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Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic lung disease

¹Department of Pediatrics, Stanford University School of Medicine, Stanford, California; ²Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; ³Department of Pediatrics, State University of New York, Buffalo, New York; and ⁴Departments of Anatomy, Biochemistry and Physiology, and Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii

Submitted 15 September 2006 ; accepted in final form 3 February 2007

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 O₂-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)-, 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 1 day, 3 days, or 3 wk, 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-3 wk, 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 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.

bronchopulmonary dysplasia; lung development; mechanical ventilation; alveolar, lung capillary, and elastic fiber formation; TGF-; TGF-1; PDGF; VEGF

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