scholarly journals Antenatally administered PPAR-γ agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury

2010 ◽  
Vol 299 (5) ◽  
pp. L672-L680 ◽  
Author(s):  
Virender K. Rehan ◽  
Reiko Sakurai ◽  
Julia Corral ◽  
Melissa Krebs ◽  
Basil Ibe ◽  
...  
Keyword(s):  
Lung Injury ◽  
Transforming Growth Factor ◽  
Fetal Lung ◽  
Transforming Growth Factor Β ◽  
Lung Maturation ◽  
Ppar Γ ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Fetal Lung Maturation ◽  
Enhancer Factor

The physiological development and homeostasis of the lung alveolus is determined by the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) by the interstitial lipofibroblast. We have recently shown (Dasgupta C et al., Am J Physiol Lung Cell Mol Physiol 296: L1031–L1041, 2009.) that PPAR-γ agonists administered postnatally accelerate lung maturation and prevent hyperoxia-induced lung injury. However, whether the same occurs antenatally is not known. The objective of this study was to test the hypothesis that the potent PPAR-γ agonist rosiglitazone (RGZ), administered antenatally, enhances fetal lung maturation and protects against hyperoxia-induced neonatal lung injury. Sprague-Dawley rat dams were administered either diluent or RGZ (3 mg/kg), at late gestation, to determine its effect on lung maturation and on hyperoxia (95% O2 exposure for 24 h)-induced neonatal lung injury. The lungs were examined for the expression of specific markers of alveolar development (surfactant proteins A and B, cholinephosphate cytidylyltransferase-α, leptin receptor, triglyceride uptake, and [3H]choline incorporation into saturated phosphatidylcholine) and injury/repair, in particular, the markers of transforming growth factor-β signaling (activin receptor-like kinase-5, SMAD3, lymphoid enhancer factor-1, fibronectin, and calponin). Overall, antenatal RGZ accelerated lung maturation and blocked the inhibition of alveolar sacculation and septal wall thinning by hyperoxia. RGZ specifically stimulated the development of the alveolar epithelial type II cell, the lipofibroblast, and the vasculature. The increased expression of the transforming growth factor-β intermediates, such as SMAD3 and lymphoid enhancer factor-1, implicated in hyperoxic lung injury, was also blocked by antenatal RGZ treatment. In conclusion, PPAR-γ agonists can enhance fetal lung maturation and can effectively prevent hyperoxia-induced neonatal lung injury.

scholarly journals Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

2011 ◽  
Vol 301 (5) ◽  
pp. L721-L730 ◽  
Author(s):  
Reiko Sakurai ◽  
Yishi Li ◽  
John S. Torday ◽  
Virender K. Rehan
Keyword(s):  
Lung Injury ◽  
Intraperitoneal Administration ◽  
Lung Fibroblasts ◽  
Related Protein ◽  
Lung Maturation ◽  
Injury Repair ◽  
Parathyroid Hormone Related Protein ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Pthrp Receptor

There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O2 for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O2 for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD.

scholarly journals A Combination of the Aerosolized PPAR-γ Agonist Pioglitazone and a Synthetic Surfactant Protein B Peptide Mimic Prevents Hyperoxia-Induced Neonatal Lung Injury in Rats

Neonatology ◽  
2018 ◽  
Vol 113 (4) ◽  
pp. 296-304 ◽  
Author(s):  
Reiko Sakurai ◽  
Cindy Lee ◽  
Humphrey Shen ◽  
Alan J. Waring ◽  
Frans J. Walther ◽  
...  
Keyword(s):  
Lung Injury ◽  
Surfactant Protein ◽  
Synthetic Surfactant ◽  
Ppar Γ ◽  
Peptide Mimic ◽  
Surfactant Protein B ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Protein B

scholarly journals Antenatal PPAR-γ agonist pioglitazone stimulates fetal lung maturation equally in males and females

2020 ◽  
Vol 319 (3) ◽  
pp. L435-L443
Author(s):  
Cindy Lee ◽  
Reiko Sakurai ◽  
Eugene Shin ◽  
Ying Wang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Fetal Lung ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Lung Maturation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alveolar Epithelial ◽  
Ppar Γ ◽  
Antenatal Steroids ◽  
Males And Females ◽  
Fetal Lung Maturation

Antenatal steroids (ANS) accelerate fetal lung maturation and reduce the incidence of respiratory distress syndrome. However, sex specificity, i.e., being less effective in males, and potential long-term neurodevelopmental sequelae, particularly with repeated courses, remain significant limitations. The differential sex response to ANS is likely mediated via the inhibitory effect of fetal androgens on steroid’s stimulatory effect on alveolar epithelial-mesenchymal interactions. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists accelerate lung maturation by stimulating alveolar epithelial-mesenchymal interactions, independent of fetal sex, we hypothesized that the effect of PPAR-γ agonist pioglitazone (PGZ) would be sex-independent. Pregnant Sprague-Dawley rat dams were intraperitoneally administered dexamethasone (DEX) or PGZ on embryonic day (e) 18 and e19. At e20, pups were delivered by cesarean section, and fetal lungs and brains were examined for markers of lung maturation and apoptosis, respectively. Mixed epithelial-fibroblast cell cultures were examined to gain mechanistic insights. Antenatal PGZ increased alveolar epithelial and mesenchymal maturation markers equally in males and females; in contrast, antenatal DEX had sex-specific effects. Additionally, unlike DEX, antenatal PGZ did not increase hippocampal apoptosis. We conclude that PPAR-γ agonist administration is an effective, and probably even a superior, alternative to ANS for accelerating fetal lung maturity equally in both males and females.

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.

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