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J B Warshaw

Publications and source records attributed to J B Warshaw.

At least 19 recordsLinked to original sources
PubMed1996

Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung.

By participating in glutathione (GSH) synthesis, gamma-glutamyl transpeptidase (GGT) influences the GSH redox cycle, which is a major contributor in protecting against reactive oxygen metabolites. This study determined the effect of prolonged exposure of neonatal rats to > 98% oxygen on expression of GGT and on GSH metabolism. Lungs of neonatal rats chronically exposed to hyperoxia had increased expression of GGT mRNA, resulting in significantly higher GGT protein levels and enzyme activity than in lungs of animals raised in room air. Hyperoxia also upregulated glucose-6-phosphate dehydrogenase, but Na-K-ATPase activity was not changed. GGT mRNA, protein level, and enzyme activity returned to control levels after recovery in room air for 3 days. Levels of GSH, glutathione disulfide, and protein-bound GSH (S-glutathiolated protein) rose with hyperoxia and fell during recovery. S-glutathiolation is likely a mechanism for protection and a regulatory modification of protein sulfhydryl groups. Hyperoxia-induced upregulation of GGT and the concomitant increase in protein S-glutathiolation appear to be additional components fundamental in protecting the lung against oxidative injury.

Animals↗
PubMed1995

Chronic hypoxia causes opposite effects on glucose transporter 1 mRNA in mature versus immature rat brain.

We have shown previously that chronic hypoxia can regulate the expression of membrane proteins. Since there are virtually no glucose stores in the brain and glucose transport can be rate-limiting during stress, the role of glucose transporters becomes crucial for cell survival under stress. In the present study, we asked whether mRNA levels for glucose transporter 1 (GT1), which is expressed in a variety of cells in the brain, especially in the microvessels for glucose transport from blood vessels to brain, change in response to chronic hypoxia. Because major developmental changes occur in the rat CNS in-utero and in the first few weeks postnatally, we studied brain GT1 mRNA using Northern blot analysis at different ages after exposure of fetuses (from embryonic day 10 to birth), developing rats (from birth to 30 day old) or adult rats (from 90 to 120 day old) to hypoxia (Fractional inspired O2 9%). Our data show that (i) GT1 mRNA level was much lower in the newborn than in the adult and increased with age; (ii) chronic hypoxia caused a decrease of approximately 65% in GT1 mRNA in adult brain but induced an increase in fetal (more than 50%) and developing (approximately 80%) rats and (iii) the response of housekeeping gene (glyceraldehyde 3-phosphate dehydrogenase) was not similar to that of GT1, suggesting that the changes of GT1 mRNA are specific to glucose transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Dexamethasone enhances surfactant protein gene expression in streptozotocin-induced immature rat lungs.

Because surfactant protein (SP) mRNA levels in rat fetuses are increased by maternal dexamethasone (dex) treatment and decreased in streptozotocin-induced diabetic (STZ-DB) pregnancy, we investigated the in vivo effects of dex on SP gene expression in STZ-DB pregnancy. The mRNA levels of SP (SP-A, SP-B, SP-C) were assessed in d 18 and 20 fetuses by Northern blot analysis, and nuclear run-on assays were performed with lung nuclei from d 20 fetuses (term = 22 d). Our findings indicate: 1) dex causes a greater increase in SP-A and SP-B mRNA levels in d 18 (12-16-fold) compared with day 20 (4-6-fold) fetuses (p < 0.05) in normal and STZ-DB pregnancy; 2) a 2-3-fold increase in SP-C mRNA levels was observed in response to dex in d 18 and 20 fetuses; 3) the increase in transcription of SP-A and SP-B in d 20 fetuses after dex is 68 and 60%, respectively, of the increase in their mRNA levels whereas in STZ-DB, the decrease in transcription compared with mRNA levels is 3.67-fold for SP-A and 2.42 fold SP-B; and 4) changes in SP-C transcription in either in vivo model, dex-treated or STZ-DB, correspond well with changes in mRNA levels. Together, these findings indicate that dex can enhance SP expression in STZ-DB immature lungs and support differential regulation of fetal SP genes in the models studied.

Animals↗
PubMed1994

Heat shock does not induce tolerance to hyperoxia.

Thermal stress is associated with the induction of a specific set of proteins called heat shock proteins and with the induction of thermal tolerance. Heat stress has been shown to be capable of inducing at least partial tolerance to other stresses, including some oxidant stresses. Furthermore, these oxidant stresses are reported to be inducers of heat shock proteins. We hypothesized that hyperoxic stress would induce heat shock proteins and that factors induced by thermal stress, including heat shock proteins, would offer at least partial protection from hyperoxic exposure. We were particularly interested in a level of protection that would be relevant to clinical situations. Lung fibroblasts and live animals were exposed to thermal stress and/or hyperoxic stress and examined for induction of HSP70 (the most conserved of the heat shock proteins) and for induced tolerance as determined by the ability of cells to metabolize 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and by comparison of lung wet to dry weight ratios in live animals. Each stress induced tolerance to itself, but there was no evidence of heat stress inducing tolerance to hyperoxic stress. Furthermore, there was only minimal induction of HSP70 mRNA by hyperoxic exposure. We conclude that some overlap of mechanisms of induced tolerance by hyperoxic and thermal stress exists, but that differences far outweigh similarities.

Animals↗
PubMed1992

Surfactant protein A expression is delayed in fetuses of streptozotocin-treated rats.

The content and distribution of the 26-to 38-kDa surfactant protein (SP-A) and its mRNA were determined in fetuses of control and streptozotocin (STZ)-treated Sprague-Dawley rats using immunohistochemistry, RNA blotting, and in situ hybridization. Female rats were treated with 50 mg/kg STZ before mating, and the fetuses were killed at fetal days 18-21 or on neonatal days 1 and 2 (day of birth = end of day 22). SP-A was barely detectable on fetal day 18 in controls and easily detected by fetal day 21. In the STZ group, SP-A was decreased compared with controls at fetal days 18-21. However, by neonatal days 1-2, there were no significant differences in SP-A levels between groups. SP-A mRNA was detectable at fetal day 18 in controls, but it was decreased in the STZ group at day 18-21 (P less than 0.02) and differences were no longer detected by neonatal days 1-2. SP-A and SP-A mRNA accumulated with advancing gestational age in both groups until neonatal days 1-2. The differences in SP-A and SP-A mRNA levels in the two groups diminished with advancing age but remained significant at fetal day 21. These data suggest that STZ-induced diabetes interferes with normal expression of SP-A in the developing fetal lung.

Animals↗
PubMed1992

Delayed hydrophobic surfactant protein (SP-B, SP-C) expression in fetuses of streptozotocin-treated rats.

Tissues from fetuses and neonates of control and streptozotocin (STZ)-treated Sprague-Dawley rats were used to study the content and distribution of the hydrophobic surfactant protein B (SP-B) and the mRNAs for SP-B and SP-C using immunohistochemistry, RNA blotting, and tissue in situ hybridization. A dose of 50 mg/kg STZ was used to treat female rats before mating. The fetuses were sacrificed at fetal days 18 through 21 and neonates were obtained on neonatal days 1 and 2 (day of birth = end of day 22). At fetal day 18, SP-B was barely detectable by immunohistochemistry in control animals but the levels were progressively increased through gestation and easily detected by fetal day 21. At all fetal ages, SP-B was decreased in the STZ group compared with control animals. Both SP-B and SP-C mRNA were detectable at fetal day 18 in the control group and increased with advancing gestational age. In fetal lungs from the STZ group, SP-B and SP-C mRNA also showed an increase with advancing gestational age, but the levels were decreased compared with controls at fetal days 18, 20, and 21 (P less than 0.05). At fetal day 19, this difference did not achieve statistical significance. Differences between the two groups were no longer detected by neonatal days 1 and 2. The difference between the STZ and control groups, in both protein (SP-B) and mRNA (SP-B and SP-C), diminished with advancing fetal age but remained significant up to fetal day 21.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1991

Effects of maternal diabetes on fetal rat lung ion transport. Contribution of alveolar and bronchiolar epithelial cells to Na+,K(+)-ATPase expression.

Fetuses of streptozotocin-induced diabetic rats exhibited delayed lung maturation and a 40% reduction in the steady-state level of lung Na+,K(+)-ATPase alpha 1 subunit mRNA and Na+,K(+)-ATPase activity at 21 d of gestation. In in situ hybridization experiments the signal specific for Na(+)-pump alpha 1 subunit message was strongest above columnar epithelial cells of air-conducting structures. Strong labeling was also present above cuboidal cells lining the forming alveoli, but not above mesenchymal cells. Immunocytochemical localization of the protein paralleled the distribution of the mRNA. Mesenchymal cells were more abundant in fetal lungs of diabetic mothers, and thus the decreased overall levels of Na+,K(+)-ATPase may result from the observed morphological pulmonary immaturity. One day after birth there was no apparent difference in lung morphology at the light microscopic level, in the localization or the steady-state level of Na+,K(+)-ATPase alpha 1 isoform mRNA, or in enzyme activity. Na+,K(+)-ATPase has a likely role in the active phase of fluid absorption in the airways of newborns before the onset of breathing. Decreased fluid clearance and lack of thinning of the lung's connective tissue may contribute to the increased risk for respiratory distress in infants of diabetic mothers.

Animals↗
PubMed1991

Nutritional perturbations in infants of diabetic mothers and intrauterine growth retardation.

The fetal nutritional milieu may have important regulatory influences on fetal growth and maturation. Fetuses of diabetics exposed to excessive glucose in late gestation show delayed maturation, whereas, fetuses subjected to nutrient deprivation resulting from decreased uterine blood flow exhibit restricted growth and accelerated maturation. Under conditions of nutrient deficiency, restricted growth and accelerated maturation may be important adaptations mediated through hormonal and growth factor signalling.

Animals↗
PubMed1990

Nutritional correlates of fetal growth.

Fetal growth is regulated by an interplay of genetic and environmental factors. Fetuses with growth restriction secondary to decreased nutritional supply exhibit maturation whereas hyperglycemic fetuses of diabetic mothers show delayed lung and placental maturation. Membranes from fetuses of diabetics have a decrease in epidermal-growth-factor (EGF) binding, whereas EGF binding is increased in lung and placenta of growth-restricted fetuses. These results suggest that the EGF receptor is responsive to altered nutritional states and may be important to substrate flow to the fetus.

Animals↗
PubMed1989

Increased binding of epidermal growth factor to placental membranes of intrauterine growth restricted fetal rats.

To examine the relationship between nutrient supply and fetal and placental growth, we examined epidermal growth factor (EGF) binding to membranes prepared from placentas of growth-restricted fetal rats. Intrauterine growth retardation was accomplished by unilateral ligation of the uterine artery; fetal rats on the contralateral uterine horn served as controls. Fetal growth restriction was accompanied by decreased placental wt at 19 and 20 day's gestation and significantly decreased placental glycogen content at 20 and 21 days, 30% and 15%, respectively. Placental DNA content and protein/DNA ratios were similar in the growth-restricted and control groups. Specific binding of 125I-EGF was increased in growth-restricted placentas at 19 and 20 days' gestation by 32% and 16%, respectively. 125I-EGF binding at 20-21 days increased linearly with the extent of placental growth restriction. Competitive binding experiments yielded linear Scatchard plots with an increased receptor density in growth-restricted placenta at 19 and 20 days' gestation, 74% and 60%, respectively. Binding affinities for the EGF receptor were similar in the two groups. The increased binding of EGF to membranes prepared from growth-restricted fetal rats may serve to enhance nutrient uptake under conditions of decreased uterine blood flow.

Animals↗
PubMed1989

Effect of hyperoxia on antioxidants in neonatal rat type II cells in vitro and in vivo.

Relative resistance to oxygen toxicity in newborn animals (compared to adults) has been associated with increased antioxidant enzymes and glutathione in lung homogenate. The cell type(s) involved in this increase is unknown. We investigated the effect of hyperoxia in vitro and in vivo on the following antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and glutathione) in alveolar type II cells from neonatal rats. Type II cells were exposed to 95% oxygen or air for 48 h in vitro. When expressed per microgram DNA, all the antioxidants except catalase increased during in vitro incubation; only glucose-6-phosphate dehydrogenase and glutathione increased when expressed per mg protein. None of the antioxidants was higher in oxygen-exposed cells than in air-exposed cells. Neonatal rats were exposed to 100% oxygen or air in vivo for 4 d before determination of antioxidants in lung homogenate supernatant and alveolar type II cells. Catalase, glutathione peroxidase, and glutathione reductase were higher but glucose-6-phosphate dehydrogenase and glutathione were lower in type II cells than in lung homogenate from control animals. Alveolar type II cell glucose-6-phosphate dehydrogenase and glutathione were increased but catalase and glutathione reductase were decreased by exposure to hyperoxia. We conclude that the oxygen-induced increase in whole lung antioxidants is not explained by alveolar type II cell hypertrophy or increased antioxidants within type II cells during hyperoxia.

Animals↗
PubMed1988

Rat lung antioxidant enzyme activities and their specific proteins during hyperoxia.

The hyperoxia-induced increases in the activity of lung glucose-6-phosphate dehydrogenase (G-6-P) and glutathione reductase (GR) after exposure of rats to greater than 97% O2 for 6 days were accompanied by equivalent increases in the amount of the respective immunoreactive proteins. Hyperoxia also increased lung glutathione (GSH) + oxidized glutathione (GSSG) content and the magnitude of this hyperoxic response of increased GSH + GSSG, G-6-P, and GR (maximal 1.3- to 1.8-fold) declined as a function of age during the first 3 wk of life. Fetal rat lung explants cultured 4 days in 95% O2 showed increased G-6-P and GR activity and increased levels of the specific proteins 1.5-fold those of explants at 2 days of culture. We conclude that the hyperoxic response of increased rat lung G-6-P and GR activity in vivo and in vitro involves not just alteration of enzyme activity but also specific increases in the proteins catalyzing the reactions.

Aging↗
PubMed1988

Control of fatty acid oxidation by intramitochondrial [NADH]/[NAD+] in developing rat small intestine.

The oxidation of palmityl-coenzyme A and acetate to CO2 by mitochondria isolated from rat small intestine increases 10-fold at the time of weaning (18-21 days of age). Carnitine palmitoyltransferase (EC 2.3.1.21) activity is 2-fold greater in mitochondria of suckling rat intestine compared to postweaned intestine. These data indicate that carnitine palmitoyltransferase does not control the increase in intestinal fatty acid oxidation during weaning. We have previously reported that the estimated intramitochondrial [NADH]/[NAD+] as determined by the ratio of tissue levels of 3-hydroxybutyrate and acetoacetate is fivefold greater in suckling rat intestine compared to postwean animals. High intramitochondrial [NADH]/[NAD+] which is present in suckling rat small intestine is associated with a decrease in citric acid cycle activity and beta oxidation. The addition of acetoacetate causes a decrease in intramitochondrial [NADH]/[NAD+]. The oxidation of acetate and glucose to CO2 by suckling rat intestine mitochondria was stimulated by the addition of 1 mM acetoacetate. These data suggest that the lower rate of fatty acid oxidation by suckling rat small intestine is controlled by elevated intramitochondrial [NADH]/[NAD+].

Animals↗
PubMed1987

Decreased binding of epidermal growth factor in placentas from streptozotocin-diabetic rats.

Placentas from streptozotocin-diabetic rats have previously been shown to be morphologically and biochemically immature when compared with those of control rats. The binding of epidermal growth factor (EGF) to plasma membranes prepared from placentas of control and streptozotocin-diabetic fetuses has been characterized on days 17 and 21 of gestation. Results from competitive binding data analyzed by Scatchard analysis indicate the presence of a single class of receptors on day 17 (KD = 5.4 X 10(-10)) and the appearance of a second class of binding sites for 125I-EGF by day 21 (Kd = 3.5 X 10(-9)) in membranes from control fetuses. Placental membranes from diabetic fetuses show decreased specific binding (approximately 30%) on both days and the absence of a second class of binding sites on day 21 of gestation. Results from a radioreceptor assay indicate that the quantity of EGF in the serum of fetuses removed from control rats on day 21 is twofold greater than the quantity in serum of fetuses from diabetic rats. These data reveal a developmental increase in EGF-binding sites in the placenta of normal, near-term fetal rats, largely because of the appearance of a second class of binding sites with a lower affinity for EGF. The failure (or delay) of this second class to develop in the diabetic may be important for the control of maturation and growth of this tissue.

Animals↗
PubMed1986

Fetal and maternal corticosterone and corticosteroid binding globulin in the diabetic rat gestation.

Delayed fetal lung development is a feature of the diabetic pregnancy. Since fetal glucocorticoids are important in the regulation of lung maturation, we measured corticosterone and corticosteroid-binding globulin binding capacity in streptozotocin-diabetic pregnant rats and their fetuses. Previous studies have demonstrated delayed fetal lung maturation in this animal model. In control fetuses, total corticosterone concentration increased through day 20 of gestation, then declined until day 22 (term). The unbound steroid, which accounted for 5-10% of the total, increased approximately 3-fold from day 18 to term. Corticosteroid-binding globulin binding capacity peaked on day 19 after which it decreased. Maternal total and unbound corticosterone levels and corticosteroid-binding globulin binding capacity remained relatively constant throughout the final week of normal gestation. When compared to controls, fetuses from diabetic pregnancies had significantly lower total corticosterone from day 19 through 22. Corticosteroid-binding globulin binding capacity was also significantly decreased in these fetuses for the last 4 days of gestation. Similar differences were noted in maternal samples. However, no significant differences in unbound, biologically active, corticosterone were seen when diabetic and control groups were compared. Thus, delayed fetal lung maturation observed in fetuses of streptozotocin-diabetic rats is associated with a decrease in total circulating corticosteroid levels late in gestation. However, since unbound corticosteroid levels were similar in fetuses of control and diabetic animals, it is likely that other mechanisms may be responsible for the observed delay in lung development in fetuses of diabetic pregnancies.

Animals↗