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Biomedical subjects

I Gross

Publications and source records attributed to I Gross.

At least 55 records · Page 3Linked to original sources
PubMed1989

Congenital lobar emphysema. The roles of CT and V/Q scan.

An infant with congenital lobar emphysema of the left upper lobe presented with unusually severe mediastinal shift and underwent computed tomography (CT) and radionuclide V/Q scans. The V/Q scan confirmed the non-functioning nature of the hyperinflated lobe while the CT scan depicted the abnormal anatomy as well as the normal morphologic characteristics of the remaining lung thus allowing for safe and appropriate surgical management.

Emphysema↗
PubMed1989

Initiation of fetal rat lung phospholipid and surfactant-associated protein A mRNA synthesis.

To determine whether the initiation of fetal lung surfactant phospholipid production and the activation of the gene for the 35-kD surfactant-associated protein are dependent on circulating corticosteroids, we cultured dexamethasone-responsive explants of 15- to 17-d fetal rat lung in medium with 1% FCS (controls), charcoal-stripped 1% FCS, or a variety of glucocorticoid antagonists. The steroid antagonist RU 486 almost completely abolished specific cytoplasmic and nuclear dexamethasone binding in the explants but had no glucocorticoid-agonist activity. There was a significant increase in disaturated phosphatidylcholine synthesis during 7 d in culture in control explants (78%) and in those cultured with Charcoal-stripped serum (83%), RU 486 (82%), or the other glucocorticoid antagonists--clotrimazole, cortexelone, and 11-ketoprogesterone. Specific mRNA for surfactant-associated protein A was not detectable in preculture 17-d lung tissue, but accumulated to the same extent in cultures with or without RU 486 in the medium. These findings support the view that expression of the genes responsible for the synthesis of the various components of surfactant is not induced by glucocorticoids, but by signals contained within the lung tissue itself. The role of circulating hormones is later acceleration and modulation of surfactant production.

Animals↗
PubMed1989

Survival of infants with persistent pulmonary hypertension without extracorporeal membrane oxygenation.

A retrospective evaluation was performed of the survival after conservative therapy of infants with persistent pulmonary hypertension who met the published criteria of Bartlett et al (Pediatrics. 1985;76:479-487) or Short et al (Clinics in Perinatology. 1987;14:737-748) for extracorporeal membrane oxygenation (ECMO) therapy. An 80% to 90% mortality rate can be predicted with these criteria, which are based on historical data, if ECMO is not used. The records of infants with the diagnosis of persistent pulmonary hypertension, weighing greater than 2 kg at birth and who were treated during two time periods, January 1980 to December 1981 [23 patients] and January 1986 to December 1988 [17 patients], were reviewed. During the earlier period, hyperventilation was the mainstay of our therapy, whereas during the later period, a more conservative approach (avoidance of hyperventilation) was adopted. In 1980 to 1981, 1 of the 6 patients (17%) who were eligible for ECMO by criteria of Bartlett et al survived, which is consistent with the published data. However, in 1986 to 1988, 9 of 10 ECMO-eligible patients (90%) survived (P less than .02). The corresponding survival figures using the alveolar-arterial oxygen difference criteria of Short et al were 0 of 5 survivors (0%) in 1980 to 1981 and 8 of 9 (89%) in 1986 to 1988 (P less than .006). These data indicate that approximately 90% of patients who are candidates for ECMO now survive in our institution without the use of that therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Birth Weight↗
PubMed1988

Activities of enzymes of phospholipid and fatty acid synthesis in fetal and adult rat type II pneumocytes.

Although differentiated fetal and adult type II pneumocytes are ultrastructurally similar, it is not known whether there are metabolic differences between them. We measured the activities of selected enzymes of phospholipid and fatty acid synthesis in fetal and adult rat type II cells, in late gestation fetal rat lung explants and in intact lung from rat fetuses of comparable gestational age. The activity of 1-acylglycerophosphocholine acyltransferase was significantly greater in adult type II cells than in fetal type II cells, fetal explants or intact fetal lung. The activity of CDP diacylglycerol:glycerol-3-phosphate 3-phosphatidyltransferase was similar in fetal and adult type II cells, but significantly lower in explants and intact fetal lung. There was a significant positive correlation between the percentage of alveolar epithelial cells in the cultures and tissue studied and CDP diacylglycerol:glycerol-3-phosphate 3-phosphatidyltransferase activity. This suggests that the previously reported correlation between phosphatidylglycerol synthesis and the percentage of alveolar epithelial cells in various lung culture systems may be related to the activity of this enzyme. Phosphatidylglycerol synthesis and CDP diacylglycerol:glycerol-3-phosphate 3-phosphatidyltransferase activity may be metabolic markers of type II cells, whereas the acyltransferase activity may be an indicator of type II cell maturation.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1988

Prevention of respiratory distress syndrome: synergistic therapies.

Postnatal surfactant therapy, antenatal glucocorticoid therapy and now antenatal combined hormone therapy with glucocorticoids and TRH all appear to be effective in reducing the incidence of RDS or in ameliorating the severity of this condition. There is also evidence from animal and human studies that a combination of hormone therapy and surfactant therapy is more effective than either therapy alone. If the current trials of combined hormone therapy for the prevention of RDS continue to produce encouraging results, it is likely that in the near future threatened premature delivery before 33 weeks will be treated with tocolytics and a combination of glucocorticoid and TRH therapy. This is likely to be followed with prevention or rescue surfactant therapy. These new approaches should have a major impact in reducing the mortality and morbidity associated with premature birth.

Animals↗
PubMed1988

Prevention of respiratory distress syndrome.

RDS continues to be a major problem for premature infants despite a better understanding of its pathophysiology and of ways to try to prevent it. To date, prenatal administration of glucocorticoids has been the most widely used method of accelerating fetal lung development. However, several limitations of this therapy have prompted the search for alternative approaches. Most efforts have focused on the potential use of combined hormonal therapy with glucocorticoids and either thyroid hormones or TRH. The easy transplacental passage of the latter tends to favor its use. The use of hormonal therapy prenatally and surfactant administration at birth appears currently to be the best approach to prevent RDS. The greatest benefit would clearly come from the prevention of prematurity (Fig 1), but this has not proved to be an easy task.

Adrenal Cortex Hormones↗
PubMed1987

Culture of differentiated and undifferentiated type II cells from fetal rat lung.

We have developed a relatively simple and reproducible method for the isolation and culture of both differentiated and undifferentiated type II cells from fetal rat lung. The technique involves an initial period of explant culture in serum and hormone free medium, followed by enzymatic dissociation of the explants, differential adhesion to remove fibroblasts, incubation of the cell pellet to promote aggregation of the type II cells and monolayer culture of the type II cells. The type II cells form clusters which are surrounded by scattered fibroblasts. When the technique was performed with three differential adhesion steps, cultures contained 86.0 +/- 1.4% type II cells. To obtain a higher degree of purity and greater yield, two differential adhesions followed by gentle trypsinization of the cultures which selectively removes the isolated fibroblasts was performed. This resulted in cultures with 89.4 +/- 1.7% type II cells. The differentiated fetal type II cell cultures were prepared from 19-day fetal rat lungs which were initially maintained in explant culture for 48 h. These differentiated cells demonstrated the characteristic morphologic features of type II cells including lamellar bodies and microvilli. Undifferentiated fetal cells were prepared in a similar manner from 18-day fetal rat lung maintained in explant culture for 24 h. These cells did not contain intracellular osmiophilic granules; the appearance of these granules could, however, be induced by hormones. For this reason they are considered to be pre-type II cells. The viability of the cultured cells was 97%. Both the differentiated and undifferentiated fetal type II cells specifically bound the Maclura pomifera lectin, a type II cell surface marker. The phospholipid profile of the fetal cells was similar to that of adult rat type II cells; the differentiated fetal cells, however, synthesized less phosphatidylcholine than the adult cells did, but more than the undifferentiated fetal cells. The differentiated fetal cells secreted phosphatidylcholine at a basal rate of 0.6% +/- 0.1% during a 90-min incubation. There was dose-dependent stimulation of phosphatidylcholine secretion after exposure to terbutaline. Maximum stimulation (76%) was observed at a concentration of 10 microM. This culture system provides a valuable model for studies of the maturation of the undifferentiated fetal type II cell and surfactant metabolism and secretion in the differentiated fetal type II cell.

Acetates↗
PubMed1987

The biochemistry of fetal lung development.

Surfactant therapy for RDS is likely to become widespread in the near future. Animal data indicate that this will not preclude a role for hormonal acceleration of lung maturation. In studies with prematurely delivered and ventilated fetal rabbits, Fiascone et al. have shown that the administration of betamethasone antenatally improves lung compliance, as does intratracheal administration of excess amounts of adult rabbit natural surfactant. If the two therapies are combined, however, an additive effect is observed. This suggests that some of the effects of glucocorticoids on lung compliance are not related to surfactant. Prior glucocorticoid therapy may provide a benefit that differs from that of surfactant therapy because steroids mature the lungs anatomically and enhance nonsurfactant-related tissue compliance. It is also possible that surfactant therapy itself may be more effective in the presence of larger and increased numbers of alveoli. It thus seems likely that in the future both hormonal enhancement of lung maturation and surfactant therapy may be used in combination to further reduce the morbidity and mortality from RDS.

Animals↗
PubMed1986

Glucocorticoid stimulation of choline-phosphate cytidylyltransferase activity in fetal rat lung: receptor-response relationships.

A number of previous studies using in vivo and cultured fetal lung models have shown that the activity of choline-phosphate cytidylyltransferase, the enzyme which catalyzes a rate-limiting reaction in de novo phosphatidylcholine synthesis, is increased by glucocorticoids and other hormones which accelerate fetal lung maturation. To examine the mechanism of this glucocorticoid action further, we examined the effect of dexamethasone on cytidylyltransferase activity in cultured fetal rat lung explants and related it to specific dexamethasone binding. Dexamethasone stimulated cytidylyltransferase activity in the homogenate, microsomal and 105,000 X g supernatant fractions. The hormone did not alter the subcellular distribution of the enzyme, however; the bulk of the activity was in the supernatant fraction in both the control and dexamethasone-treated cultures. The dose-response curves for stimulation of cytidylyltransferase activity in the supernatant fraction and specific nuclear binding of dexamethasone were similar and both plateaued at approx. 20 nM. The EC50 for cytidylyltransferase stimulation was 6.6 nM and the Kd for dexamethasone binding was 6.8 nM. The relative potencies of various steroids for stimulating choline-phosphate cytidylyltransferase and for specific nuclear glucocorticoid binding were the same: dexamethasone greater than cortisol = corticosterone = dihydrocorticosterone greater than progesterone. The stimulation by dexamethasone of cytidylyltransferase activity and of choline incorporation into phosphatidylcholine were both abolished by actinomycin D. These data show that the stimulatory effect of dexamethasone on fetal rat lung choline-phosphate cytidylyltransferase activity is largely on the enzyme in the supernatant fraction and does not involve enzyme translocation to the microsomes as has been reported for cytidylyltransferase activation in some other systems. This effect of dexamethasone is a receptor-mediated process dependent on RNA and protein synthesis.

Animals↗
PubMed1986

Influence of epidermal growth factor on fetal rat lung development in vitro.

Epidermal growth factor (EGF) has been shown to enhance cell multiplication or differentiation in a number of developing tissues. We have examined the effects of this growth factor on the biochemical development of explants of fetal rat lung, cultured in serum-free medium for 48 h. EGF enhanced the rate of choline incorporation into phosphatidylcholine and disaturated phosphatidylcholine in a dose dependent fashion. Half maximal stimulation occurred at a concentration of 1.0 nM, similar to the Kd for EGF binding to rat lung cell membranes. There was also significant stimulation of acetate incorporation into all phospholipids, particularly phosphatidylglycerol (539%), and increased distribution of radioactivity from acetate in this phospholipid fraction. Exposure to EGF stimulated PC synthesis in 18- and 19-day explants (term is 22 days) whereas maximal enhancement of DNA synthesis occurred after this time. This sequence differs from that observed during early embryonic development when EGF initially enhances cell multiplication. An additive interaction with regard to enhancement of PC synthesis was observed with EGF and thyroid hormone, but not EGF and dexamethasone. EGF had no effect on the activity of the enzymes of the choline incorporation pathway of phosphatidylcholine synthesis or on the activity of enzymes involved with acidic phospholipid synthesis. Fetal lung EGF content and EGF binding capacity were not increased by glucocorticoid treatment and similarly glucocorticoid binding capacity was not increased by EGF. These data indicate that EGF enhances fetal rat lung phospholipid synthesis in a dose-dependent manner and suggest that this is a direct effect on the lung tissue mediated by specific receptors.

Animals↗
PubMed1986

Response of the maternal, fetal, and neonatal pituitary-thyroid axis to thyrotropin-releasing hormone.

Thyrotropin releasing hormone (TRH) readily crosses the placenta and stimulates the fetal pituitary. We studied the response of the maternal and fetal pituitary-thyroid axes to TRH and the influence of prenatal exposure to TRH on the physiological postnatal increase in thyrotropin (TSH) and triiodothyronine (T3) in the neonate. Twenty-six pregnant women received TRH (400 or 600 micrograms) intravenous or saline (controls) either 2 or 12 h before elective cesarean section at term. Administration of 400 micrograms of TRH resulted in significant elevations of maternal TSH (15.7 +/- 2.9 versus 3.2 +/- 0.4 microU/ml, p less than 0.01) and prolactin (416 +/- 94 versus 223 +/- 41 ng/ml, p less than 0.05) 2 h later. Maternal T3 remained unchanged. A higher dose of TRH (600 micrograms) produced comparable results. Maternal administration of TRH (400 micrograms) 2 h before delivery resulted in significant increases in fetal TSH and T3 over controls (21.1 +/- 3.7 versus 4.8 +/- 1.0 microU/ml, and 132 +/- 12 versus 64 +/- 9 ng/dl, p less than 0.01, respectively). Cord blood hormone levels 12 hours after TRH administration were similar to controls. Higher doses of TRH did not produce further increases in fetal TSH or T3. Control and treated neonates demonstrated similar physiological postnatal increases in TSH and T3, suggesting that prior exposure to TRH did not blunt this response. These data suggest that maternal administration of TRH is an effective way of increasing fetal T3 levels, and that this treatment does not inhibit the postnatal surge in TSH and T3.

Female↗
PubMed1985

Influence of theophylline on fetal rat lung phosphatidylcholine synthesis in vivo.

In an attempt to resolve conflicting reports on the effectiveness of theophylline in stimulating fetal lung surfactant production in vivo, we examined the influence of theophylline on fetal rat lung phosphatidylcholine synthesis. Intraperitoneal administration of theophylline to the pregnant rat produced elevated serum levels in both mother and fetus. The fetal:maternal ratio was 0.85:0.90. Doses of theophylline ranging between 5 and 180 mg/kg/day resulted in no increase in the rate of incorporation of choline into phosphatidylcholine or its disaturated species. There was also no increase in the lung tissue concentration of these phospholipids. Theophylline does not appear to stimulate fetal rat lung phosphatidylcholine synthesis at nontoxic serum levels.

Animals↗
PubMed1985

Delayed pulmonary maturation in the fetus of the streptozotocin-diabetic rat.

Pulmonary maturation was studied in fetuses in streptozotocin-diabetic rats on the final four days of gestation. Diabetes was induced prior to conception by the intravenous injection of streptozotocin. Fetuses were hyperglycemic but did not manifest hyperinsulinemia. Whole lung total phospholipid, phosphatidylcholine, and disaturated phosphatidylcholine were significantly decreased in the diabetic group on day 21 (term = 22 days), but not prior to or after that point in gestation. Morphologic analysis also revealed a decreased number of type II cells and lamellar bodies per alveolar lining cell in the diabetic group only on day 21, coincident with the changes in phospholipid analysis. Activities of enzymes involved in fetal pulmonary phospholipid synthesis were measured to see if differences could account for the observed developmental delay. No significant differences between diabetic and control lungs were noted in any of the enzymes studied from days 20-22, with the exception of an increase in cholinephosphate cytidylyltransferase activity in the diabetic fetuses on day 22. Immaturity in both biochemical and morphologic indices of lung development was present at a specific time late in the diabetic rat gestation. This maturational delay could not be accounted for by changes in the activities of enzymes involved in phospholipid synthesis. The fetus of the streptozotocin-diabetic rat provides a useful model to study the effects of hyperglycemia on fetal lung development.

Animals↗
PubMed1984

Corticosteroid binding by fetal rat and rabbit lung in organ culture.

To further characterize glucocorticoid action in fetal lung cells, we investigated corticosteroid metabolism and binding in explants of fetal rat and rabbit lung. Cortisone (E) was concerted to cortisol (F) and bound by receptor with a time course only somewhat slower than for F. Production of F (0.243 pmol/min/mg DNA) was the same in male and female rabbits and was not affected by prior exposure to glucocorticoid in utero or in culture. The t 1/2 for dissociation of nuclear-bound [3H]F was 84 min on changing the culture medium and 21 min on addition of excess non-labeled dexamethasone. Dissociation of [3H]dexamethasone was approx 5-fold slower by both procedures. The KD for nuclear binding of dexamethasone, F, E, and corticosterone in rabbit lung were 0.7, 7.3, 6.8 and 70.6 nM, respectively. In rat lung, the KD for dexamethasone was 6.8 nM. The concentrations of dexamethasone and F required for half-maximal stimulation of phosphatidylcholine synthesis were similar to the KD values. Dexamethasone binding capacity (sites/mg DNA) increased with age in both rat (+103% increase from day 16 to 22) and rabbit (+47% between day 23 and 30). Receptor concentration was the same in both sexes, and there were no developmental changes in non-specific binding, nuclear:cytoplasmic distribution, or KD. In 27-day rabbit fetuses, the rate of choline incorporation was higher in lungs with greater binding capacity. We conclude that (1) E is rapidly converted to F in rabbit lung to become an active glucocorticoid, whereas corticosterone probably has little physiologic activity, (2) there is a species difference in the affinity of dexamethasone binding which is reflected in responsiveness (3) there is no difference between sexes in E conversion, receptor capacity, or phosphatidylcholine synthesis, and (4) the concentration of binding sites per lung cell increases during fetal development. We suggest that developmental increases in both F production and receptor may be important factors in the expression of endogenous glucocorticoid effects.

Animals↗
PubMed1984

Glucocorticoid-thyroid hormone interactions in fetal rat lung.

Previous studies have shown that triiodothyronine (T3) enhances the effect of dexamethasone on phosphatidylcholine (PC) synthesis in organ cultures of fetal rat lung. The aim of this study was to investigate whether similar interactions occurred in vivo and to explore possible mechanisms for this phenomenon. Injection of 7.0 mg/kg T3 into pregnant rats on d 18 and 19 of gestation resulted in a mean fetal serum T3 level of 2380 ng/dl on d 20 (control, 84 ng/dl) and in maximal (34%) stimulation of choline incorporation into PC. Injection of 1.0 mg/kg betamethasone using the same protocol as for T3 resulted in maximal stimulation of 33% and administration of both hormones together produced a 69% increase, an additive affect. The percentage of PC that was disaturated was increased with betamethasone, but decreased with T3. Betamethasone treatment resulted in an increase in the whole lung disaturated PC content, but treatment with T3 did not. Betamethasone administration also increased fetal serum T3 levels, but T3 injection did not produce elevated fetal serum corticosterone levels. Injection of T3 in vivo, or exposure of explants of 18-d fetal lung to 100 nm T3 for up to 48 h did not result in an increase in cytoplasmic glucocorticoid binding or nuclear translocation of the receptor steroid complex. Exposure of explants to glucocorticoid or T3 in vivo or in culture (dexamethasone, 100 nM and T3, 100 nM; for 48 h) resulted in a significant increase in the activity of cholinephosphate cytidylyltransferase, an enzyme in the choline incorporation pathway of PC synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Fetal rat lung maturation: initiation and modulation.

The purpose of this study was to determine whether a rise in the level of circulating hormones is responsible for initiating fetal lung maturation. Explants of 13- to 20-day fetal rat lung were cultured in a constant chemically defined medium containing 0 or 1% serum. Growth, morphological maturation, and two biochemical markers of lung development, disaturated phosphatidylcholine (DSPC) synthesis and specific nuclear glucocorticoid binding, showed evidence of continuing development in culture. There is normally a marked increase in DSPC content and in the rate of choline incorporation into DSPC after 20 days gestation. Regardless of the gestational age of the fetal lungs used, there was a similar increase in culture at an equivalent gestational age of 20 days (e.g., 14-day lung after 6 days, 16-day lung after 4 days). Removal of 50 or 75% of the lung mesenchymal tissue at the initiation of the culture period did not prevent the increase in choline incorporation. Since the culture environment was constant and contained virtually no hormones, we conclude that the stimulus for the initiation of fetal lung maturation is most likely located in the lung tissue itself. The role of circulating hormones is probably later modulation of the maturational process.

Animals↗