Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status

McGrath‐Morrow, Sharon A.; Lauer, Thomas; Collaco, Joseph M.; Lopez, Armando Luna; Malhotra, Deepti; Alekseyev, Yuriy O.; Neptune, Enid; Wise, Robert A.; Biswal, Shyam

doi:10.1016/j.cyto.2013.09.021

Cited by 40 publications

(27 citation statements)

References 29 publications

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“…GDF15 is expressed and induced in response to hypoxia in human pulmonary vascular endothelial cells (Nickel et al, 2011). It is also induced in animal models of lung injury in both adult and neonatal mice (Bhattacharya et al, 2012; Lingappan et al, 2014; McGrath-Morrow et al, 2014; Zimmers et al, 2005). We have previously shown that GDF15 is induced in pulmonary epithelial (BEAS-2B) and endothelial (HPMEC) cells upon exposure to hyperoxia (Tiwari et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

Zhang

Jiang

Wang

et al. 2017

Toxicology and Applied Pharmacology

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Male premature neonates are more susceptible than females to the development of bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. GDF15 (Growth and differentiation factor 15) is a secreted cytokine and plays a role in cell proliferation, apoptosis, and angiogenesis. In this study, we sought to elucidate the sex-specific expression of Gdf15 in the lung in vivo in neonatal hyperoxic lung injury and its regulation by Hif-1α, and to delineate the differences in GDF15 expression in male and female human umbilical venous endothelial cells in an in vitro model of oxygen toxicity. Following hyperoxia exposure (95% FiO2, PND (postnatal day 1-5: saccular stage of lung development), neonatal male mice (C57BL/6) show increased GDF15 and decreased HIF-1α expression compared to female mice. For the in vitro experiments, male and female HUVECs were exposed to room air condition (21% O2, 5% CO2) or in hyperoxia condition (95% O2, 5% CO2) for up to 72 h. Male HUVECs had greater expression of GDF15 mRNA and protein. To study the inter-relationship between GDF15 and HIF-1α, we measured the expression of GDF15 in H441 cells after HIF-1α knockdown using promoter dual luciferase reporter assay, which showed that HIF-1α and GDF15 expression are inversely related under normoxia and hyperoxia. The results indicate that sex differences exist in the expression and modulation of GDF15 by HIF-1α in neonatal hyperoxic injury both in vivo and in vitro. These differences could explain in part the mechanisms behind sex-specific differences in BPD.

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Section: Discussionmentioning

confidence: 99%

Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

Zhang

Jiang

Wang

et al. 2017

Toxicology and Applied Pharmacology

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“…It is expressed and induced in response to hypoxia in human pulmonary vascular endothelial cells and treatment with recombinant human GDF15 decreased apoptosis and improved cellular proliferation. GDF15 is induced in animal models of lung injury (McGrath-Morrow et al, 2014; Zimmers et al, 2005). We have shown that GDF15 was among the top five genes induced in the murine lungs in vivo when subjected to hyperoxia (Lingappan et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Role of GDF15 (growth and differentiation factor 15) in pulmonary oxygen toxicity

Tiwari

Moorthy

Lingappan

2015

Toxicology in Vitro

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GDF15 (Growth and differentiation factor 15) is a secreted cytokine, a direct target of p53 and plays a role in cell proliferation and apoptosis. It is induced by oxidative stress and has anti-apoptotic effects. The role of GDF15 in hyperoxic lung injury is unknown. We tested the hypothesis that GDF15 will be induced in vitro, in a model of pulmonary oxygen toxicity, and will play a critical role in decreasing cell death and oxidative stress. BEAS-2B (human bronchial epithelial cells) and human pulmonary vascular endothelial cells (HPMEC) were exposed to hyperoxia, and expression of GDF15 and effect of GDF15 disruption on cell viability and oxidative stress was determined. Furthermore, we studied the effect of p53 knockdown on GDF15 expression. In vitro, both BEAS-2B and HPMEC cells showed a significant increase in GDF15 expression upon exposure to hyperoxia. After GDF15 knockdown, there was a significant decrease in cell viability and increase in oxidative stress compared to control cells transfected with siRNA with a scrambled sequence. Knockdown of p53 significantly decreased the induction of GDF15 by hyperoxia. In conclusion, we show that GDF15 has a pro-survival and anti-oxidant role in hyperoxia and that p53 plays a key role in its induction.

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“…We have previously shown in a variety of disease models that pharmacologic activation of Nrf2 can reduce inflammation and oxidative stress, which are hallmark features of PTB. Additionally, prenatal treatment with sulforaphane, an Nrf2 activator21, showed beneficial effects in mouse models of postnatal hyperoxia58 and epidermolysis bullosa simplex59. Thus, Nrf2 activators, such as sulforaphane, may represent a promising strategy to reduce PTB.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

Sussan

Sudini

Talbot

et al. 2017

Sci Rep

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Preterm birth (PTB) is the leading cause of neonatal mortality, and surviving infants are at increased risk for lifelong disabilities. Intrauterine inflammation is an etiological factor that drives PTB, and oxidative stress is associated with PTB. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and inflammatory stress. Here, we used the established mouse model of intrauterine inflammation-induced PTB to determine whether Nrf2 is a modifier of susceptibility to PTB and prematurity-related morbidity and mortality in the offspring. We determined that Nr2-deficient (Nrf2−/−) mice exhibited a greater sensitivity to intrauterine inflammation, as indicated by decreased time to delivery, reduced birthweight, and 100% mortality. Placentas from preterm Nrf2−/− mice showed elevated levels of markers of inflammation, oxidative stress, and cell death, and transcriptomic analysis identified numerous key signaling pathways that were differentially expressed between wild-type (WT) and Nrf2−/− mice in both preterm and control samples. Thus, Nrf2 could be a critical factor for gene-environment interactions that may determine susceptibility to PTB. Further studies are needed to determine if Nrf2 is a viable therapeutic target in women who are at risk for PTB and associated complications in the affected offspring.

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Transcriptional responses of neonatal mouse lung to hyperoxia by Nrf2 status

Cited by 40 publications

References 29 publications

Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

Role of GDF15 (growth and differentiation factor 15) in pulmonary oxygen toxicity

Nrf2 regulates gene-environment interactions in an animal model of intrauterine inflammation: Implications for preterm birth and prematurity

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