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1 Pediatrics, Stanford University, School of Medicine, Stanford, California, United States
2 Pediatrics, University of Utah, School of Medicine, Salt Lake City, Utah, United States
3 Pediatrics, State University of New York at Buffalo, Buffalo, New York, United States
4 Anatomy, Biochemistry and Physiology, University of Hawaii, John A Burns School of Medicine, Honolulu, Hawaii, United States
* To whom correspondence should be addressed. E-mail: rbland{at}stanford.edu.
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 to term lambs that had mechanical ventilation with O2-rich gas for 3wk (MV-3wk). We hypothesized that in preterm more than in term lambs, MV-3wk would reduce lung expression of growth factors that regulate alveolarization (VEGF, PDGF-A), and increase lung expression of growth factors (TGF-
, TGF-
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 1d, 3d or 3wk, and in fetal controls. Lung mRNA for VEGF, PDGF-A and their receptors (VEGF-R2, PDGF-R) decreased in preterm and term lambs after MV-3wk, with reduced lung content of the relevant proteins in preterm lambs with CLD. TGF- and TGF-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 were unchanged (fibulin-5) or reduced (lysyl oxidase) in preterm lambs with CLD. Thus, MV-3wk 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 1-3d, likely contribute to CLD.
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