Characterization and Modulation of the Pro-inflammatory Molecular Program in Hypoplastic Lungs of Congenital Diaphragmatic Hernia

• Applicant: Privatdozent Dr. Richard Wagner
• Subject Area: Pediatric and Adolescent Medicine ; General and Visceral Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565624816

Congenital diaphragmatic hernia (CDH) is a commonly occurring congenital malformation of the diaphragm and lungs. Since 2000, more than 500,000 newborns with CDH worldwide (30%) have died due to the consequences of lung immaturity, and survivors suffer from long-term sequelae. Despite CDH being as common as cystic fibrosis, the disease is often unknown, and the underlying pathobiology is inadequately understood. Pediatric surgeons can surgically close the defect in the diaphragm, but the underlying lung hypoplasia is only partially treatable. With this project, our goal is to utilize modern stem cell-based human models and established animal models of CDH to better understand abnormal lung development in CDH and establish new prenatal therapy options. We have recently shown that pro-inflammatory processes (e.g., NF-kB signaling) are pathologically enriched in hypoplastic CDH lungs. Using cell culture models from patient samples and established rat and sheep models for CDH, we will investigate how anti-inflammatory therapy (e.g., NF-kB inhibition) can contribute to improving lung maturation. Proteome profiles of CDH rat lungs show pro-inflammatory changes. We will now examine human fetal CDH lungs using proteomics to validate and transfer these results from the animal model. Additionally, we will examine human lung stem cells from tracheal aspirates of intubated children with CDH and control samples, testing whether they secrete pro-inflammatory cytokines that may interfere with normal lung development. In the mentioned animal models, we will then attempt to rescue prenatal lung maturation through anti-inflammatory therapy. Overall, this project will explore in various human and animal models whether the overactivation of pro-inflammatory processes leads to lung hypoplasia in CDH and whether targeted anti-inflammatory prenatal therapy can improve lung development in CDH.

• DFG Programme: Research Grants
• International Connection: Belgium, Canada, France, USA
• Cooperation Partners: Professorin Dr. Xingbin Ai, Ph.D.; Professorin Dr. Alexandra Benachi, Ph.D.; Professor Dr. Richard Keijzer, Ph.D.; Professorin Dr. Francesca Russo, Ph.D.