Intrafetal glucose infusion alters glucocorticoid signaling and reduces surfactant protein mRNA expression in the lung of the late-gestation sheep fetus

2014 ◽  
Vol 307 (5) ◽  
pp. R538-R545 ◽  
Author(s):  
Erin V. McGillick ◽  
Janna L. Morrison ◽  
I. Caroline McMillen ◽  
Sandra Orgeig
Keyword(s):  
Mrna Expression ◽  
Fetal Lung ◽  
Glucose Transporters ◽  
Surfactant Protein ◽  
Glucose Infusion ◽  
Late Gestation ◽  
Lung Maturation ◽  
Increased Risk ◽  
Sheep Fetus ◽  
Diabetic Mothers

Increased circulating fetal glucose and insulin concentrations are potential inhibitors of fetal lung maturation and may contribute to the pathogenesis of respiratory distress syndrome (RDS) in infants of diabetic mothers. In this study, we examined the effect of intrafetal glucose infusion on mRNA expression of glucose transporters, insulin-like growth factor signaling, glucocorticoid regulatory genes, and surfactant proteins in the lung of the late-gestation sheep fetus. The numerical density of the cells responsible for producing surfactant was determined using immunohistochemistry. Glucose infusion for 10 days did not affect mRNA expression of glucose transporters or IGFs but did decrease IGF-1R expression. There was reduced mRNA expression of the glucocorticoid-converting enzyme HSD11B-1 and the glucocorticoid receptor, potentially reducing glucocorticoid responsiveness in the fetal lung. Furthermore, surfactant protein ( SFTP) mRNA expression was reduced in the lung following glucose infusion, while the number of SFTP-B-positive cells remained unchanged. These findings suggest the presence of a glucocorticoid-mediated mechanism regulating delayed maturation of the surfactant system in the sheep fetus following glucose infusion and provide evidence for the link between abnormal glycemic control during pregnancy and the increased risk of RDS in infants of uncontrolled diabetic mothers.

scholarly journals Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation

2021 ◽  
Author(s):  
Erin V. McGillick ◽  
Sandra Orgeig ◽  
Beth J. Allison ◽  
Kirsty L. Brain ◽  
Youguo Niu ◽  
...  
Keyword(s):  
Vitamin C ◽  
Lung Development ◽  
Fetal Lung ◽  
Late Gestation ◽  
Lung Maturation ◽  
Maternal Vitamin ◽  
Healthy Pregnancy ◽  
Daily Vitamin ◽  
Expression Of Genes ◽  
Fetal Lung Maturation

Abstract Background In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. Methods We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105–138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. Results Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. Conclusions Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. Impact Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

Increased lung prolyl hydroxylase and decreased glucocorticoid receptor are related to decreased surfactant protein in the growth-restricted sheep fetus

2015 ◽  
Vol 309 (1) ◽  
pp. L84-L97 ◽  
Author(s):  
Sandra Orgeig ◽  
Erin V. McGillick ◽  
Kimberley J. Botting ◽  
Song Zhang ◽  
I. Caroline McMillen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mrna Expression ◽  
Transforming Growth Factor ◽  
Acute Hypoxia ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Prolyl Hydroxylase ◽  
Fetal Sheep ◽  
Chronic Hypoxemia ◽  
Hypoxia Signaling

Experimental placental restriction (PR) by carunclectomy in fetal sheep results in intrauterine growth restriction (IUGR), chronic hypoxemia, increased plasma cortisol, and decreased lung surfactant protein (SP) expression. The mechanisms responsible for decreased SP expression are unknown but may involve decreased glucocorticoid (GC) action or changes in hypoxia signaling. Endometrial caruncles were removed from nonpregnant ewes to induce PR. Lungs were collected from control and PR fetuses at 130–135 ( n = 19) and 139–145 ( n = 28) days of gestation. qRT-PCR and Western blotting were used to quantify lung mRNA and protein expression, respectively, of molecular regulators and downstream targets of the GC and hypoxia-signaling pathways. We confirmed a decrease in SP-A, -B, and -C, but not SP-D, mRNA expression in PR fetuses at both ages. There was a net downregulation of GC signaling with a reduction in GC receptor (GR)-α and -β protein expression and a decrease in the cofactor, GATA-6. GC-responsive genes including transforming growth factor-β1, IL-1β, and β2-adrenergic receptor were not stimulated. Prolyl hydroxylase domain ( PHD) 2 mRNA and protein and PHD3 mRNA expression increased with a concomitant increase in hypoxia-inducible factor-1α ( HIF-1α) and HIF-1β mRNA expression. There was an increase in mRNA expression of several, but not all, hypoxia-responsive genes. Hence, both GC and hypoxia signaling may contribute to reduced SP expression. Although acute hypoxia normally inactivates PHDs, chronic hypoxemia in the PR fetus increased PHD abundance, which normally prevents HIF signaling. This may represent a mechanism by which chronic hypoxemia contributes to the decrease in SP production in the IUGR fetal lung.

scholarly journals Liraglutide Enhances the Activity of the ACE-2/Ang(1–7)/Mas Receptor Pathway in Lungs of Male Pups from Food-Restricted Mothers and Prevents the Reduction of SP-A

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
J. Fandiño ◽  
A. A. Vaz ◽  
L. Toba ◽  
M. Romaní-Pérez ◽  
L. González-Matías ◽  
...  
Keyword(s):  
Lung Function ◽  
Mrna Expression ◽  
Food Restriction ◽  
Early Stage ◽  
Surfactant Protein ◽  
In Utero ◽  
Respiratory Morbidity ◽  
Alveolar Type ◽  
Lung Maturation ◽  
Positive Effects

In utero growth restriction and being born small for gestational age are risk factors for respiratory morbidity. IUGR (in utero growth retardation) is associated to overall reduction in lung weight, surfactant content and activity, impaired maturation of the alveolar type II cells, and decreased alveolar formation. The renin-angiotensin system (RAS) may be a key target underlying pathophysiological lung alterations. GLP-1 and agonists of its receptor modulate the expression levels of different components of RAS and also are very important for lung maturation and the production of surfactant proteins. The aim of this study was to elucidate the effects of IUGR induced by perinatal food restriction of the mother in the lung function of pups at early stages of life (PD21) and to determine if liraglutide had any effect during gestational period. Sprague-Dawley pregnant rats were randomly assigned to 50% food restriction (MPFR) or ad libitum control (CT) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant MPFR and CT rats were treated with liraglutide or vehicle. At postnatal day 21 and before weaning, 20 CT and 20 FR male pups were sacrificed and lungs were analyzed by RT-PCR. Liraglutide restored surfactant protein A (SP-A) mRNA expression in pup lungs from food-restricted mothers. Surfactant protein B (SP-B) mRNA expression is not affected by neither IUGR nor liraglutide treatment. Moreover, liraglutide modulated different elements of RAS, increasing angiotensin-converting enzyme 2 (ACE2) and MasR mRNA expression only in pups from food-restricted mothers (MPFR), despite food restriction had not any direct effect at this early stage. Liraglutide also increased endothelial nitric oxide synthase (eNOS) expression in MPFR lungs, reflecting the activation of MasR by angiotensin 1–7. In conclusion, liraglutide prevented the alteration in lung function induced by IUGR and promoted the positive effects of ACE2-Ang(1–7)-MasR in restoring lung function.

Oxygen modulates surfactant protein mRNA expression and phospholipid production in human fetal lung in vitro

1995 ◽  
Vol 268 (5) ◽  
pp. L818-L825 ◽  
Author(s):  
M. J. Acarregui ◽  
J. J. Brown ◽  
R. K. Mallampalli
Keyword(s):  
Mrna Expression ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Mrna Levels ◽  
Choline Incorporation ◽  
Associated Proteins ◽  
Dependent Protein ◽  
Surfactant Composition ◽  
Human Fetal Lung

We studied the effect of 20-95% O2 on mRNA levels for the surfactant-associated proteins (SP)-A, SP-B, and SP-C and [3H]choline incorporation into total phosphatidylcholine and type II cell-specific disaturated phosphatidylcholine (DPPC) in human fetal lung in culture. SP-A mRNA levels were increased by 25 and 39% in lung explants incubated in 70 and 95% O2, respectively, compared with levels in tissues incubated in 20% O2. SP-B mRNA levels were unaffected by O2, whereas SP-C mRNA levels were increased by 85, 102, and 115% in atmospheres of 35, 50, and 70% O2, respectively. [3H]choline incorporation into total phosphatidylcholine and DPPC were both increased in human fetal lung explants incubated in increased O2 concentrations compared with tissues incubated in 20% O2. Tissue levels of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) activity were not affected by O2 concentration, implying that the changes observed in SP mRNA levels and [3H]choline incorporation may not be mediated through alterations in PKA enzyme activity. These findings demonstrate that O2 regulates SP mRNA expression and phospholipid production in human fetal lung in vitro. We speculate that surfactant composition and possibly function may be regulated by O2 in human lung.

Differential regulation of suppressor of cytokine signaling-3 in the liver and adipose tissue of the sheep fetus in late gestation

2006 ◽  
Vol 290 (4) ◽  
pp. R1044-R1051 ◽  
Author(s):  
Sheridan Gentili ◽  
Michael J. Waters ◽  
I. Caroline McMillen
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Late Gestation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Perirenal Adipose Tissue ◽  
Plasma Prl ◽  
Sheep Fetus

It is unknown whether the JAK/STAT/suppressor of cytokine signaling-3 (SOCS-3) intracellular signaling pathway plays a role in tissue growth and metabolism during fetal life. We investigated whether there is a differential profile of SOCS-3 expression in the liver and perirenal adipose tissue during the period of increased fetal growth in late gestation and the impact of fetal growth restriction on SOCS-3 expression in the fetal liver. We also determined whether basal SOCS-3 expression in the fetal liver and perirenal adipose tissue is regulated by endogenous fetal prolactin (PRL). SOCS-3 mRNA abundance was higher in the liver than in the pancreas, spleen, and kidney of the sheep fetus during late gestation. In the liver, SOCS-3 mRNA expression was increased ( P < 0.05) between 125 ( n = 4) and 145 days ( n = 7) gestation and lower ( P < 0.05) in growth-restricted compared with normally grown fetal sheep in late gestation. The relative expression of SOCS-3 mRNA in the fetal liver was directly related to the mean plasma PRL concentrations during a 48-h infusion of either a dopaminergic agonist, bromocriptine ( n = 7), or saline ( n = 5), such that SOCS-3 mRNA expression was lower when plasma PRL concentrations decreased below ∼20 ng/ml [ y = 0.99 − (2.47/ x) + (4.96/ x2); r2 = 0.91, P < 0.0001, n = 12]. No relationship was shown between the abundance of phospho-STAT5 in the fetal liver and circulating PRL. SOCS-3 expression in perirenal adipose tissue decreased ( P < 0001) between 90–91 ( n = 6) and 140–145 days ( n = 9) gestation and was not related to endogenous PRL concentrations. Thus SOCS-3 is differentially expressed and regulated in key fetal tissues and may play an important and tissue-specific role in the regulation of cellular proliferation and differentiation before birth.

scholarly journals Intrafetal Insulin-Like Growth Factor-I Infusion Stimulates Adrenal Growth But Not Steroidogenesis in the Sheep Fetus during Late Gestation

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5424-5432 ◽  
Author(s):  
J. T. Ross ◽  
I. C. McMillen ◽  
F. Lok ◽  
A. G. Thiel ◽  
J. A. Owens ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Adrenal Cortex ◽  
Plasma Cortisol ◽  
Zona Glomerulosa ◽  
Late Gestation ◽  
Zona Fasciculata ◽  
Synthetic Enzymes ◽  
Fetal Plasma ◽  
Igf I ◽  
Sheep Fetus

We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 μg/kg·h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.

Ovine surfactant protein cDNAs: use in studies on fetal lung growth and maturation after prolonged hypoxemia

2000 ◽  
Vol 278 (4) ◽  
pp. L754-L764 ◽  
Author(s):  
Geert A. Braems ◽  
Li-Juan Yao ◽  
Kevin Inchley ◽  
Anne Brickenden ◽  
Victor K. M. Han ◽  
...  
Keyword(s):  
Pulmonary Surfactant ◽  
Specific Binding ◽  
Fetal Lung ◽  
Surfactant Protein ◽  
Mrna Levels ◽  
Fetal Hypoxia ◽  
Lung Maturation ◽  
Igf I ◽  
Surfactant Apoprotein ◽  
Mild Hypoxia

cDNAs for ovine surfactant-associated protein (SP) A, SP-B, and SP-C have been cloned and shown to possess strong similarity to cDNAs for surfactant apoproteins in other species. These reagents were employed to examine the effect of fetal hypoxia on the induction of surfactant apoprotein expression in the fetal lamb. Postnatal lung function is dependent on adequate growth and maturation during fetal development. Insulin-like growth factor (IGF) I and IGF-II, which are present in all fetal tissues studied, possess potent mitogenic and proliferative actions, and their effects can be modulated by IGF-specific binding proteins (IGFBPs). Hypoxia can lead to increases in circulating cortisol and catecholamines that can influence lung maturation. Therefore, the effects of mild hypoxia in chronically catheterized fetal lambs at gestational days 126– 130 and 134– 136 (term 145 days) on the expression of pulmonary surfactant apoproteins and IGFBPs were examined. Mild hypoxia for 48 h resulted in an increase in plasma cortisol that was more pronounced at later gestation, and in these animals, there was a twofold increase in SP-A mRNA. SP-B mRNA levels also increased twofold, but this was not significant. SP-C mRNA was not altered. No significant changes in apoprotein mRNA were observed with the younger fetuses. However, these younger animals selectively exhibited reduced IGFBP-5 mRNA levels. IGF-I mRNA was also reduced at 126–130 days, although this conclusion is tentative due to low abundance. IGF-II levels were not affected at either gestational age. We conclude that these data suggest that mild prolonged fetal hypoxia produces alterations that could affect fetal cellular differentiation early in gestation and can induce changes consistent with lung maturation closer to term.

scholarly journals Leptin receptor expression in fetal lung increases in late gestation in the baboon: a model for human pregnancy

Reproduction ◽  
2004 ◽  
Vol 127 (1) ◽  
pp. 87-94 ◽  
Author(s):  
M C Henson ◽  
K F Swan ◽  
D E Edwards ◽  
G W Hoyle ◽  
J Purcell ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Late Pregnancy ◽  
Fetal Lung ◽  
Transcript Abundance ◽  
Receptor Expression ◽  
Late Gestation ◽  
Receptor Protein ◽  
Lung Maturation ◽  
Primate Model ◽  
Human Pregnancy

Leptin produced by both adipose tissue and the placental trophoblast, has been proposed to regulate numerous aspects of human conceptus development. Although recent animal studies have suggested an additional role for the polypeptide in fetal lung maturation, no evidence has been reported in primates. Therefore, we employed the baboon (Papio sp.), a well-characterized primate model for human pregnancy, to determine the presence and ontogeny of leptin receptor in fetal lung with advancing gestation. Lungs were collected from fetal baboons, early in gestation (days 58–62, n = 4), at mid gestation (days 98–102, n = 4), and late in gestation (days 158–165, n = 4) (term 184 days). mRNA transcripts for leptin (LEP) and both long and short intracellular domain isoforms of the leptin receptor (LEP-RL and LEP-RS) were assessed by RT-PCR. leptin receptor protein was evaluated by immunoblotting and cell types expressing leptin receptor were identified in late pregnancy by immunohistochemistry. Fetal serum leptin concentrations, determined by RIA, remained relatively unchanged at 5.7 ± 1.1 ng/ml (mean ± s.e.m.) in mid pregnancy and 8.4 ± 3.0 ng/ml in late pregnancy (P > 0.05). Although leptin were detectable in fetal lung, no changes in transcript abundance were apparent with advancing gestation. However, transcripts for both LEP-RL and LEP-RS receptor isoforms increased several-fold (P < 0.05) in fetal lung between mid and late gestation, while leptin receptor protein was detectable only in late pregnancy. leptin receptor was localized in distal pulmonary epithelial cells, including type II pneumocytes. In conclusion, leptin is present in the fetal baboon and its receptor is enhanced during late gestation in cells responsible for the synthesis of pulmonary surfactant. Collectively, these and past findings may suggest a modulatory role for the polypeptide in pulmonary development and/or may identify leptin receptor as a physiological marker of primate fetal lung maturity.

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