Dataset Information

CELLULAR SENESCENCE CONTRIBUTES TO THE PROGRESSION OF HYPEROXIC BRONCHOPULMONARY DYSPLASIA

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE223745 | GEO | 2024/01/01

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Myeloperoxidase (MPO), oxidative stress (OS), and endoplasmic reticulum (ER) stress are all increased in the lungs of neonatal rat pups raised in hyperoxia (HOX, >90% O2), an established model of bronchopulmonary dysplasia (BPD). However, the relationship between OS, MPO, and ER stress has not been examined in HOX rat pups. To determine the relationship between OS, MPO, and ER stress in BPD we treated Sprague-Dawley neonatal rat pups with Tunicamycin (Tun) or with HOX. Tun directly induces ER stress and simplifies neonatal lung alveolarization. Previously, we showed that HOX induces a cycle of destruction that we hypothesize through increased OS, MPO, and ER stress to induce BPD. To inhibit ER stress specifically, we used tauroursodeoxycholic acid (TUDCA), a molecular chaperone. To break the cycle of destruction and reduce OS and MPO we used N-acetyl-lysyltyrosylcysteine-amide (KYC), a systems pharmacology agent. Lung structure was studied morphometrically. ER stress was detected using immunofluorescence (IF), transcriptomic, proteomic, and electron microscopic analyses. Increased ER stress was observed in the lungs of HOX rat pups and also in human BPD lungs by IF. Morphometric and proteomic studies of rat lungs showed that Tun treatment decreased lung complexity and increased ER stress and BPD severity. The fact that TUDCA improved lung complexity in Tun-treated neonatal rat pups, and decreased BPD induced by HOX provides strong support for the idea that ER stress plays a causal role in BPD. Additional support comes from data showing TUDCA decreased lung myeloid cells and MPO levels in the lungs of both Tun- and HOX-treated neonatal rat pups. These data link OS and MPO to ER stress in the mechanisms mediating BPD. KYC's effective inhibition of ER stress in the lungs of Tun-treated rat pups provides additional support for the idea that MPO-induced ER stress plays a direct causal role in BPD. Thus, ER stress appears to expand our proposed cycle of destruction. Our results suggest ER stress evolves from OS and MPO to increase neonatal lung injury and impaired neonatal lung growth and development. The encouraging effect of TUDCA indicates chemical chaperone has the potential in treating BPD. Using multiomic data to investigate the role of endoplasmic reticulum stress in the development of BPD in rat model.

Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-Î² (TGF-Î²)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-Î²/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.

Project description:Background: Nrf2 is an essential cytoprotective transcription factor. However, association of Nrf2 in organ development and neonatal disease is rarely examined. Hyperoxia exposure to newborn rodents generates pulmonary phenotypes which resemble bronchopulmonary dysplasia (BPD) of prematurity. Methods: To investigate the role of Nrf2 in lung maturation and BPD pathogenesis, Nrf2-deficient (Nrf2-/-) and wild-type (Nrf2+/+) neonates were exposed to air or hyperoxia (O2). Transcriptome analysis determined Nrf2-directed mechanisms in premature lung. Lung injury was assessed by bronchoalveolar lavage analysis and histopathology. Results: In Nrf2-/- neonates, basal expression of cell cycle machinery, redox balance, and lipid/carbohydrate metabolism genes were suppressed while immunity genes were overexpressed compared to Nrf2+/+ pups. O2-induced mortality and pulmonary inflammation/injury were significantly higher in Nrf2-/- than in Nrf2+/+. Lung DNA lesion and oxidation were greater in Nrf2-/- than in Nrf2+/+, constitutively and after O2. Nrf2-dependent genes modulated cellular growth/proliferation, defense, immunity, and lipid metabolism against hyperoxia. Bioinformatic elucidation of Nrf2 binding motifs and augmented O2-induced inflammation in genetically deficient neonates validated Gpx2 and Marco as Nrf2 effectors. Conclusion: Overall, Nrf2 in underdeveloped lungs orchestrated cell cycle, morphogenesis, and immunity as well as cellular defense constitutively and under oxidant stress. Results provide putative molecular mechanisms of Nrf2-directed lung alveolarization and BPD of prematurity. PARALLEL study design with 42 samples comparing 14 groups of age (P1 to P4 corresponding to day 0 to day 3 animals), gene, and exposure: (4 groups Nrf+/+ wild type P1-P4 air exposure) (4 groups Nrf -/- knockout P1-P4 air exposure), (3 groups Nrf+/+ wild type P2-P4 with 100 percent O2 (hyperoxia exposure) and 3 groupsNrf -/- knockout P2-P4 with 100 percent O2 (hyperoxia exposure)) Biological replicates: 3 per group

Dataset Information

CELLULAR SENESCENCE CONTRIBUTES TO THE PROGRESSION OF HYPEROXIC BRONCHOPULMONARY DYSPLASIA

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure