Sage Journals: Discover world-class research

Abstract

Background:

Bronchopulmonary dysplasia (BPD), a common pulmonary condition in infants causing neonatal death, has a complicated pathogenic mechanism. As the new iron-dependent cell death type, ferroptosis can result from lipid peroxidation and exert a critical effect on the pathogenic mechanism of BPD. This study aimed to investigate ferroptosis-related genes with regard to their expression patterns and functional roles in BPD.

Methods:

Clinical and gene expression data were obtained based on the Gene Expression Omnibus (GEO) database, and the web-based analysis approach GEO2R was used for selecting differentially expressed genes (DEGs). For significant ferroptosis-related DEGs (FDEGs), their bioinformatic functions and molecular interactions were explored using the WEB-based Gene Set Analysis Toolkit (WebGestalt) and Metascape, protein–protein interaction network analysis, and Kyoto Encyclopedia of Genes and Genomes enrichment. In addition, hub FDEG expression levels in BPD were verified through quantitative reverse transcription polymerase chain reaction (RT-qPCR).

Results:

There were totally 3,673 DEGs detected in BPD infants compared with controls, including 36 FDEGs with upregulation, whereas 13 with downregulation. Functional enrichment analysis revealed the significant activation of biological processes in response to stress and ferroptosis. Through RT-qPCR validation, five hub FDEGs were identified, including mitogen-activated protein kinase 14 (MAPK14), tumor antigen p53 (TP53), signal transducer and activator of transcription 3 (STAT3), toll-like receptor 4 (TLR4), and dual-specificity protein phosphatase 1 (DUSP1). Based on the outcomes of receiver operating characteristic curve analysis, the area under the curve values of these genes were >0.7, revealing that they might be used to identify BPD.

Conclusions:

The results in this study shed more insights on the diagnosis and mechanism of ferroptosis in BPD. Further research should be carried out to assess its clinical utility.

Keywords

bronchopulmonary dysplasia preterm infant ferroptosis bioinformatics diagnosis

Get full access to this article

View all access options for this article.

References

Stoll

, Hansen

, Bell

, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993–2012. JAMA, 2015; 314(10):1039–1051; doi: 10.1001/jama.2015.10244

Jobe

. The new bronchopulmonary dysplasia. Curr Opin Pediatr, 2011; 23(2):167–172; doi: 10.1097/MOP.0b013e3283423e6b

Thébaud

, Goss

, Laughon

, et al. Bronchopulmonary dysplasia. Nat Rev Dis Primers, 2019; 5(1):78; doi: 10.1038/s41572-019-0127-7

Hansmann

, Sallmon

, Roehr

, et al.; European Pediatric Pulmonary Vascular Disease Network (EPPVDN). Pulmonary hypertension in bronchopulmonary dysplasia. Pediatr Res, 2021; 89(3):446–455; doi: 10.1038/s41390-020-0993-4

Wang

, Dong

. Oxidative stress and bronchopulmonary dysplasia. Gene, 2018; 678:177–183; doi: 10.1016/j.gene.2018.08.031

Kimble

, Robbins

, Perez

. Pathogenesis of bronchopulmonary dysplasia: Role of oxidative stress from ‘omics’ studies. Antioxidants, 2022; 11(12):2380; doi: 10.3390/antiox11122380

Wang

, Tsao

. Phenotypes of bronchopulmonary dysplasia. Int J Mol Sci, 2020; 21(17):6112; doi: 10.3390/ijms21176112

Steinhorn

, Davis

, Göpel

, et al.; International Neonatal Consortium. Chronic pulmonary insufficiency of prematurity: Developing optimal endpoints for drug development. J Pediatr, 2017; 191:15–21.e1; doi: 10.1016/j.jpeds.2017.08.006

Jobe

, Bancalari

. Bronchopulmonary dysplasia. Am J Respir Crit Care Med, 2001; 163(7):1723–1729; doi: 10.1164/ajrccm.163.7.2011060

10.

Dixon

, Lemberg

, Lamprecht

, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell, 2012; 149(5):1060–1072; doi: 10.1016/j.cell.2012.03.042

11.

, Cao

, Xiao

, et al. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ, 2020; 27(9):2635–2650; doi: 10.1038/s41418-020-0528-x

12.

Yoshida

, Minagawa

, Araya

, et al. Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat Commun, 2019; 10(1):3145; doi: 10.1038/s41467-019-10991-7

13.

Wenzel

, Tyurina

, Zhao

, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell, 2017; 171(3):628–641.e26; doi: 10.1016/j.cell.2017.09.044

14.

Yang

, Tai

, Lu

, et al. lncRNA ZFAS1 promotes lung fibroblast-to-myofibroblast transition and ferroptosis via functioning as a ceRNA through miR-150-5p/SLC38A1 axis. Aging, 2020; 12(10):9085–9102; doi: 10.18632/aging.103176

15.

Jiang

, Mao

, Yang

, et al. EGLN1/c-Myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics, 2017; 7(13):3293–3305; doi: 10.7150/thno.19988

16.

Barrett

, Wilhite

, Ledoux

, et al. NCBI GEO: Archive for functional genomics data sets—update. Nucleic Acids Res, 2013; 41(Database issue):D991–D995; doi: 10.1093/nar/gks1193

17.

Zhou

, Bao

. FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database, 2020; 2020:baaa021; doi: 10.1093/database/baaa021

18.

Wang

, Vasaikar

, Shi

, et al. WebGestalt 2017: A more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res, 2017; 45(W1):W130–W137; doi: 10.1093/nar/gkx356

19.

Zhou

, Zhou

, Pache

, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun, 2019; 10(1):1523; doi: 10.1038/s41467-019-09234-6

20.

Kanehisa

, Goto

. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res, 2000; 28(1):27–30; doi: 10.1093/nar/28.1.27

21.

Szklarczyk

, Morris

, Cook

, et al. The STRING database in 2017: Quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res, 2017; 45(D1):D362–D368; doi: 10.1093/nar/gkw937

22.

Sucre

, Haist

, Bolton

, et al. Early changes and indicators characterizing lung aging in neonatal chronic lung disease. Front Med (Lausanne), 2021; 8:665152; doi: 10.3389/fmed.2021.665152

23.

Capasso

, Vento

, Loddo

, et al. Oxidative stress and bronchopulmonary dysplasia: Evidences from microbiomics, metabolomics, and proteomics. Front Pediatr, 2019; 7:30; doi: 10.3389/fped.2019.00030

24.

, Cao

, Yin

, et al. Ferroptosis: Past, present and future. Cell Death Dis, 2020; 11(2):88; doi: 10.1038/s41419-020-2298-2

25.

Moreno-Fernandez

, Ochoa

, Lopez-Frias

, et al. Iron deficiency and iron homeostasis in low birth weight preterm infants: A systematic review. Nutrients, 2019; 11(5):1090; doi: 10.3390/nu11051090

26.

de Almeida

, Pereira

, Amantéa

, et al. Neonatal diseases and oxidative stress in premature infants: An integrative review. J Pediatr (Rio J), 2022; 98(5):455–462; doi: 10.1016/j.jped.2021.11.008

27.

Lembo

, Buonocore

, Perrone

. Oxidative stress in preterm newborns. Antioxidants, 2021; 10(11):1672; doi: 10.3390/antiox10111672

28.

Chen

, Zheng

, Yang

. The emerging roles of ferroptosis in neonatal diseases. J Inflamm Res, 2023; 16:2661–2674; doi: 10.2147/JIR.S414316

29.

Chou

, Chen

. Hyperoxia induces Ferroptosis and impairs lung development in neonatal mice. Antioxidants, 2022; 11(4):641; doi: 10.3390/antiox11040641

30.

Fabiano

, Gavilanes

, Zimmermann

, et al. The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia. Acta Paediatr, 2016; 105(5):535–541; doi: 10.1111/apa.13233

31.

Abdel Ghany

, Alsharany

, Ali

, et al. Anti-oxidant profiles and markers of oxidative stress in preterm neonates. Paediatr Int Child Health, 2016; 36(2):134–140; doi: 10.1179/2046905515Y.0000000017

32.

Thompson

, Oliveira

, Hermann

, et al. Distinct TP53 mutation types exhibit increased sensitivity to ferroptosis independently of changes in iron regulatory protein activity. Int J Mol Sci, 2020; 21(18):6751; doi: 10.3390/ijms21186751

33.

Xie

, Zhu

, Song

, et al. The tumor suppressor p53 limits Ferroptosis by blocking DPP4 activity. Cell Rep, 2017; 20(7):1692–1704; doi: 10.1016/j.celrep.2017.07.055

34.

, Jia

, Xiao

, et al. TRIM-containing 44 aggravates cardiac hypertrophy via TLR4/NOX4-induced Ferroptosis. J Mol Med (Berl), 2023; 101(6):685–697; doi: 10.1007/s00109-023-02318-3

35.

Zhu

, Zhu

, Sun

, et al. Inhibition of TLR4 prevents hippocampal hypoxic-ischemic injury by regulating Ferroptosis in neonatal rats. Exp Neurol, 2021; 345:113828; doi: 10.1016/j.expneurol.2021.113828

36.

Wang

Y-G

, Yu

X-J

, Qu

Y-K

, et al. Ferrostatin-1 inhibits toll-like receptor 4/NF-κB signaling to alleviate intervertebral disc degeneration in rats. Am J Pathol, 2023; 193(4):430–441; doi: 10.1016/j.ajpath.2022.12.014

37.

Yao

, Shi

, Zhao

, et al. Vitamin D attenuates hyperoxia-induced lung injury through downregulation of toll-like receptor 4. Int J Mol Med, 2017; 39(6):1403–1408; doi: 10.3892/ijmm.2017.2961

38.

Ballinger

, Newstead

, Zeng

, et al. TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death. J Immunol, 2012; 189(1):356–364; doi: 10.4049/jimmunol.1103124

39.

Mackie

, Ma

, Tangye

, et al. The ups and downs of STAT3 function: Too much, too little and human immune dysregulation. Clin Exp Immunol, 2023; 212(2):107–116; doi: 10.1093/cei/uxad007

40.

Ouyang

, Li

, Lou

, et al. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol, 2022; 52:102317; doi: 10.1016/j.redox.2022.102317

41.

Luo

, Deng

, Chen

, et al. Identification of lipocalin 2 as a ferroptosis-related key gene associated with hypoxic-ischemic brain damage via STAT3/NF-κB signaling pathway. Antioxidants, 2023; 12(1):186; doi: 10.3390/antiox12010186

42.

Zhu

, Peng

, Huo

, et al. STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice. Free Radic Biol Med, 2023; 201:111–125; doi: 10.1016/j.freeradbiomed.2023.03.003

43.

Lin

, Yan

, Wang

, et al. STAT3-mediated ferroptosis is involved in sepsis-associated acute respiratory distress syndrome. Inflammation, 2024; 47(4):1204–1219; doi: 10.1007/s10753-024-01970-2

44.

, Bai

, Ebenezer

, et al. Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury. Thorax, 2022; 77(1):47–57; doi: 10.1136/thoraxjnl-2020-216469

45.

Shi

, Zha

, Pan

, et al. DUSP1 protects against ischemic acute kidney injury through stabilizing mtDNA via interaction with JNK. Cell Death Dis, 2023; 14(11):724; doi: 10.1038/s41419-023-06247-4

46.

Chen

, Kang

, Kroemer

, et al. Cellular degradation systems in ferroptosis. Cell Death Differ, 2021; 28(4):1135–1148; doi: 10.1038/s41418-020-00728-1

47.

Xie

, Liu

, Kang

, et al. DUSP1 blocks autophagy-dependent ferroptosis in pancreatic cancer. J Pancreatol, 2020; 3(3):154–160; doi: 10.1097/JP9.0000000000000054

48.

Zhao

, Ma

, Cai

, et al. Caffeine inhibits NLRP3 inflammasome activation by suppressing MAPK/NF-κB and A2aR signaling in LPS-induced THP-1 macrophages. Int J Biol Sci, 2019; 15(8):1571–1581; doi: 10.7150/ijbs.34211

49.

Madkour

, Anbar

, El-Gamal

. Current status and future prospects of p38α/MAPK14 kinase and its inhibitors. Eur J Med Chem, 2021; 213:113216; doi: 10.1016/j.ejmech.2021.113216

50.

Wang

, Lv

, Sun

, et al. Caffeine reduces oxidative stress to protect against hyperoxia-induced lung injury via the adenosine A2A receptor/cAMP/PKA/Src/ERK1/2/p38MAPK pathway. Redox Rep, 2022; 27(1):270–278; doi: 10.1080/13510002.2022.2143114

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.04 MB

Expression Profiles of Ferroptosis-Related Genes and Their Diagnostic Value in Infants with Bronchopulmonary Dysplasia

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Get full access to this article

References

Supplementary Material