Hajime Maeda, Fukushima Medical University, Fukushima, Fukushima, Japan; Hayato Go, Fukushima Medical University, Fukushima, Fukushima, Japan; Hongwei Yao, Providence VA Medical Center, Providence, RI, United States; Phyllis À.. Dennery, Brown University, Providence, RI, United States
Assistant professor Fukushima Medical University Fukushima, Fukushima, Japan
Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, characterized by alveolar dysplasia and impaired vascularization. Supplemental oxygen and mechanical ventilation, commonly used in premature infants, may result in BPD. Previous studies have shown that miR-34a is increased in the lung of patients with BPD and hyperoxia-exposed mice. We have shown that exposure to high concentration of oxygen (95% O2/5% CO2; hyperoxia) increased miR-34a-5p, leading to senescence in cultured lung epithelial cells. Whether increased miR-34 expression contributes to hyperoxia-induced senescence in the lung is unknown. Objective: To investigate whether hyperoxia increases miR-34a levels, leading to cellular senescence in mouse lung. Design/Methods: Newborn mice ( < 12 h old) were exposed to hyperoxia (>95% O2) for 3 days and allowed to recover in room air until postnatal day (PND) 7. We intranasally administered 4 µl of miR-34a inhibitor (Ambion, #4464086, TX, USA) at 20 µM or miRNA inhibitor negative control (Ambion, #4464079, TX, USA) at 20 µM as control at PND0 and PND2 during hyperoxic exposure. At PND3 and PND7, we evaluated miR-34a expression and lung senescence biomarkers, including p53, p21, p16, PAI-1, and Cxcl2 gene expression. Results: Hyperoxic exposure significantly increased lung miR-34a expression at PND3 (2.1-fold), but not at PND7. Hyperoxia increased lung expression of p53, p21, p16, and PAI-1 mRNA at PND3 (1.6-fold, 25.9-fold, 1.7-fold, and 2.1-fold, respectively). Expression of p16 genes were significantly reduced at PND3 after administration of miR-34a inhibitor. Hyperoxia increased lung expression of p53, p21, and PAI-1 genes at PND7 (1.9-fold, 2.4-fold, and 2.6-fold, respectively). Administration of the miR-34a inhibitor suppressed these expressions at PND7.
Conclusion(s): Hyperoxia increases miR-34a, leading to senescence in mouse lung. Inhibiting miR-34a attenuates could be a novel therapeutic strategy to mitigate hyperoxic lung injury by repressing senescence in neonates.
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