Overactivated Epithelial NF-κB Disrupts Lung Development in Congenital Diaphragmatic Hernia

Overactivated Epithelial NF-κB Disrupts Lung Development in Congenital Diaphragmatic Hernia

Abnormal lung development is the main cause of morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH), a common birth defect (1:2500) of largely unknown pathobiology. Recent studies discovered that inflammatory processes, and specifically NF-κB associated pathways are enriche...

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Published in:American journal of respiratory cell and molecular biology Vol. 69; no. 5; pp. 545 - 555
Main Authors: Dylong, Florentine, Riedel, Jan, Amonkar, Gaurang M, Peukert, Nicole, Lieckfeldt, Paula, Sturm, Katinka, Höxter, Benedikt, Tse, Wai Hei, Miyake, Yuichiro, Moormann, Maria, Bode, Lena Marie, Mayer, Steffi, Keijzer, Richard, Lacher, Martin, Ai, Xingbin, Gosemann, Jan-Hendrik, Wagner, Richard
Format: Journal Article
Language:English
Published: United States American Thoracic Society 01-11-2023
Subjects:
Airway management
Dexamethasone
Diaphragm
Epithelium
Hernia
Hypoplasia
Inflammation
Lung cancer
Lung diseases
Lungs
Morbidity
Neonates
NF-κB protein
Pulmonary fibrosis
Therapeutic targets
Prenatal Inflammation
Congenital Diaphragmatic Henria
Lung hypoplasia
Nitrofen Rat Model
NF-kB
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Summary:Abnormal lung development is the main cause of morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH), a common birth defect (1:2500) of largely unknown pathobiology. Recent studies discovered that inflammatory processes, and specifically NF-κB associated pathways are enriched in human and experimental CDH. However, the molecular signaling of NF-κB in abnormal CDH lung development and its potential as a therapeutic target requires further investigation. Using sections and hypoplastic lung explant cultures from the nitrofen rat model of CDH and human fetal CDH lungs, we demonstrate that NF-κB and its downstream transcriptional targets are hyperactive during abnormal lung formation in CDH. NF-κB activity was especially elevated in the airway epithelium of nitrofen and human CDH lungs at different developmental stages. Fetal rat lung explants had impaired pseudoglandular airway branching after exposure to nitrofen, together with increased phosphorylation and transcriptional activity of NF-κB. Dexamethasone, the broad and clinically applicable anti-inflammatory NF-κB antagonist, rescued lung branching and normalized NF-κB signaling in hypoplastic lung explants. Moreover, specific NF-κB inhibition with curcumenol similarly rescued ex vivo lung hypoplasia and restored NF-κB signaling. Lastly, we showed that prenatal intraperitoneal dexamethasone administration to pregnant rat dams carrying fetuses with hypoplastic lungs, significantly improves lung branching and normalizes NF-κB in vivo. Our results indicate that NF-κB is aberrantly activated in human and nitrofen CDH lungs. Anti-inflammatory treatment with dexamethasone and/ or specific NF-κB inhibition should be investigated further as a therapeutic avenue to target lung hypoplasia in CDH.
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ISSN:1044-1549
1535-4989
DOI:10.1165/rcmb.2023-0138OC