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

先天性膈疝 膈式呼吸 膈疝 医学 左肺 解剖 病理 生物 内科学 放射科 胎儿 遗传学 替代医学 怀孕
作者
Florentine Dylong,Jan Riedel,Gaurang M. Amonkar,Nicole Peukert,Paula Lieckfeldt,Katinka Sturm,Benedikt Höxter,Wai Hei Tse,Yuichiro Miyake,Maria Moormann,Lena Marie Bode,Steffi Mayer,Richard Keijzer,Martin Lacher,Xingbin Ai,Jan‐Hendrik Gosemann,Richard Wagner
出处
期刊:American Journal of Respiratory Cell and Molecular Biology [American Thoracic Society]
卷期号:69 (5): 545-555 被引量:8
标识
DOI:10.1165/rcmb.2023-0138oc
摘要

Abnormal lung development is the main cause of morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH), a common birth defect (1:2,500) 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 require 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 antiinflammatory 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. Last, 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. Antiinflammatory 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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