Faculty Collaboration Database

Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia. Am J Respir Cell Mol Biol 2024 Feb;70(2):94-109

Date

10/24/2023

Pubmed ID

37874230

DOI

10.1165/rcmb.2023-0038OC

Abstract

Oxidative stress, 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) and P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4 dri were administered intraperitoneally to mitigate myeloperoxidase oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblotting. 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. In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, administered intraperitoneally, effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells. Foxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing myeloperoxidase toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.

Author List

Jing X, Jia S, Teng M, Day BW, Afolayan AJ, Jarzembowski JA, Lin CW, Hessner MJ, Pritchard KA Jr, Naylor S, Konduri GG, Teng RJ

Authors

Adeleye James Afolayan MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Jason A. Jarzembowski MD, PhD Sr Associate Dean, CEO CSG, Professor in the Pathology department at Medical College of Wisconsin
Xi-Gang Jing Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Chien-Wei Lin PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Bronchopulmonary Dysplasia
Cellular Senescence
Disease Models, Animal
Humans
Hyperoxia
Infant, Newborn
Lung
Oxidants
Peroxidase
Rats
Rats, Sprague-Dawley
Taurochenodeoxycholic Acid