ducts in the unventilated lungs. Mechanical ventilation resulted in distension of alveolar ducts accompanied by the shallowing and loss of well-defined alveoli and areas of atelectasis at 3 h. These abnormalities increased in severity after 24 and 48 h of ventilation. Surfactant treatment before ventilation significantly reduced the extent and degree of dilatation and concomitant atelectasis. The fraction of normal parenchyma was 38 +/- 7% in untreated lambs vs. 64 +/- 6% in treated lambs after 24 h of ventilation. After 48 h of ventilation, significant differences between control (39 +/- 6%) and surfactant-treated (55 +/- 6%) lambs were still evident. Alveolar type II cells contained approximately 15% lamellar bodies by volume. Neither surfactant treatment nor time of ventilation altered the volume density of lamellar bodies or other organelles, except for a decrease in glycogen from 8% in nonventilated lungs to 2.5% in lungs ventilated for 24 h. These findings indicate that a surfactant treatment at birth results in the maintenance of more normal parenchyma with less atelectasis during prolonged ventilation of the immature lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Time course of changes in lung mechanics following fetal steroid treatment.

We studied the effect of a single-dose, corticosteroid treatment on preterm lambs (gestational age: 128 d). A low, medium, or high betamethasone dose (0.1, 0.5, and 2.0 mg/kg) or saline control was administered directly to the fetus by ultrasound-guided intramuscular injection 48 h before delivery. A second group received either the high dose of betamethasome or saline 24 h before delivery. The lambs were delivered at 128 d gestation, anesthetized with ketamine, and ventilated for 50 min. Respiratory system elastance and resistance were measured at 10-min intervals using multiple linear regression analysis of pressure, flow, and volume. Similarly, estimates of lung mechanics were calculated from transpulmonary pressure. The viscoelastic time constant (tau) was calculated by fitting an exponential to the pressure changes occurring after occluding the airway during expiration. Excised lung volume at 40 cm H2O and lung weight were used to calculate specific elastance and resistance correcting for lung size using volume or weight, respectively. Of the 13 lambs in the 48-h high-dose betamethasone group, five developed pulmonary interstitial emphysema (PIE) as did 3 of 11 animals in the high-dose group treated 24 h before delivery. These animals were analyzed separately. The lambs receiving medium- or high-dose (24 and 48 h predelivery) betamethasone had significantly lower elastance and a trend toward lower resistance when compared with the control groups. Ten minutes after delivery, the animals that developed PIE all had elastance values comparable to that of the control animals despite corticosteroid treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗