Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia

Am J Respir Cell Mol Biol. 2023 Oct 24. doi: 10.1165/rcmb.2023-0038OC. Online ahead of print.ABSTRACTOxidative stress (OS), inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between postnatal day 1 (P1) to P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4dri were given i.p. to mitigate myeloperoxidase (MPO)-oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblots. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells (AT2). In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, i.p., effectively...
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Source Type: research