scholarly journals In utero exposures to electronic-cigarette aerosols impair the Wnt signaling during mouse lung development

2020 ◽  
Vol 318 (4) ◽  
pp. L705-L722 ◽  
Author(s):  
Alexandra Noël ◽  
Shannon Hansen ◽  
Anusha Zaman ◽  
Zakia Perveen ◽  
Rakeysha Pinkston ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Lung Development ◽  
Electronic Cigarettes ◽  
Fetal Lung ◽  
In Utero ◽  
Mouse Lung ◽  
Childbearing Age ◽  
Lung Structure ◽  
Tissue Fraction ◽  
In Utero Exposures

Currently, more than 9 million American adults, including women of childbearing age, use electronic-cigarettes (e-cigs). Further, the prevalence of maternal vaping now approaching 10% is similar to that of maternal smoking. Little, however, is known about the effects of fetal exposures to nicotine-rich e-cig aerosols on lung development. In this study, we assessed whether in utero exposures to e-cig aerosols compromised lung development in mice. A third-generation e-cig device was used to expose pregnant BALB/c mice by inhalation to 36 mg/mL of nicotine cinnamon-flavored e-cig aerosols for 14–31 days. This included exposures for either 12 days before mating plus during gestation (preconception groups) or only during gestation (prenatal groups). Respective control mice were exposed to filtered air. Subgroups of offspring were euthanized at birth or at 4 wk of age. Compared with respective air-exposed controls, both preconception and prenatal exposures to e-cig aerosols significantly decreased the offspring birth weight and body length. In the preconception group, 7 inflammation-related genes were downregulated, including 4 genes common to both dams and fetuses, denoting an e-cig immunosuppressive effect. Lung morphometry assessments of preconception e-cig-exposed offspring showed a significantly increased tissue fraction at birth. This result was supported by the downregulation of 75 lung genes involved in the Wnt signaling, which is essential to lung organogenesis. Thus, our data indicate that maternal vaping impairs pregnancy outcomes, alters fetal lung structure, and dysregulates the Wnt signaling. This study provides experimental evidence for future regulations of e-cig products for pregnant women and developmentally vulnerable populations.

scholarly journals Effect of Intrauterine Smoke Exposure on microRNA-15a Expression in Human Lung Development and Subsequent Asthma Risk

Healthcare ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 536
Author(s):  
Sunita Sharma ◽  
Alvin T. Kho ◽  
Divya Chhabra ◽  
Kathleen Haley ◽  
Carrie Vyhlidal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Development ◽  
Human Lung ◽  
Expression Profiles ◽  
Fetal Lung ◽  
In Utero ◽  
Differentially Expressed ◽  
Mouse Lung ◽  
Asthma Susceptibility ◽  
Human Fetal Lung

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p < 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p < 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.

scholarly journals Effects of antenatal melatonin therapy on lung structure in growth-restricted newborn lambs

2017 ◽  
Vol 123 (5) ◽  
pp. 1195-1203 ◽  
Author(s):  
Graeme R. Polglase ◽  
Jade Barbuto ◽  
Beth J. Allison ◽  
Tamara Yawno ◽  
Amy E. Sutherland ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Lung Development ◽  
Fetal Lung ◽  
Growth Restriction ◽  
Fetal Sheep ◽  
Respiratory Dysfunction ◽  
Melatonin Administration ◽  
Lung Structure

Oxidative stress arising from suboptimal placental function contributes to a multitude of pathologies in infants compromised by fetal growth restriction (FGR). FGR infants are at high risk for respiratory dysfunction after birth and poor long-term lung function. Our objective was to investigate the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. Placental insufficiency and FGR was surgically induced in 13 fetal sheep at ∼105 days of gestation by ligation of a single umbilical artery. Maternal intravenous melatonin infusion was commenced in seven of the ewes 4 h after surgery and continued until birth. Lambs delivered normally at term and lungs were collected 24 h after birth for histological assessment of lung structure and injury and compared with appropriately grown control lambs ( n = 8). FGR fetuses were hypoxic and had lower glucose during gestation compared with controls. Melatonin administration prevented chronic hypoxia. Within the lung, FGR caused reduced secondary septal crest density and altered elastin deposition compared with controls. Melatonin administration had no effect on the changes to lung structure induced by FGR. We conclude that chronic FGR disrupts septation of the developing alveoli, which is not altered by melatonin administration. These findings suggest that oxidative stress is not the mechanism driving altered lung structure in FGR neonates. Melatonin administration did not prevent disrupted airway development but also had no apparent adverse effects on fetal lung development. NEW & NOTEWORTHY Fetal growth restriction (FGR) results in poor respiratory outcomes, which may be caused by oxidation in utero. We investigated the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. FGR disrupted septation of the developing alveoli, which is not altered by melatonin administration. Oxidative stress may not be the mechanism driving altered lung structure in FGR neonates.

scholarly journals In utero administration of GABA promotes fetal lung development

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Narendranath Reddy Chintagari ◽  
Yang Wang ◽  
Dong Xi ◽  
Lin Liu
Keyword(s):  
Lung Development ◽  
Fetal Lung ◽  
In Utero ◽  
Fetal Lung Development

scholarly journals LPS-induced chorioamnionitis and antenatal corticosteroids modulate Shh signaling in the ovine fetal lung

2012 ◽  
Vol 303 (9) ◽  
pp. L778-L787 ◽  
Author(s):  
Jennifer J. P. Collins ◽  
Elke Kuypers ◽  
Ilias Nitsos ◽  
J. Jane Pillow ◽  
Graeme R. Polglase ◽  
...  
Keyword(s):  
Lung Development ◽  
Collagen Type ◽  
Fetal Lung ◽  
Collagen Type I ◽  
Late Gestation ◽  
Type I ◽  
Mrna Levels ◽  
Antenatal Corticosteroids ◽  
Shh Signaling ◽  
Lung Structure

Chorioamnionitis and antenatal corticosteroids mature the fetal lung functionally but disrupt late-gestation lung development. Because Sonic Hedgehog (Shh) signaling is a major pathway directing lung development, we hypothesized that chorioamnionitis and antenatal corticosteroids modulated Shh signaling, resulting in an altered fetal lung structure. Time-mated ewes with singleton ovine fetuses received an intra-amniotic injection of lipopolysaccharide (LPS) and/or maternal intramuscular betamethasone 7 and/or 14 days before delivery at 120 days gestational age (GA) (term = 150 days GA). Intra-amniotic LPS exposure decreased Shh mRNA levels and Gli1 protein expression, which was counteracted by both betamethasone pre- or posttreatment. mRNA and protein levels of fibroblast growth factor 10 and bone morphogenetic protein 4, which are important mediators of lung development, increased 2-fold and 3.5-fold, respectively, 14 days after LPS exposure. Both 7-day and 14-day exposure to LPS changed the mRNA levels of elastin ( ELN) and collagen type I alpha 1 (Col1A1) and 2 (Col1A2), which resulted in fewer elastin foci and increased collagen type I deposition in the alveolar septa. Corticosteroid posttreatment prevented the decrease in ELN mRNA and increased elastin foci and decreased collagen type I deposition in the fetal lung. In conclusion, fetal lung exposure to LPS was accompanied by changes in key modulators of lung development resulting in abnormal lung structure. Betamethasone treatment partially prevented the changes in developmental processes and lung structure. This study provides new insights into clinically relevant prenatal exposures and fetal lung development.

Chronic in Utero Beta-Blockade Alters Fetal Lung Development

1992 ◽  
Vol 19 (2-3) ◽  
pp. 131-140 ◽  
Author(s):  
Kevin P. Petit ◽  
Herber C. Nielsen
Keyword(s):  
Lung Development ◽  
Fetal Lung ◽  
In Utero ◽  
Beta Blockade ◽  
Fetal Lung Development

Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung

2004 ◽  
Vol 286 (1) ◽  
pp. L165-L173 ◽  
Author(s):  
Lin Shan ◽  
Rodica L. Emanuel ◽  
Denise Dewald ◽  
John S. Torday ◽  
Nithiananthan Asokanathan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Development ◽  
Gene Expression Regulation ◽  
Receptor Gene ◽  
Fetal Lung ◽  
Mouse Lung ◽  
Receptor Subtype ◽  
Fetal Lung Development ◽  
And Function ◽  
Receptor Gene Expression

Bombesin-peptide (BLP) immunoreactivity occurs at high levels in fetal lung. Previous studies showed that bombesin promotes fetal lung development. To test the hypothesis that such effects are mediated by known mammalian bombesin receptors [gastrin-releasing peptide (GRP)/bombesin-preferring receptor (GRPR), neuromedin B (NMB) receptor (NMBR), and the orphan bombesin receptor subtype-3 (BRS-3)], we analyzed the ontogeny of GRPR, NMBR, and BRS-3 gene expression in mouse lung. We examined the regulation of these three genes by dexamethasone and bombesin, which modulate lung development. Using incorporation of [3H]thymidine and [3H]choline, we then assessed whether GRP, NMB, and Leu8-phyllolitorin modulate lung growth and maturation in fetal lung explants. GRPR gene expression was detected predominantly in utero, whereas NMBR and BRS-3 genes were expressed from embryonic days 13–16 and on multiple postnatal days. All three mRNAs are present in airway epithelium and mesenchymal cells but occur in different relative patterns. These genes were regulated differently. Dexamethasone and bombesin increased GRPR mRNA, bombesin downregulated NMBR, and neither agent affected BRS-3. GRP increased incorporation of [3H]thymidine and [3H]choline in explants, whereas NMB induced cell proliferation and Leu8-phyllolitorin yielded variable results. Cumulative data suggest the involvement of multiple BLP receptors, including novel molecules, and argue against simple functional redundancy within this gene family during lung development.

scholarly journals Smad1 and its target gene Wif1 coordinate BMP and Wnt signaling activities to regulate fetal lung development

Development ◽  
2011 ◽  
Vol 138 (5) ◽  
pp. 925-935 ◽  
Author(s):  
B. Xu ◽  
C. Chen ◽  
H. Chen ◽  
S.-G. Zheng ◽  
P. Bringas ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Lung Development ◽  
Target Gene ◽  
Fetal Lung ◽  
Fetal Lung Development

Laminin 2 attachment selects myofibroblasts from fetal mouse lung

1998 ◽  
Vol 275 (3) ◽  
pp. L622-L630
Author(s):  
Guillermo Flores-Delgado ◽  
Pablo Bringas ◽  
David Warburton
Keyword(s):  
Lung Development ◽  
Cell Biology ◽  
Smooth Muscle Actin ◽  
Primary Cultures ◽  
Fetal Lung ◽  
Mesenchymal Cells ◽  
Mouse Lung ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Fetal Mouse

Laminins (LNs) are extracellular matrix glycoproteins that are involved in cell adhesion, proliferation, and differentiation. So far, 11 LN variants (LN1 to LN11) have been described. In the lung, at least six LN variants have been identified. However, only the role of LN1 has been characterized to any extent. In this study, we hypothesized that the LN2 variant may play a role during lung development. We identified, by RT-PCR analysis, that the α2-chain mRNA of LN2 is expressed during mouse lung development. LN2 adhesion assays were then performed with cells from fetal mouse lung primary cultures. Our results showed that a specific subpopulation of fetal lung cells that expressed vimentin, α-smooth muscle actin, and desmin attached onto LN2, whereas the cells that did not adhere to LN2 as well as the total cell population were able to adhere readily on fibronectin. Cell attachment onto LN2 was inhibited by EDTA. In addition, we demonstrated, by RT-PCR and Western analysis, that the LN2-adherent cells autoexpressed the α2-chain of LN2. In the late pseudoglandular period, LN2 was localized by immunohistochemistry in the basement membrane of airways and blood vessels and around mesenchymal cells. We conclude that LN2 is expressed during lung development and that a specific subpopulation of fetal lung mesenchymal cells expressing a myofibroblastic phenotype can be selected by attachment to LN2 in primary culture. These findings lead us to speculate that LN2 may play a key role in the cell biology of myofibroblasts during lung development.

Thyroid hormone affects embryonic mouse lung branching morphogenesis and cellular differentiation

2002 ◽  
Vol 282 (3) ◽  
pp. L359-L369 ◽  
Author(s):  
Kwanchai Archavachotikul ◽  
Teriggi J. Ciccone ◽  
Mala R. Chinoy ◽  
Heber C. Nielsen ◽  
Maryann V. Volpe
Keyword(s):  
Cell Differentiation ◽  
Thyroid Hormone ◽  
Lung Development ◽  
Mesenchymal Cell ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Embryonic Mouse ◽  
Fetal Lung Development ◽  
Terminal Bud

Although thyroid hormone (T3) influences epithelial cell differentiation during late fetal lung development, its effects on early lung morphogenesis are unknown. We hypothesized that T3 would alter embryonic lung airway branching and temporal-spatial differentiation of the lung epithelium and mesenchyme. Gestational day 11.5 embryonic mouse lungs were cultured for 72 h in BGJb serum-free medium without or with added T3 (0.2, 2.0, 10.0, or 100 nM). Evaluation of terminal bud counts showed a dose- and time-dependent decrease in branching morphogenesis. Cell proliferation was also significantly decreased with higher doses of T3. Morphometric analysis of lung histology showed that T3 caused a dose-dependent decrease in mesenchyme and increase in cuboidal epithelia and airway space. Immunocytochemistry showed that with T3 treatment, Nkx2.1 and surfactant protein SP-C proteins became progressively localized to cuboidal epithelial cells and mesenchymal expression of Hoxb5 was reduced, a pattern resembling late fetal lung development. We conclude that exogenous T3 treatment during early lung development accelerated epithelial and mesenchymal cell differentiation at the expense of premature reduction in new branch formation and lung growth.

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