Leptin does not influence surfactant synthesis in fetal sheep and mice lungs

In the fetus, leptin in the circulation increases at late gestation and likely influences fetal organ development. Increased surfactant by leptin was previously demonstrated in vitro using fetal lung explant. We hypothesized that leptin treatment given to fetal sheep and pregnant mice might increase surfactant synthesis in the fetal lung in vivo. At 122–124 days gestational age (term: 150 days), fetal sheep were injected with 5 mg of leptin or vehicle using ultrasound guidance. Three and a half days after injection, preterm lambs were delivered, and lung function was studied during 30-min ventilation, followed by pulmonary surfactant components analyses. Pregnant A/J mice were given 30 or 300 mg of leptin or vehicle by intraperitoneal injection according to five study protocols with different doses, number of treatments, and gestational ages to treat. Surfactant components were analyzed in fetal lung 24 h after the last maternal treatment. Leptin injection given to fetal sheep increased fetal body weight. Control and leptin-treated groups were similar in lung function (preterm newborn lamb), surfactant components pool sizes (lamb and fetal mice), and expression of genes related to surfactant synthesis in the lung (fetal mice). Likewise, saturated phosphatidylcholine and phospholipid were normal in mice lungs with absence of circulating leptin (ob/ob mice) at all ages. These studies coincided in findings that neither exogenously given leptin nor deficiency of leptin influenced fetal lung maturation or surfactant pool sizes in vivo. Furthermore, the key genes critically required for surfactant synthesis were not affected by leptin treatment.

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Betamethasone-mediated vascular dysfunction and changes in hematological profile in the ovine fetus

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.276.4.h1137 ◽

1999 ◽

Vol 276 (4) ◽

pp. H1137-H1143 ◽

Cited By ~ 18

Author(s):

M. A. Anwar ◽

M. Schwab ◽

L. Poston ◽

P. W. Nathanielsz

Keyword(s):

Vascular Resistance ◽

Vascular Dysfunction ◽

Hematological Parameters ◽

Pressure Rise ◽

Fetal Lung ◽

Systemic Blood Pressure ◽

Lung Maturation ◽

Fetal Sheep ◽

Enhanced Sensitivity

Glucocorticoid administration to fetal sheep induces a sustained systemic blood pressure rise and an associated increase in femoral vascular resistance. We utilized a small vessel myograph to compare isometric vascular responses of small femoral arterial branches from fetal sheep infused intravenously with either betamethasone or vehicle in vivo from 128 days gestation. Changes in hematological parameters were also determined. Betamethasone was infused for 48 h to produce fetal plasma betamethasone concentrations similar to those observed in human fetuses after maternal treatment with betamethasone to accelerate fetal lung maturation. When compared with vessels removed from vehicle-infused fetuses, vessels obtained from betamethasone-treated fetuses exhibited 1) enhanced sensitivity to depolarizing potassium solutions; 2) no differences in response to the thromboxane mimetic U-46619 or norepinephrine; and 3) differential responses to vasodilators, enhanced sensitivity to ACh, but decreased response to bradykinin and forskolin. In addition, erythrocyte and leukocyte counts were increased in betamethasone-infused fetuses. These observations indicate that multiple mechanisms operate to increase fetal vascular resistance during antenatal betamethasone exposure.

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Prepartum maturation of the lung in fetal sheep: relation to cortisol

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.2.384 ◽

1981 ◽

Vol 51 (2) ◽

pp. 384-390 ◽

Cited By ~ 54

Author(s):

J. A. Kitterman ◽

G. C. Liggins ◽

G. A. Campos ◽

J. A. Clements ◽

C. S. Forster ◽

...

Keyword(s):

Lung Tissue ◽

Fetal Lung ◽

Lavage Fluid ◽

Late Gestation ◽

Morphological Development ◽

Lung Maturation ◽

Physiological Factor ◽

Fetal Sheep ◽

Wide Range ◽

Fetal Lung Maturation

We studied the relationship of certain fetal and maternal hormones to indicators of lung maturation in 12 fetal lambs delivered at gestational ages (GA) of 123-149 days. Maternal estrogen, maternal progesterone, and fetal prolactin did not correlate with GA or the indicators of fetal lung maturation. Fetal cortisol (range 4-165 ng X ml-1) increased with advancing GA (r = 0.747, P less than 0.01). All of the following showed a wide range of late gestation and showed a significant positive correlation with fetal cortisol: lung volumes at 40 cmH2O and 10 cmH2O on the deflation during air pressure-volume studies; saturated phosphatidylcholine (SPC) in lung tissue and in lavage fluid expressed both as mg X g-1 of wet lung and as percent of total phospholipids (%PL); total SPC (lung tissue plus lavage fluid): and SPC in lavage fluid as percent of total SPC. Lung DNA correlated inversely with GA and cortisol. All variables (except lavage fluid SPC as %PL) correlated more closely with cortisol than GA. Morphological development of lung was also related more closely to cortisol than GA. These results suggest that functional lung maturity is attained late in gestation and that endogenous cortisol is an important physiological factor in control of fetal lung maturation.

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Intra-amniotic injection of IL-1 induces inflammation and maturation in fetal sheep lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00097.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. L411-L420 ◽

Cited By ~ 73

Author(s):

Karen E. Willet ◽

Boris W. Kramer ◽

Suhas G. Kallapur ◽

Machiko Ikegami ◽

John P. Newnham ◽

...

Keyword(s):

Escherichia Coli ◽

Lung Function ◽

Lung Inflammation ◽

Fetal Lung ◽

Surfactant Protein ◽

Lung Compliance ◽

Fetal Membranes ◽

Lung Maturation ◽

Fetal Sheep ◽

Fetal Lung Maturation

Antenatal inflammation may be an important triggering event in the pathogenesis of bronchopulmonary dysplasia but may also accelerate fetal lung maturation. We examined the effects of intra-amniotic (IA) interleukin (IL)-1α and IL-1β on maturation of the fetal sheep lung. These cytokine effects were compared with IA endotoxin, a potent proinflammatory stimulus that accelerated lung maturation. Date-bred ewes received 15 or 150 μg recombinant ovine IL-1α or IL-1β or 10 mg Escherichia coli endotoxin by IA injection at 118 days gestation (term = 150 days), and fetuses were delivered at 125 days. IL-1α and IL-1β improved lung function and increased alveolar saturated phosphatidylcholine (Sat PC) and surfactant protein mRNA expression at the higher dose. The maturation response to IL-1α was greater than that to IL-1β, which was similar to endotoxin response. Inflammation was also more pronounced after IL-1α treatment. Only endotoxin animals had residual inflammation of the fetal membranes at 7 days. Lung compliance, lung volume, and alveolar Sat PC were positively correlated with residual alveolar wash leukocyte numbers 7 days after IL-1 treatment, suggesting a link between lung inflammation and maturation.

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Thyrotrophin-releasing hormone (TRH) and lung maturation

Reproduction Fertility and Development ◽

10.1071/rd9950443 ◽

1995 ◽

Vol 7 (3) ◽

pp. 443 ◽

Cited By ~ 7

Author(s):

GC Liggins

Keyword(s):

Fetal Lung ◽

Lung Maturation ◽

Rabbit Lung ◽

Glucocorticoid Treatment ◽

Fetal Sheep ◽

Thyrotrophin Releasing Hormone ◽

Releasing Hormone ◽

Fetal Plasma

Clinical trials of thyrotrophin-releasing hormone (TRH) in conjunction with antepartum glucocorticoid treatment in the prevention of respiratory distress syndrome is based on experimental evidence that fetal lung maturation is accelerated by exposure to raised concentrations of triiodothyronine (T3) in fetal plasma. Studies of fetal rat and rabbit lung in vitro show an inconsistent increase in surfactant synthesis in response to T3 and potentiation of the response to corticosteroid. Experiments with fetal rodents in vivo are difficult to interpret because of confounding effects of the procedures and the responses to T3 are variable. In fetal sheep, very high concentrations of T3 are without effect on lung maturation. These observations suggest that the action of TRH on the lung may be mediated at least in part by one of the numerous, non-hormonal pathways known to be stimulated by TRH, particularly the autonomic nervous system. Experiments in rats and sheep lend support to this possibility. It is concluded that available evidence is inadequate to determine the mechanism of action of TRH.

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PPARγ activation in late gestation does not promote surfactant maturation in the fetal sheep lung

Journal of Developmental Origins of Health and Disease ◽

10.1017/s204017442000135x ◽

2021 ◽

pp. 1-12

Author(s):

Jiaqi Ren ◽

Mitchell C. Lock ◽

Jack R. T. Darby ◽

Sandra Orgeig ◽

Stacey L. Holman ◽

...

Keyword(s):

Mrna Expression ◽

Target Genes ◽

Alveolar Epithelial Cells ◽

Late Gestation ◽

Peroxisome Proliferator ◽

Phospholipid Synthesis ◽

Lung Maturation ◽

Fetal Sheep ◽

Surfactant Synthesis ◽

Pparγ Agonist

Abstract Respiratory distress syndrome results from inadequate functional pulmonary surfactant and is a significant cause of mortality in preterm infants. Surfactant is essential for regulating alveolar interfacial surface tension, and its synthesis by Type II alveolar epithelial cells is stimulated by leptin produced by pulmonary lipofibroblasts upon activation by peroxisome proliferator-activated receptor γ (PPARγ). As it is unknown whether PPARγ stimulation or direct leptin administration can stimulate surfactant synthesis before birth, we examined the effect of continuous fetal administration of either the PPARγ agonist, rosiglitazone (RGZ; Study 1) or leptin (Study 2) on surfactant protein maturation in the late gestation fetal sheep lung. We measured mRNA expression of genes involved in surfactant maturation and showed that RGZ treatment reduced mRNA expression of LPCAT1 (surfactant phospholipid synthesis) and LAMP3 (marker for lamellar bodies), but did not alter mRNA expression of PPARγ, surfactant proteins (SFTP-A, -B, -C, and -D), PCYT1A (surfactant phospholipid synthesis), ABCA3 (phospholipid transportation), or the PPARγ target genes SPHK-1 and PAI-1. Leptin infusion significantly increased the expression of PPARγ and IGF2 and decreased the expression of SFTP-B. However, mRNA expression of the majority of genes involved in surfactant synthesis was not affected. These results suggest a potential decreased capacity for surfactant phospholipid and protein production in the fetal lung after RGZ and leptin administration, respectively. Therefore, targeting PPARγ may not be a feasible mechanistic approach to promote lung maturation.

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

Pediatric Research ◽

10.1038/s41390-021-01489-4 ◽

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.

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Regulation of lactic acid production during exercise

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.2.509 ◽

1988 ◽

Vol 65 (2) ◽

pp. 509-518 ◽

Cited By ~ 102

Author(s):

A. Katz ◽

K. Sahlin

Keyword(s):

Lactic Acid ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Synergistic Effect ◽

Lactic Acid Production ◽

Fetal Lung ◽

Lung Maturation ◽

Fetal Sheep ◽

Epidermal Growth ◽

Ovine Fetal

Cortisol has minimal effects on lung maturation in fetal sheep before 130 days gestation. To test whether there is enhancement of cortisol action by other hormones, cortisol (F), triiodothyronine (T3), epinephrine (E), prolactin (PRL), and epidermal growth factor (EGF), alone or in combination, were infused into fetal sheep for 84 h between 124 and 128 days gestation. A mixture of F + T3 + PRL, but not any combination of two hormones, increased both distensibility [1.71 +/- 0.12 (SE) ml of air/g wet wt at 40 cmH2O, V40] and stability (1.16 +/- 0.09 ml of air per g wet wt at 5 cmH2O, V5) to near full-term values, above values resulting from treatment with F alone (0.91 +/- 0.12 and 0.43 +/- 0.09 ml/g, P less than 0.01). Only F had an effect when given alone, V40 increasing (P less than 0.05). Treatment with F + T3 (0.81 +/- 0.18 ml/g) and F + E (0.77 +/- 0.07 ml/g) increased V5 above values obtained with F alone (P less than 0.05). Alveolar saturated phosphatidylcholine (SPC) was higher after treatment with F + T3 (161 +/- 52 micrograms/g), F + T3 + PRL (156 +/- 53 micrograms/g, P less than 0.05), and F + E (113 +/- 40 micrograms/g, P = 0.07) than after F (12 +/- 3 micrograms/g). We conclude that F, T3, and PRL have a synergistic effect on the development of distensibility and stability of the ovine fetal lung.

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Fetal lung in organ culture. IV. Supra-additive hormone interactions

Journal of Applied Physiology ◽

10.1152/jappl.1982.52.6.1420 ◽

1982 ◽

Vol 52 (6) ◽

pp. 1420-1425 ◽

Cited By ~ 36

Author(s):

I. Gross ◽

C. M. Wilson

Keyword(s):

Organ Culture ◽

Animal Studies ◽

Fetal Lung ◽

Cellular Level ◽

Lung Maturation ◽

Hormone Interactions ◽

Fetal Lung Maturation ◽

Stimulation Of

Corticosteroids, thyroid hormones, and theophylline have previously been shown to accelerate fetal lung maturation. We have examined the interactions between these agents in relation to phospholipid synthesis in explants of 18-day fetal rat lung in organ culture. Maximal stimulation of the rate of incorporation of choline into phosphatidylcholine, the most abundant phospholipid in pulmonary surfactant, was observed at a dexamethasone concentration of 100 nM. Exposure to 100 nM dexamethasone, 1.0 mM theophylline, or a combination of the two agents for 48 h resulted, respectively, in 144, 157, and 508% stimulation of the rate of incorporation of choline into disaturated phosphatidylcholine. Similar supra-additive interactions between dexamethasone and dibutyryl adenosine 3′,5′-cyclic monophosphate (cAMP) were observed, but the effects with caffeine were less striking. The increase in the rate of precursor incorporation was associated with a significant increase in the disaturated phosphatidylcholine content of the cultures. Combination of dexamethasone with 100 nM triiodothyronine (the concn producing maximal effects) also resulted in supra-additive stimulation but to a smaller degree. These findings of interactions in vitro suggest that the agents act on the lung at different biochemical sites, but the mechanisms whereby they interact at the cellular level have yet to be established. The data provide a rationale for in vivo animal studies of the effects of combined hormone administration on fetal lung maturation.

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Invited Review: Mechanochemical signal transduction in the fetal lung

Journal of Applied Physiology ◽

10.1152/jappl.2000.89.5.2078 ◽

2000 ◽

Vol 89 (5) ◽

pp. 2078-2084 ◽

Cited By ~ 93

Author(s):

Mingyao Liu ◽

Martin Post

Keyword(s):

Signal Transduction ◽

Cell Proliferation ◽

Fetal Lung ◽

Mechanical Stretch ◽

Model Systems ◽

Lung Cells ◽

Physical Factors ◽

Lung Maturation

Growth and maturation of fetal lungs are regulated by both humoral and physical factors. Mechanical stretch stimulates fetal lung cell proliferation and affects fetal lung maturation by influencing the production of extracellular matrix molecules and the expression of specific genes of fetal lung cells. These effects are mediated through special signal transduction pathways in fetal lung cells. Various in vivo and in vitro model systems have been developed to investigate the mechanotransduction process. The diversity and discrepancy of these studies have raised many questions. We will briefly summarize mechanical force-induced signals in fetal lung cell proliferation and differentiation and then discuss several important issues related to these studies.

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