Understanding Pulmonary Neuroendocrine and Immune Cell Interactions: Implications for Congenital Diaphragmatic Hernia

• Applicant: Dr. Annika Brandau
• Subject Area: General and Visceral Surgery ; Pediatric and Adolescent Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582775427

Congenital diaphragmatic hernia (CDH) is a developmental disorder of newborns characterized by a complex multi-level pathology. At the anatomical level, a diaphragmatic defect and pulmonary hypoplasia are characteristic features, commonly associated with pulmonary hypertension. These structural malformations are accompanied by cellular differentiation defects, such as hyperplasia of pulmonary neuroendocrine cells (PNECs) in CDH lungs. PNECs are innervated sensory epithelial cells that release neuropeptides, which, in addition to transmitting chemical and physical stimuli from the airway, may also mediate interactions with local immune cells. Lastly, CDH is further characterized by a local inflammatory response in the lungs and recurrent respiratory infections, both of which may contribute to an inflammatory milieu. In addition, therapy-related factors such as mechanical ventilation may further amplify or sustain this inflammatory environment. Against this background, the proposed project aims to investigate the cellular and molecular mechanisms underlying the bidirectional crosstalk between PNECs and immune cells in the pulmonary epithelium in order to uncover novel mechanisms of immunopathology in the lung. To this end, Air-Liquid-Interface (ALI) cultures derived from tracheal aspirates of healthy donors and CDH patients will be established and characterized. Sequential stimulation with TNF-α (inflammatory signal) and cGRP (PNEC activation) will be used to analyze effects on PNEC differentiation, clustering, neuropeptide secretion, cytokine profiles, and immune cell activation. Live-cell imaging will be employed to monitor PNEC dynamics under these conditions. The comparison of cultures with and without added immune cells will allow the identification of reciprocal responses. In addition, targeted modulation of the Notch signaling pathway will be used to assess whether, and to what extent, inflammation-induced Notch reactivation in PNECs affects their proliferation and transdifferentiation. The mechanistic insights gained will provide a fundamental understanding of epithelial-immune communication in the lung and reveal how inflammatory cues and PNEC activation jointly regulate tissue homeostasis. Building on these findings, potential pathophysiological implications for CDH will be derived, particularly regarding enhanced immune cell infiltration and pulmonary remodeling. Thus, this project will contribute to a deeper understanding of the role of PNEC-immune crosstalk in pulmonary health and disease.

• DFG Programme: Fellowship
• International Connection: Netherlands
• Host: Professor Dr. Robbert J. Rottier