Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic lung disease.
Failed alveolar formation and excess, disordered elastin are key features of neonatal chronic lung disease (CLD). We previously found fewer alveoli and more elastin in lungs of preterm compared with term lambs that had mechanical ventilation (MV) with O(2)-rich gas for 3 wk (MV-3 wk). We hypothesized that, in preterm more than in term lambs, MV-3 wk would reduce lung expression of growth factors that regulate alveolarization (VEGF, PDGF-A) and increase lung expression of growth factors [transforming growth factor (TGF)-alpha, TGF-beta(1)] and matrix molecules (tropoelastin, fibrillin-1, fibulin-5, lysyl oxidases) that regulate elastin synthesis and assembly. We measured lung expression of these genes in preterm and term lambs after MV for 1 day, 3 days, or 3 wk, and in fetal controls. Lung mRNA for VEGF, PDGF-A, and their receptors (VEGF-R2, PDGF-Ralpha) decreased in preterm and term lambs after MV-3 wk, with reduced lung content of the relevant proteins in preterm lambs with CLD. TGF-alpha and TGF-beta(1) expression increased only in lungs of preterm lambs. Tropoelastin mRNA increased more with MV of preterm than term lambs, and expression levels remained high in lambs with CLD. In contrast, fibrillin-1 and lysyl oxidase-like-1 mRNA increased transiently, and lung abundance of other elastin-assembly genes/proteins was unchanged (fibulin-5) or reduced (lysyl oxidase) in preterm lambs with CLD. Thus MV-3 wk reduces lung expression of growth factors that regulate alveolarization and differentially alters expression of growth factors and matrix proteins that regulate elastin assembly. These changes, coupled with increased lung elastase activity measured in preterm lambs after MV for 1-3 days, likely contribute to CLD.
Bland
Richard D
RD
Department of Pediatrics, Stanford University School of Medicine, CCSR Bldg., Rm. 1225, 269 Campus Drive, Stanford, CA 94305-5162, USA. rbland@stanford.edu
Xu
Liwen
L
Ertsey
Robert
R
Rabinovitch
Marlene
M
Albertine
Kurt H
KH
Wynn
Karen A
KA
Kumar
Vasanth H
VH
Ryan
Rita M
RM
Swartz
Daniel D
DD
Csiszar
Katalin
K
Fong
Keith S K
KS
D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology* / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011247:Pregnancy; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D012121:Respiration, Artificial; D012694:Serine / Q000378:metabolism; D012756:Sheep; D014333:Tropoelastin / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D014333:Tropoelastin; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D012694:Serine; D009195:Peroxidase; D020796:Receptor, Platelet-Derived Growth Factor alpha; D040301:Vascular Endothelial Growth Factor Receptor-2; D010196:Pancreatic Elastase; D010100:Oxygen