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@ARTICLE{Storti:274372,
author = {M. Storti and M. L. Faietti and X. Murgia and C. Catozzi
and I. Minato and D. Tatoni and S. Cantarella$^*$ and F.
Ravanetti and L. Ragionieri and R. Ciccimarra and M. Zoboli
and M. Vilanova and E. Sánchez-Jiménez and M. Gay and M.
Vilaseca and G. Villetti and B. Pioselli and F. Salomone and
S. Ottonello and B. Montanini and F. Ricci},
title = {{T}ime-resolved transcriptomic profiling of the developing
rabbit's lungs: impact of premature birth and implications
for modelling bronchopulmonary dysplasia.},
journal = {Respiratory research},
volume = {24},
number = {1},
issn = {1465-9921},
address = {London},
publisher = {BioMed Central},
reportid = {DKFZ-2023-00574},
pages = {80},
year = {2023},
abstract = {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.},
keywords = {Animals / Pregnancy / Female / Rabbits / Infant, Newborn /
Humans / Bronchopulmonary Dysplasia: genetics /
Bronchopulmonary Dysplasia: pathology / Premature Birth:
metabolism / Hyperoxia: metabolism / Transcriptome /
Endothelial Cells: metabolism / Proteomics / Animals,
Newborn / Lung: metabolism / Inflammation: metabolism /
Bronchopulmonary dysplasia (Other) / Lung development
(Other) / Premature birth (Other) / Proteomics (Other) /
Transcriptomics (Other)},
cin = {B150},
ddc = {610},
cid = {I:(DE-He78)B150-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36922832},
pmc = {pmc:PMC10015812},
doi = {10.1186/s12931-023-02380-y},
url = {https://inrepo02.dkfz.de/record/274372},
}