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01.12.2023 | Original Article

Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model

verfasst von: Mar Romero-Lopez, Marc Oria, Fernando Ferrer-Marquez, Maria Florencia Varela, Kristin Lampe, Miki Watanabe-Chailland, Leopoldo Martinez, Jose L. Peiro

Erschienen in: Pediatric Surgery International | Ausgabe 1/2023

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Abstract

Purpose

Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development.

Methods

To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1.

Results

The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase.

Conclusion

Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

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Titel: Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model
verfasst von: Mar Romero-Lopez
Marc Oria
Fernando Ferrer-Marquez
Maria Florencia Varela
Kristin Lampe
Miki Watanabe-Chailland
Leopoldo Martinez
Jose L. Peiro
Publikationsdatum: 01.12.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Surgery International / Ausgabe 1/2023
Print ISSN: 0179-0358
Elektronische ISSN: 1437-9813
DOI: https://doi.org/10.1007/s00383-023-05452-8

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Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model