Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0242706 (
hyperoxia
)
5,219
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Rationale:
Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT
+
endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown.
Objectives:
To determine whether c-KIT
+
EC progenitors stimulate alveologenesis in the neonatal lung.
Methods:
We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT
+
EC progenitors. A mouse model of perinatal
hyperoxia
-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT
+
EC progenitors in the neonatal lung.
Measurements and Main Results:
Pulmonary c-KIT
+
EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT
+
ECs was conserved in mouse and human lungs and enriched in
FOXF1
-regulated transcriptional targets. Expression of
FOXF1
and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal
hyperoxia
decreased the number of c-KIT
+
EC progenitors. Haploinsufficiency or endothelial-specific deletion of
Foxf1
in mice increased apoptosis and decreased proliferation of c-KIT
+
ECs. Inactivation of either
Foxf1
or
c-Kit
caused alveolar simplification. Adoptive transfer of c-KIT
+
ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to
hyperoxia
.
Conclusions:
Cell therapy involving c-KIT
+
EC progenitors can be beneficial for the treatment of BPD.
...
PMID:Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT
+
Endothelial Progenitor Cells. 3134 12
Rationale
: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.
Objectives
: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or
FOXF1
(forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.
Methods
: Newborn mice were exposed to 75% O
2
for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with
Foxm1
or
Foxf1
cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.
Measurements and Main Results
: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or
FOXF1
did not protect endothelial cells from apoptosis caused by
hyperoxia
but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and
FOXF1
improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.
Conclusions
: Nanoparticle delivery of FOXM1 or
FOXF1
stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.
...
PMID:Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia. 3233 96
