Impaired alveolar formation is associated with chronic lung disease (CLD) of prematurity (bronchopulmonary dysplasia or BPD) or prolonged drainage of amniotic liquid (oligohydramnios). The mechanisms by which alveolar formation is inhibited with both diseases remain unclear, and treatment strategies to reduce their incidence or severity have achieved modest success at best. We have developed a model of BPD in lambs that reproduces the pathophysiology and pathology of this disease, including impairment of alveolar formation. The lambs are delivered prematurely and mechanically ventilated for 3-4 wks. Their lungs have impaired growth of alveolar secondary crests (septa), resulting in reduced numbers of alveoli. Alveolar capillaries do not grow into the abnormal secondary crests. These pathological changes are associated with respiratory insufficiency. Our immunohistochemical, biochemical, and molecular analysis suggest that extracellular matrix components and growth factor expression are adversely affected (elastin gene expression is upregulated; elastic fiber and proteoglycan accumulation are excessive; vascular endothelial growth factor protein expression is reduced). Preliminary studies suggest that these changes can be reversed by daily parenteral administration of vitamin A (retinol). How these changes occur is not known and is the basis of our grant application. We propose to study the regulation of alveolar formation, including the role of retinoids, in our lamb model of BPD, and in a fetal lamb model of oligohydramnios that will allow us to investigate the regulation of alveolar formation in utero. Paired preterm and fetal lambs, respectively, will be treated with or without retinoids daily to test 3 hypotheses: (1) retinoids will reverse the impaired alveolar formation by regulating the expression of growth factors that promote mesenchymal, endothelial, and epithelial development such that more normal alveolar septation occurs; (2) retinoids will have an early effect (postnatal days 3-4) on extracellular matrix components and growth factors that are likely to be involved with development of distal airspace mesenchyme, endothelium, and epithelium; and (3) retinoids will reverse arrest of alveolar formation and lung hypoplasia during fetal development in utero by augmenting the expression of growth factors that promote mesenchymal, endothelial, and epithelial development. This work should provide important insights into the molecular mechanisms that contribute to impairment of alveolar formation in 2 large-animal, chronic models of 2 important pediatric diseases. The experiments also should help establish the molecular basis for the potentially therapeutic benefit of retinoids.
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