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Congenital diaphragmatic hernia (CDH) is a dangerous malformation of the lungs and diaphragm that causes almost a third of affected babies to die from underdeveloped lungs. So far, there have been no concrete options for treating this malformation with medication. Now, in an international study, paediatric scientists at the University of Leipzig Medical Center have shown that inflammatory cells play a previously underestimated role in the underdeveloped lungs of children with diaphragmatic hernia – both before and after birth. The findings lay the foundation for potential new treatment approaches and have been published in the American Journal of Respiratory and Critical Care Medicine.
Congenital diaphragmatic hernia is one of the deadliest malformations in newborns. The main problem is the underdevelopment of the lungs. The condition also involves a hole in the diaphragm, which paediatric surgeons repair during the first week of life. However, even after a successful operation, many children with diaphragmatic hernia still die as a result of their underdeveloped lungs. So far, so-called pulmonary hypoplasia has scarcely been amenable to therapeutic intervention. Researchers in paediatric surgery at the University of Leipzig Medical Center therefore set out to discover which molecular mechanisms cause this malformation – and whether they might be specifically targeted for treatment.
“In our current study we were able to show in human lungs that certain inflammatory cells – particularly macrophages – appear in increased numbers both before and after birth. This may influence the development of lung structure as we see it in congenital diaphragmatic hernia,” explains PD Dr Richard Wagner, lead investigator of the study in Leipzig. “We also confirmed several parallels in the inflammatory processes of diaphragmatic hernia between animal models and human samples – a crucial step towards potentially translating future therapies to humans,” says the senior physician and research group leader for paediatric surgery at the University of Leipzig Medical Center.
The latest scientific analyses of congenital diaphragmatic hernia, carried out in collaboration with researchers in Mannheim, Paris, Winnipeg and Boston, show that the inflammatory signalling pathways of the immune system are overactivated. One striking finding was the so-called macrophage migration inhibitory factor, which is associated with disruptions in lung development.
For the study, state-of-the-art research methods were used, including proteomics technology to analyse a wide range of proteins in foetal lungs. Specialised microscopic staining and cell-measurement techniques were also applied. The results were then examined using bioinformatic tools and compared with findings from a stem cell model and animal models. In an earlier study, PD Dr Jan-Hendrik Gosemann, executive senior physician and research group leader in paediatric surgery at the University of Leipzig Medical Center, had already demonstrated in animal experiments that increased numbers of macrophages are found in the lungs of unborn rats with diaphragmatic hernia.
“The current results of our study have the potential one day to be translated into new treatment approaches. If we succeed in specifically reducing the heightened inflammation during pregnancy, we may be able to promote lung development and thereby improve both the survival prospects and the quality of life of affected children. The hope is to develop an additional drug therapy that could be administered before birth,” says PD Dr Wagner.
To pursue this approach further, the Leipzig team is currently establishing a major research programme funded by the German Research Foundation (DFG). Planned steps include testing various anti-inflammatory substances in animal models as well as in patient-derived stem cells, with the long-term aim of preparing clinical trials for prenatal treatment. “So far, our studies are still at the level of molecular and cellular observations. But our ongoing research and the findings published in earlier and current studies provide strong indications that increased inflammation is a central driver of this severe malformation,” says paediatric surgeon PD Dr Wagner. “I am especially delighted that Ms Katinka Sturm, a doctoral researcher in our department, is joint first author of this study – a wonderful recognition for such a young researcher.”
Translation: Matthew Rockey
Richard Wagner
senior physician and research group leader for paediatric surgery,
University of Leipzig Medical Center
Mail: richard.wagner@medizin.uni-leipzig.de
Original publication in American Journal of Respiratory and Critical Care Medicine: Macrophages Are Enriched Pre- and Postnatally in Hypoplastic Lungs from Patients with Congenital Diaphragmatic Hernia. DOI: 10.1164/rccm.202501-0153RL, https://www.atsjournals.org/doi/10.1164/rccm.202501-0153RL
https://www.uni-leipzig.de/en/newsdetail/artikel/new-stem-cell-model-developed-f...
https://www.uni-leipzig.de/en/newsdetail/artikel/new-research-into-life-threaten...
Congenital diaphragmatic hernia is one of the deadliest malformations in newborns.
Copyright: Colourbox
PD Dr. Richard Wagner.
Quelle: Stefan Straube
Copyright: UKL
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