Hyperoxia causes senescence and increases glycolysis in cultured lung epithelial cells

Scaffa, Alejandro; Peterson, Adam; Carr, Jennifer F.; Garcia, David; Yao, Hongwei; Dennery, Phyllis A.

doi:10.14814/phy2.14839

Cited by 15 publications

(11 citation statements)

References 64 publications

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“…The phosphorylation event of p53 at S15 in humans and S18 in mice is able to increase its recruitment on the p21 promoter, thereby augmenting p21 gene expression 41 , 42 . Our recent report showed that p53 deletion inhibits hyperoxia-induced senescence in cultured lung epithelial cells 15 . Thus, an activated phosphorylated p53/p21 pathway contributes to developmental and hyperoxia-induced lung senescence.…”

Section: Discussionmentioning

confidence: 97%

Timing and cell specificity of senescence drives postnatal lung development and injury

et al. 2023

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Senescence causes age-related diseases and stress-related injury. Paradoxically, it is also essential for organismal development. Whether senescence contributes to lung development or injury in early life remains unclear. Here, we show that lung senescence occurred at birth and decreased throughout the saccular stage in mice. Reducing senescent cells at this stage disrupted lung development. In mice (<12 h old) exposed to hyperoxia during the saccular stage followed by air recovery until adulthood, lung senescence increased particularly in type II cells and secondary crest myofibroblasts. This peaked during the alveolar stage and was mediated by the p53/p21 pathway. Decreasing senescent cells during the alveolar stage attenuated hyperoxia-induced alveolar and vascular simplification. Conclusively, early programmed senescence orchestrates postnatal lung development whereas later hyperoxia-induced senescence causes lung injury through different mechanisms. This defines the ontogeny of lung senescence and provides an optimal therapeutic window for mitigating neonatal hyperoxic lung injury by inhibiting senescence.

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Section: Discussionmentioning

confidence: 97%

Timing and cell specificity of senescence drives postnatal lung development and injury

et al. 2023

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“…Senescent cells are generally identified by a combination of indicators including an absence of proliferation markers, loss of the nuclear lamina protein lamin B1, increased senescence-associated β galactosidase, increased expression of cell-cycle inhibitors, such as the cyclin-dependent kinase inhibitors p21 and p16, as well as evidence of DNA damage [ 37 ]. We previously reported that hyperoxia causes senescence in MLE-12 cells [ 28 ]. This is associated with increased double-stranded DNA damage, p53 phosphorylation and nuclear localization.…”

Section: Discussionmentioning

confidence: 99%

“…This is associated with increased double-stranded DNA damage, p53 phosphorylation and nuclear localization. Furthermore, hyperoxia-induced senescence was p53-dependent, but not pRB-dependent, in these cells [ 28 ]. Nuclear lamin B1 exclusion is a robust hallmark of senescence in culture and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung epithelial cells

Maeda

Yao

et al. 2022

Respir Res

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Background Premature infants, subjected to supplemental oxygen and mechanical ventilation, may develop bronchopulmonary dysplasia, a chronic lung disease characterized by alveolar dysplasia and impaired vascularization. We and others have shown that hyperoxia causes senescence in cultured lung epithelial cells and fibroblasts. Although miR-34a modulates senescence, it is unclear whether it contributes to hyperoxia-induced senescence. We hypothesized that hyperoxia increases miR-34a levels, leading to cellular senescence. Methods We exposed mouse lung epithelial (MLE-12) cells and primary human small airway epithelial cells to hyperoxia (95% O2/5% CO2) or air (21% O2/5% CO2) for 24 h. Newborn mice (< 12 h old) were exposed to hyperoxia (> 95% O2) for 3 days and allowed to recover in room air until postnatal day 7. Lung samples from premature human infants requiring mechanical ventilation and control subjects who were not mechanically ventilated were employed. Results Hyperoxia caused senescence as indicated by loss of nuclear lamin B1, increased p21 gene expression, and senescence-associated secretory phenotype factors. Expression of miR-34a-5p was increased in epithelial cells and newborn mice exposed to hyperoxia, and in premature infants requiring mechanical ventilation. Transfection with a miR-34a-5p inhibitor reduced hyperoxia-induced senescence in MLE-12 cells. Additionally, hyperoxia increased protein levels of the oncogene and tumor-suppressor Krüppel-like factor 4 (KLF4), which were inhibited by a miR-34a-5p inhibitor. Furthermore, KLF4 knockdown by siRNA transfection reduced hyperoxia-induced senescence. Conclusion Hyperoxia increases miR-34a-5p, leading to senescence in lung epithelial cells. This is dictated in part by upregulation of KLF4 signaling. Therefore, inhibiting hyperoxia-induced senescence via miR-34a-5p or KLF4 suppression may provide a novel therapeutic strategy to mitigate the detrimental consequences of hyperoxia in the neonatal lung.

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“…Recent studies demonstrated that cellular senescence in the alveolar epithelium contributes to the pathogenesis and progression of BPD [ 36 , 37 ]. This study identified a significant upregulation of Serpine1 in the lung tissue of neonatal mice with IUI.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of Serpine1 mediates lung injury in neonatal mice prenatally exposed to intrauterine inflammation

et al. 2022

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Background Intrauterine inflammation (IUI) alters epigenetic modifications in offspring, leading to lung injury. However, the epigenetic mechanism underlying IUI-induced lung injury remains uncertain. In the present study, we aim to investigate the effect of IUI on lung development, and to identify the key molecule involved in this process and its epigenetic regulatory mechanism. Results Serpine1 was upregulated in the lung tissue of neonatal mice with IUI. Intranasal delivery of Serpine1 siRNA markedly reversed IUI-induced lung injury. Serpine1 overexpression substantially promoted cell senescence of both human and murine lung epithelial cells, reflected by decreased cell proliferation and increased senescence-associated β-galactosidase activity, G0/G1 cell fraction, senescence marker, and oxidative and DNA damage marker expression. IUI decreased the methylation level of the Serpine1 promoter, and methylation of the promoter led to transcriptional repression of Serpine1. Furthermore, IUI promoted the expression of Tet1 potentially through TNF-α, while Tet1 facilitated the demethylation of Serpine1 promoter. DNA pull-down and ChIP assays revealed that the Serpine1 promoter was regulated by Rela and Hdac2. DNA demethylation increased the recruitment of Rela to the Serpine1 promoter and induced the release of Hdac2. Conclusion Increased Serpine1 expression mediated by DNA demethylation causes lung injury in neonatal mice with IUI. Therefore, therapeutic interventions targeting Serpine1 may effectively prevent IUI-induced lung injury.

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Hyperoxia causes senescence and increases glycolysis in cultured lung epithelial cells

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 64 publications

Timing and cell specificity of senescence drives postnatal lung development and injury

Timing and cell specificity of senescence drives postnatal lung development and injury

Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung epithelial cells

Aberrant methylation of Serpine1 mediates lung injury in neonatal mice prenatally exposed to intrauterine inflammation

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