The role of oxygen tension in the regulation of embryonic lung development

Shinkai, Toko; Sato, Masato; Pirker, Martina A.; Montedónico, Sandra; Puri, Prem

doi:10.1016/j.jpedsurg.2004.09.010

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…Embryonic lung buds explants can undergo branching morphogenesis in culture [14,16,17]. This in vitro lung culture technique is useful to evaluate the process involved in normal lung development and has proved to have many advantages: the developing lung's environment can be precisely controlled while maintaining the architecture and structure of an intact lung unit.…”

Section: Introductionmentioning

confidence: 99%

“…This in vitro lung culture technique is useful to evaluate the process involved in normal lung development and has proved to have many advantages: the developing lung's environment can be precisely controlled while maintaining the architecture and structure of an intact lung unit. The environment can be manipulated by altering the composition of the medium and substances elaborated by the developing lung tissue can be assayed from the medium [14,16,17].…”

Section: Introductionmentioning

confidence: 99%

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Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants

2005

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There is increasing evidence to suggest that the retinoid pathway is involved in the pathogenesis of congenital diaphragmatic hernia (CDH). We hypothesised that retinoids are involved in the pathogenesis of associated pulmonary hypoplasia in CDH and therefore designed this study to investigate the effects of retinoid acid on nitrofen-induced hypoplastic lungs. Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day 9.5 of gestation. Foetal lungs were harvested on embryonic day 13.5 and were cultured for 96 h with or without exogenous retinoic acid (RA) (1 muM) added daily to the culture medium. Lungs were divided into four study groups: control (n=31); control + RA (n=19); nitrofen (n=19); and nitrofen + RA (n=12). Lung growth was assessed in each group by measuring branching morphogenesis, total DNA content and the proportion of proliferating cells stained by immunohistochemistry. One-way ANOVA test was used for statistical analysis. Retinoic acid significantly increased the growth of nitrofen-induced hypoplastic lungs, whilst growth of control lungs did not change. The number of lung buds and lung area of nitrofen-exposed hypoplastic lungs after 96 h of culture significantly increased after the addition of RA compared to the non-treated hypoplastic lungs (25.75+/-6.47 vs 15.11+/-3.29 and 0.98+/-0.18 mm(2) vs 0.65+/-0.13 mm(2), respectively; P<0.0001). Lung perimeter was also higher when RA was added to hypoplastic lungs compared to the non-treated ones, although it did not reach significance (12.51+/-2.53 mm vs 11.19+/-2.56 mm; P=0.17). Conversely, the addition of RA to control lungs did not affect the number of lung buds, lung area or lung perimeter after 96 h in culture compared to the non-treated ones (31.28+/-4.66 vs 31.81+/-6.67; 1.29+/-0.18(2) vs 1.29+/-0.23 mm(2) and 18.47+/-3.47 mm vs 17.89+/-2.94 mm, respectively; P=NS). Retinoic acid also increased the total DNA content and the proportion of proliferating cells in hypoplastic lungs compared to the non-treated ones (2.59+/-0.58 mug vs 1.96+/-0.31 mug and 57.89+/-9.46% vs 36.76+/-8.15%, respectively; P<0.001). The addition of RA did not affect either total DNA content or the proportion of proliferating cells in control lungs compared to the non-treated ones (4.04+/-0.64 mug vs 3.79+/-0.85 mug and 58.67+/-11.23% vs 56.03+/-10.36%, respectively; P=NS). This study demonstrates for the first time that RA rescues lung hypoplasia in nitrofen-induced hypoplastic lungs. These results suggest that retinoid pathway may be involved in the pathogenesis of associated pulmonary hypoplasia in CDH.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants

2005

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“…In the embryonic lung, low P o 2 favors airway branching and bud formation (18, 19, 54), yet a critical morphogenic role for hypoxia is unlikely, as branched airway growth occurs at higher oxygen tensions (7, 37, 46, 49, 54). Vascular branching, by contrast, is almost completely dependent on the low P o 2 of the fetal lung and is abolished by experimental increases in oxygen tension (1, 22, 54).…”

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confidence: 99%

Control of HIF-1α and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock

Scott

Walker

Cwiklinski

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lung development requires coordinated signaling between airway and vascular growth, but the link between these processes remains unclear. Mammalian target of rapamycin complex-1 (mTORC1) can amplify hypoxia-inducible factor-1α (HIF-1α) vasculogenic activity through an NH2-terminal mTOR binding (TOS) motif. We hypothesized that this mechanism coordinates vasculogenesis with the fibroblast growth factor (FGF)-10/FGF-receptor2b/Spry2 regulator of airway branching. First, we tested if the HIF-1α TOS motif participated in epithelial-mesenchymal vascular signaling. mTORC1 activation by insulin significantly amplified HIF-1α activity at fetal Po2 (23 mmHg) in human bronchial epithelium (16HBE14o-) and induced vascular traits (Flk1, sprouting) in cocultured human embryonic lung mesenchyme (HEL-12469). This enhanced activation of HIF-1α by mTORC1 was abolished on expression of a HIF-1α (F99A) TOS-mutant and also suppressed vascular differentiation of HEL-12469 cocultures. Next, we determined if vasculogenesis in fetal lung involved regulation of mTORC1 by the FGF-10/FGFR2b/Spry2 pathway. Fetal airway epithelium displayed distinct mTORC1 activity in situ, and its hyperactivation by TSC1−/− knockout induced widespread VEGF expression and disaggregation of Tie2-positive vascular bundles. FGF-10-coated beads grafted into fetal lung explants from Tie2-LacZ transgenic mice induced localized vascular differentiation in the peripheral mesenchyme. In rat fetal distal lung epithelial (FDLE) cells cultured at fetal Po2, FGF-10 induced mTORC1 and amplified HIF-1α activity and VEGF secretion without induction of ERK1/2. This was accompanied by the formation of a complex between Spry2, the cCBL ubiquitin ligase, and the mTOR repressor, TSC2, which abolished GTPase activity directed against Rheb, the G protein inducer of mTORC1. Thus, mTORC1 links HIF-1α-driven vasculogenesis with the FGF-10/FGFR2b/Spry2 airway branching periodicity regulator.

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Mammalian Ste20-like protein kinase 3 plays a role in hypoxia-induced apoptosis of trophoblast cell line 3A-sub-E

Lin

Chen³

et al. 2011

The International Journal of Biochemistry & Cell Biology

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The role of oxygen tension in the regulation of embryonic lung development

Cited by 4 publications

References 14 publications

Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants

Retinoic acid rescues lung hypoplasia in nitrofen-induced hypoplastic foetal rat lung explants

Control of HIF-1α and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock

Mammalian Ste20-like protein kinase 3 plays a role in hypoxia-induced apoptosis of trophoblast cell line 3A-sub-E

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