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Biomedical subjects

M Ikegami

Publications and source records attributed to M Ikegami.

At least 127 records · Page 7Linked to original sources
PubMed1997

Glucocorticoid regulation of surfactant components in immature lambs.

To assess effects of dose and duration of glucocorticoid exposure on maturation of the fetal lung, we administered single or multiple doses of betamethasone (0.5 mg/kg im) to pregnant sheep for 2 or 21 days before preterm delivery at 125 days of gestation. Lung function (compliance, lung volume at 40 cmH2O pressure, and ventilatory efficiency index) was increased after two to four weekly doses of glucocorticoid (2.5- to 4-fold increase) and after 48 h of exposure (1.4- to 2.3-fold). Total protein of lavage fluid decreased similarly with three doses, four doses, and 48 h of treatment. In lambs with long-term exposure to betamethasone, there was a similar, dose-dependent increase in concentrations of saturated phosphatidylcholine and surfactant proteins A (SP-A) and B (SP-B) (maximal 2- to 3-fold in tissue and 10- to 15-fold in lavage fluid). Levels of SP-A and SP-B were closely correlated in lavage fluid. In animals treated for 48 h, only tissue SP-B was increased (2.7-fold). We conclude that 48 h of glucocorticoid treatment improves lung function in the premature lamb without a detectable increase in lavage surfactant components and that longer exposure to antenatal glucocorticoid increases surfactant lipid and proteins in a coordinated fashion. The enhanced response with repetitive dosing indicates that the process of glucocorticoid-induced lung maturation is either reversible and/or gestational age dependent.

Animals↗
PubMed1997

Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone.

The optimal dose, route of administration, and treatment-to-delivery interval necessary to induce beneficial extrapulmonary effects of glucocorticoids are not known. Pregnant ewes (127 days gestation) were randomized to receive maternal or fetal intramuscular injections of betamethasone (0.2 or 0.5 mg/kg body wt) or saline 24 h before cesarean delivery of their lambs. Three hours after delivery, low-dose maternal vs. control lamb mean arterial pressure [64 +/- 4 vs. 47 +/- 2 (SE) mmHg], glomerular filtration rate (1.7 +/- 0.2 vs. 0.7 +/- 0.1 ml.min-1.kg-1), and total renal sodium reabsorption (219 +/- 31 vs. 85 +/- 12 mueq.min-1.kg-1) were increased. Comparable increases were observed in the high-dose maternal and fetal groups without effects in the low-dose fetal group. This study provides the first quantitative data demonstrating that even short-term (24-h) antenatal betamethasone exposure alters preterm newborn cardiovascular and renal functions. These responses are route and dose dependent and are comparable to glucocorticoid-induced maturational effects after longer-term antenatal exposure.

Administration, Topical↗
PubMed1997

Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs.

We evaluated postnatal lung function and intravascular albumin loss to tissues of 123-days-gestation preterm surfactant-treated and ventilated lambs 15 h after direct fetal (n = 8) or maternal (n = 9) betamethasone treatment or saline placebo (n = 9). The betamethasone-treated groups had similar increases in dynamic compliances, ventilatory efficiency indexes, and lung volumes relative to controls (P < 0.05). The losses of 125I-labeled albumin from blood, a marker of intravascular integrity, and the recoveries of 125I-albumin in muscle and brain were similar for control and betamethasone-exposed lambs. Betamethasone-treated lambs had lower recoveries of 125I-albumin in lung tissues and in alveolar washes than did controls (P < 0.01). Although blood pressures were higher for the treated groups (P < 0.05), all groups had similar blood volumes, cardiac outputs, and organ blood flows. Maternal or fetal treatment with betamethasone 15 h before preterm delivery equivalently improved postnatal lung function, reduced albumin recoveries in lungs, and increased blood pressures. However, prenatal betamethasone had no effects on the systemic intravascular losses of albumin or did not change blood volumes.

Adrenal Cortex Hormones↗
PubMed1997

Tidal volume effects on surfactant treatment responses with the initiation of ventilation in preterm lambs.

We hypothesized that initiation of ventilation in preterm lambs with high volumes would cause lung injury and decrease the subsequent response to surfactant treatment. Preterm lambs were randomized to ventilation for 30 min after birth with 5 ml/kg (VT5), 10 ml/kg (VT10), or 20 ml/kg (VT20) tidal volumes and then ventilated with approximately 10 ml/kg tidal volumes to achieve arterial PCO2 values of approximately 50 Torr to 6 h of age. VT20 lambs had lower compliances, lower ventilatory efficiencies, higher recoveries of protein, and lower recoveries of surfactant in alveolar lavages and in surfactant that had decreased compliances when tested in preterm rabbits than VT5 or VT10 lambs. Other lambs randomized to treatment with surfactant at birth and ventilation with 6, 12, or 20 ml/kg tidal volumes for 30 min had no indicators of lung injury. An initial tidal volume of 20 ml/kg decreased the subsequent response to surfactant treatment, an effect that was prevented with surfactant treatment at birth.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1997

Testing surfactant treatment responses: a comparison of two models.

We have compared treatment responses of two surfactants in two animal models of respiratory distress syndrome. Preterm rabbits at 27 days gestation and premature lambs at 126 days gestation were treated with natural sheep surfactant Survanta (Ross Laboratories), or no surfactant and then were ventilated with the same ventilation style to achieve tidal volumes of 8 ml/kg. Dynamic compliances at 15 min were higher for control and surfactant-treated rabbits than for preterm lambs. Sheep surfactant and Survanta increased compliances in rabbits, but only sheep-surfactant-treated lambs had compliances higher than controls at 15 min of age. Maximal lung volumes (milliliters per kilogram) of the rabbits (after 15 min ventilation) were about twice those of the lambs (after 4 h of ventilation). Lung volumes of sheep-surfactant-treated rabbits were larger than for Survanta-treated rabbits, but no differences in lung volume were evident between the surfactant-treated lambs. The two models for testing surfactants do not give the same results when directly compared.

Analysis of Variance↗
PubMed1997

Surfactant protein-B and lung function in surfactant-treated preterm lambs.

We asked if the amount of SP-B (range 37-410 micrograms/ml) in surfactants used to treat preterm lambs at 123 days of gestation correlated with postnatal lung function or the SP-B content of surfactant recovered by alveolar washes after 10 h ventilation. Ventilation was initiated using a low tidal volume strategy to minimize early lung injury. There were small increases in compliance for the lambs treated with surfactants containing more than 37 micrograms/ml SP-B and an increased lung volume for lambs treated with a surfactant containing 385 micrograms/ml/ml relative to the surfactant containing 37 micrograms/ml SP-B. The amount of SP-B in the surfactant used for treatment correlated linearly with the amount of SP-B in the surfactant recovered from the lambs (r = 0.95, p < 0.001). Albumin leak from the vasculature to the airspace was low as was total protein in alveolar washes, indicating minimal lung injury. The SP-B content of surfactant (from 37 to 410 micrograms/ml) had minimal effects on postnatal lung function over a 10-hour study period in lambs ventilated in a manner to minimize lung injury.

Biological Products↗
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↗
PubMed1997

[Estimation of renal transplant dysfunction by color Doppler sonography].

BACKGROUND: To clarify various conditions in the transplanted kidney, invasive biopsy must be performed in most cases. In this study, we measured blood flow in the transplanted kidney by color Doppler tomography to examine the usefulness of measuring renal blood flow in clarifying various conditions. METHOD: Blood flow in the transplanted kidney was measured using peak flow velocity (PFV) and an index of resistance, the pulsatility index (PI), as parameters. RESULT: In acute cellular rejection, there were no changes in blood flow in the segmental arteries, while there was a significant decrease in the blood flow in the interlobar artery. In acute vascular rejection, it was difficult to measure blood flow in the interlobar artery. The values of parameters were low even in the segmental arteries, suggesting markedly decreased blood flow. In chronic rejection, the values of the parameters were low in proportion to transplanted kidney function. In addition, parameters were examined with respect to vascular stenosis, fibrous stroma and edema in the histopathology of the transplanted kidney. As a result, vascular stenosis and fibrous stroma affected the segmental and interlobar arteries, severely reducing blood flow. It was also shown that interstitial edema reduced blood flow in the interlobar artery. CONCLUSION: Color Doppler tomography may facilitate diagnosis of certain conditions in the transplanted kidney biopsy.

Adult↗
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 protein B metabolism in newborn rabbits.

Surfactant protein B (SP-B) is critical to the biophysical function of surfactant. To characterize its metabolism in vivo in the newborn, we administered [35S]methionine and [3H]palmitate to newborn rabbits intravascularly. Three groups of 4 rabbits per group were killed at each of 4 time points followed by isolation of SP-B from alveolar wash and lamellar bodies. The labeling kinetics for alveolar wash associated SP-B and saturated phosphatidylcholine (Sat PC) had similar patterns. To characterize SP-B clearance from the airspace, rabbit SP-B was iodinated, mixed with [14C]dipalmitoylphosphatidylcholine and given by intratracheal injection. Alveolar washes and lamellar bodies were recovered from 4 animals at each of 7 time points. Both SP-B and Sat PC were cleared slowly from the total lung (half-life values approximately 25 h). However, SP-B was cleared more rapidly from the airspaces than was Sat PC. The ratio of [125I]SP-B to [14C]Sat PC in lamellar bodies increased 2-fold by 8 h. These results support the concept of linked secretion and clearance pathways for SP-B and Sat PC, although small differences in reuptake were detected.

1,2-Dipalmitoylphosphatidylcholine↗
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↗