Retinoids increase lung elastin expression but fail to alter morphology or angiogenesis genes in premature ventilated baboons.
Retinoids regulate elastin synthesis by alveolar myofibroblasts and affect angiogenesis pathways, both of which are processes critical for alveolar development. Retinoids accelerate alveolarization in rodents and are now used therapeutically in premature infants at risk of bronchopulmonary dysplasia (BPD). This study examined the effects of retinoid supplementation on alveolar elastin expression and deposition and angiogenesis-related signaling in a primate model of BPD. Premature baboons delivered at 125 d of gestation after maternal steroid treatment were given surfactant and ventilated with minimal supplemental oxygen for 14 d with (n = 5) and without (n = 5) supplemental vitamin A (5000 U/kg/d) and compared with 140-d unventilated controls. Ventilatory efficiency index (VEI) and oxygenation index (OI) were not statistically different between ventilated treatment groups. Expression of vascular endothelial growth factor A (VEGF-A), fms-related tyrosine kinase 1 (Flt-1), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE-1) was repressed by premature delivery and mechanical ventilation and was not altered by retinoid supplementation. Retinoid supplementation did not enhance alveolar angiogenesis. Elastin expression was repressed by premature delivery and extended ventilation, and retinoid supplementation increased elastin expression specifically in alveolar myofibroblasts within alveolar walls. These results suggest that the small decrease in mortality among premature infants receiving retinoid supplementation may not be mediated through enhanced alveolar development.
Pierce
Richard A
RA
Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri 63130, USA. rpierce@im.wustl.edu
Joyce
Belinda
B
Officer
Susan
S
Heintz
Catherine
C
Moore
Carla
C
McCurnin
Donald
D
Johnston
Carl
C
Maniscalco
William
W
D000818:Animals; D002196:Capillaries / Q000737:chemistry / Q000254:growth & development; D004549:Elastin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000737:chemistry / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010215:Papio; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D047928:Premature Birth; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000737:chemistry / Q000187:drug effects*; D012123:Pulmonary Ventilation; D042810:Receptor, TIE-1 / Q000235:genetics; D012176:Retinoids / Q000008:administration & dosage*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012176:Retinoids; D042461:Vascular Endothelial Growth Factor A; D004549:Elastin; D042810:Receptor, TIE-1; D040281:Vascular Endothelial Growth Factor Receptor-1