CELLULAR SENESCENCE CONTRIBUTES TO THE PROGRESSION OF HYPEROXIC BRONCHOPULMONARY DYSPLASIA

Oxidative stress (OS), inflammation, and endoplasmic reticulum (ER) stress sequentially occur in the rat model of hyperoxia (HOX) induced bronchopulmonary dysplasia (BPD), and they all increase DNA damage. Tumor suppressors increase after DNA damage, followed by apoptosis or cellular senescence when the damage becomes irreparable. Although cellular senescence contributes to wound healing, its persistence will inhibit growth potential. Therefore, we hypothesized that the persistence of cellular senescence plays a role in BPD progression. We detected evidence of increased cellular senescence in rat and human BPD lungs. Foxo4-p53 binding was increased in BPD rat lungs, and inhibition of this binding attenuated BPD severity, indicating that such binding contributes to BPD's cellular senescence. Treatment with tauroursodeoxycholic acid (TUDCA) decreases ER stress. N-Acetyl-lysyltyrosylcysteine-amide (KYC) reduced toxic oxidant production by myeloperoxidase (MPO) and subsequent OS and inflammation. Both agents effectively decreased cellular senescence. Concomitantly, alveolar complexity and the number of type 2 alveolar cells increased, indicating that MPO-mediated OS and ER stress preceded cellular senescence in BPD rat pup lungs. These data suggest that cellular senescence plays an essential role in BPD progression. Reducing MPO toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression. Using multiomic data to investigate the role of cellular senescence in the development of BPD in rat model. Nursing dams were cared for in a 12-h dark-light cycle and had free access to chow and water. According to the study design, two or four pregnant rats were used for each experiment. The dam and pups were cared for in either >90% oxygen chamber (HOX) or room air (NOX) from postnatal day 1 to day 10 (P1-P10). An oxygen sensor continuously monitored oxygen concentrations (Reming Bioinstruments Co., Redfield, NY). Pups were then recovered in room air between P11-P21. Pups were caged with nursing dams while the dams were alternated between oxygen environments to diminish oxygen toxicity. Lungs obtained at P21 from both NOX and HOX groups were used for transcriptomic studies using Affymetrix chips, histology, and immunoblots.