TY  - JOUR
AU  - Storti, Matteo
AU  - Faietti, Maria Laura
AU  - Murgia, Xabier
AU  - Catozzi, Chiara
AU  - Minato, Ilaria
AU  - Tatoni, Danilo
AU  - Cantarella, Simona
AU  - Ravanetti, Francesca
AU  - Ragionieri, Luisa
AU  - Ciccimarra, Roberta
AU  - Zoboli, Matteo
AU  - Vilanova, Mar
AU  - Sánchez-Jiménez, Ester
AU  - Gay, Marina
AU  - Vilaseca, Marta
AU  - Villetti, Gino
AU  - Pioselli, Barbara
AU  - Salomone, Fabrizio
AU  - Ottonello, Simone
AU  - Montanini, Barbara
AU  - Ricci, Francesca
TI  - Time-resolved transcriptomic profiling of the developing rabbit's lungs: impact of premature birth and implications for modelling bronchopulmonary dysplasia.
JO  - Respiratory research
VL  - 24
IS  - 1
SN  - 1465-9921
CY  - London
PB  - BioMed Central
M1  - DKFZ-2023-00574
SP  - 80
PY  - 2023
AB  - Premature birth, perinatal inflammation, and life-saving therapies such as postnatal oxygen and mechanical ventilation are strongly associated with the development of bronchopulmonary dysplasia (BPD); these risk factors, alone or combined, cause lung inflammation and alter programmed molecular patterns of normal lung development. The current knowledge on the molecular regulation of lung development mainly derives from mechanistic studies conducted in newborn rodents exposed to postnatal hyperoxia, which have been proven useful but have some limitations.Here, we used the rabbit model of BPD as a cost-effective alternative model that mirrors human lung development and, in addition, enables investigating the impact of premature birth per se on the pathophysiology of BPD without further perinatal insults (e.g., hyperoxia, LPS-induced inflammation). First, we characterized the rabbit's normal lung development along the distinct stages (i.e., pseudoglandular, canalicular, saccular, and alveolar phases) using histological, transcriptomic and proteomic analyses. Then, the impact of premature birth was investigated, comparing the sequential transcriptomic profiles of preterm rabbits obtained at different time intervals during their first week of postnatal life with those from age-matched term pups.Histological findings showed stage-specific morphological features of the developing rabbit's lung and validated the selected time intervals for the transcriptomic profiling. Cell cycle and embryo development, oxidative phosphorylation, and WNT signaling, among others, showed high gene expression in the pseudoglandular phase. Autophagy, epithelial morphogenesis, response to transforming growth factor β, angiogenesis, epithelium/endothelial cells development, and epithelium/endothelial cells migration pathways appeared upregulated from the 28th day of gestation (early saccular phase), which represents the starting point of the premature rabbit model. Premature birth caused a significant dysregulation of the inflammatory response. TNF-responsive, NF-κB regulated genes were significantly upregulated at premature delivery and triggered downstream inflammatory pathways such as leukocyte activation and cytokine signaling, which persisted upregulated during the first week of life. Preterm birth also dysregulated relevant pathways for normal lung development, such as blood vessel morphogenesis and epithelial-mesenchymal transition.These findings establish the 28-day gestation premature rabbit as a suitable model for mechanistic and pharmacological studies in the context of BPD.
KW  - Animals
KW  - Pregnancy
KW  - Female
KW  - Rabbits
KW  - Infant, Newborn
KW  - Humans
KW  - Bronchopulmonary Dysplasia: genetics
KW  - Bronchopulmonary Dysplasia: pathology
KW  - Premature Birth: metabolism
KW  - Hyperoxia: metabolism
KW  - Transcriptome
KW  - Endothelial Cells: metabolism
KW  - Proteomics
KW  - Animals, Newborn
KW  - Lung: metabolism
KW  - Inflammation: metabolism
KW  - Bronchopulmonary dysplasia (Other)
KW  - Lung development (Other)
KW  - Premature birth (Other)
KW  - Proteomics (Other)
KW  - Transcriptomics (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36922832
C2  - pmc:PMC10015812
DO  - DOI:10.1186/s12931-023-02380-y
UR  - https://inrepo02.dkfz.de/record/274372
ER  -