Mus musculus
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-29632
PROVIDER: PRJNA141263 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity. PARALLEL study design with 42 samples comparing 14 groups of age (P1 to P4 corresponding to day 0 to day 3 animals), gene, and exposure: (4 groups Nrf+/+ wild type P1-P4 air exposure) (4 groups Nrf -/- knockout P1-P4 air exposure), (3 groups Nrf+/+ wild type P2-P4 with 100 percent O2 (hyperoxia exposure) and 3 groupsNrf -/- knockout P2-P4 with 100 percent O2 (hyperoxia exposure)) Biological replicates: 3 per group
2012-05-24 | E-GEOD-29632 | biostudies-arrayexpress
Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity.
2012-05-25 | GSE29632 | GEO
Project description:Background: NRF2 is an essential cytoprotective transcription factor inducing antioxidant response element (ARE)-bearing genes. However, association of NRF2 with lung development has not been examined. Human lungs are not fully developed until 2-3 years of and they are fully matured at about 8 years. Murine lungs at birth are immature (at saccular stage of lung development) and have been used to study developmental lung disorders. Methods: To investigate (1) the transcriptome changes during lung development and (2) the role of NRF2 in lung development and maturation in mice, lungs were harvested from Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) mouse embryos, neonates and adults. Microarray and pathway analysis determined NRF2-directed mechanisms underlying lung development and maturation. Results: Nrf2 mRNA expression was peack at embryonic days E17.5-E18.5 (immediately before birth) probably to increase antioxidant apparatus to prepare against high O2 environment after birth. The pseudoglandular phase lungs (E13-E15) are undergoing vigorous cell proliferation under the control of high-fidelity DNA damage repair system. Fetal lungs (E13.5-E17.5) are lack in immune system, xenobiotic metabolism, and tissue damage genes. After birth at postnatal day 1 (PND1), lung cell division is quiescent but transporters and lipid metabolism are activated. When lung enters alveolar phase (PND4), cell proliferation is resumed. Mature lungs (PND14-P42) have heightened networks of host defense systems (immunity, antioxidants) and cellular injury and abnormality (e.g., glucose metabolism disorder). Nrf2 deletion in fetal lung (E13.5-E17.5) altered developmental, immunity, and metabolism genes, and it may have affected lung branching. Nrf2 deletion affected lung transcriptome changes the most at E17.5 when Nrf2 message level is maximum (E17.5-E18.5). Nrf2 deletion in newborn lung (PND0) decreased cell cycle progress and DNA damage repair. Nrf2 deletion in neonatal lung (PND1-4) enhanced tissue injury/cell death and inhibited developmental cell differentiation. Nrf2 deletion in matured mouse lung (PND42) affected not only antioxidant pathway but also immune responses and connective tissue cell migrations. Conclusion: Overall, NRF2 plays multiple roles in underdeveloped lungs and associated with lung morphogenesis, immunity, cell cycle progress, tissue differentiation and metabolism as well as cellular defense. Results provide putative molecular mechanisms of NRF2-directed lung morphogenesis and maturation.
2023-02-21 | GSE197587 | GEO
Project description:Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease of premature neonates. The development of BPD depends on several prenatal and postnatal factors that induce inflammation, altering alveolar growth and pulmonary vascular development. Animal models are essential to investigating the precise molecular pathways leading to BPD. The preterm rabbit combines many advantages of both small (e.g., rodents) and large BPD models (i.e., preterm lambs and baboons). For instance, preterm rabbits display mild-to-moderate respiratory distress at delivery, which, along with ongoing exposure to high oxygen concentration (95% O2), leads to functional and morphological lung changes that resemble the phenotype of human BPD. Nevertheless, the molecular pathways leading to the development of the BPD-like phenotype in this model remain largely ununderstood. We, therefore, aimed to characterize the longitudinal gene expression in the lungs of preterm rabbits continuously exposed to 95% O2 on postnatal days 3, 5, and 7. The longitudinal transcriptomic analysis revealed different expression patterns for several genes and pathways. Over time, extracellular matrix organization and angiogenesis were increasingly downregulated, while apoptosis, RNA processing, and inflammation showed the opposite trend.
2025-04-14 | GSE284417 | GEO
Project description:Effect of Nrf2 deletion on developmental lung transcriptomics in mice
| PRJNA811130 | ENA
Project description:Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.
2023-12-19 | GSE242718 | GEO
Project description:Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood. We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed global transcriptome analysis of all resident pulmonary immune cells. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD.
2021-01-19 | GSE161836 | GEO
Project description:A majority of the gas-exchange surface is generated during alveologenesis, and disruption of this process causes bronchopulmonary dysplasia (BPD) in preterm infants, characterized by alveolar simplification. BPD is a significant risk factor for adult emphysema, marked by alveolar loss. A comprehensive molecular understanding of alveologenesis and effective treatments for BPD and emphysema are still lacking. Here, we show that the cells expressing Hhip, a gene associated with both BPD and emphysema, expand within the alveoli during alveologenesis, followed by hedgehog (Hh) inhibition and myofibroblast transition. Stromal-specific deletion of Hhip leads to aberrant persistence of SMA+ alveolar myofibroblasts, mediated by a hyperactive Hh-IGF1 axis. Conditional knockout animal and 3D stroma-stem cell organoid models demonstrate that loss of Hhip induces alveolar stem/progenitor cell senescence in a non–cell-autonomous manner. Alveolar simplification and BPD phenotypes induced by Hhip deletion can be partially rescued by IGF1 signaling blockade. We also observe the downregulation of Hhip expression and hyperactivation of Hh-IGF1 signaling in hyperoxia-induced BPD animal models. In addition, adult mice deficient in Hhip expression develop emphysema phenotype with abnormal alveolar myofibroblasts. Finally, we develop a therapeutic Fc-fused HHIP recombinant protein that attenuates BPD phenotypes in postnatal mice and emphysema in adult mice. These findings underscore the critical role of HHIP in coordinating alveologenesis and preventing BPD and emphysema by restricting Hh-IGF1 signaling.
2025-03-26 | GSE271417 | GEO
Project description:Background Intrauterine inflammation (IUI) is involved in the development of bronchopulmonary dysplasia (BPD). Previously, we observed BPD-like pathological changes in a mouse model of IUI. Here, we aimed to investigate key molecules involved in IUI-induced neonatal lung injury along with the long-term outcomes. Methods Pregnant C57BL/6 mice were randomly divided into control and IUI groups. Lung injury was evaluated using hematoxylin-eosin and Masson's trichrome staining. An NR4A1 overexpression plasmid was used to explore the downstream molecules acting in vitro. Accordingly, IUI-induced lung injury intervention was verified using Nr4a1 siRNA. Results The lungs of IUI-induced offspring showed a simple structure from postnatal day 1 to 6 months, with increased pulmonary fibrosis from 3 to 6 months postnatal. Postnatal NR4A1 intervention reversed IUI-induced neonatal lung injury. NR4A1 overexpression decreased cell proliferation and influenced the expression of epithelial-mesenchymal transition (EMT)-related key genes in MLE-12 cells. EREG is a downstream target of NR4A1, and blocking the receptor of EREG would recover the expression of EMT-related genes. Conclusion IUI induced BPD-like lung injury in neonates and pulmonary fibrosis in adults. The NR4A1-EREG-EGFR signaling pathway in pulmonary epithelial cells plays an important role in IUI-induced lung injury in offspring.
2025-03-23 | GSE262215 | GEO
Project description:Extremely preterm infants are often treated with supraphysiological oxygen which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency. The present study was designed to develop a perinatal Se deficiency mouse model, identify the effects of newborn hyperoxia exposure, and explore alternative pathways affected by Se deficiency (SeD) that would contribute to impaired lung development. Se deficient breeding pairs were generated, once pups were born, they were exposed to room air or 85% O2 for 14 d. Survival, antioxidant and Nrf2-regulated protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in Se deficient (SeD), hyperoxia exposed pups. Surviving SeD pups had greater lung growth deficits than Se sufficient (SeS) pups exposed to hyperoxia. Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups. Nrf2-regulated proteins, NQO1 and Gclc were increased in the setting of Se deficiency and hyperoxia exposure. RNA seq revealed significant decreases in the Wnt/-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. RNA seq implicates pathways essential for normal lung development are dysregulated by Se deficiency.
2024-05-01 | GSE255744 | GEO