Related Experiment Video
Updated: Aug 18, 2025
Lung microRNA Profiling Across the Estrous Cycle in Ozone-exposed Mice
Published on: January 7, 2019
Involvement of miRNA-34a regulated Krüppel-like factor 4 expression in hyperoxia-induced senescence in lung
Hajime Maeda1,2, Hongwei Yao1, Hayato Go2
1Department of Molecular Biology, Cellular Biology, and Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA.
Insights
High oxygen levels cause lung cell senescence in premature infants by increasing miR-34a-5p and KLF4. Inhibiting these may prevent lung disease in neonates.
Area of Science:
- Neonatal medicine
- Pulmonary medicine
- Cellular senescence
Background:
- Premature infants on mechanical ventilation may develop bronchopulmonary dysplasia.
- Hyperoxia (high oxygen) is known to induce cellular senescence.
- The role of miR-34a in hyperoxia-induced senescence was previously unclear.
Purpose of the Study:
- To investigate if hyperoxia increases miR-34a levels, causing cellular senescence.
- To determine the role of miR-34a and KLF4 in hyperoxia-induced lung injury.
Main Methods:
- Exposed mouse lung epithelial cells and primary human airway cells to hyperoxia.
- Exposed newborn mice to hyperoxia and observed recovery.
- Analyzed lung samples from premature infants and control subjects.
Main Results:
- Hyperoxia induced senescence markers (lamin B1 loss, p21 increase) in cells and mice.
- miR-34a-5p levels increased with hyperoxia in cells, mice, and infants.
- Inhibiting miR-34a-5p or KLF4 reduced hyperoxia-induced senescence.
Conclusions:
- Hyperoxia elevates miR-34a-5p, promoting lung epithelial cell senescence.
- KLF4 signaling is a key mediator of this senescence.
- Targeting miR-34a-5p or KLF4 offers a potential therapeutic strategy for neonatal lung injury.
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.
More Related Videos
13:59A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
Published on: August 12, 2018
06:48A Reporter Assay to Analyze Intronic microRNA Maturation in Mammalian Cells
Published on: June 16, 2022
