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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062875-02
Application #
6184854
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F2))
Project Start
1999-09-01
Project End
2003-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$283,717
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Staub, Eveline; Dahl, Mar Janna; Yost, Calan et al. (2017) Preterm birth and ventilation decrease surface density of glomerular capillaries in lambs, regardless of postnatal respiratory support mode. Pediatr Res 82:93-100
Sutherland, Megan R; Ryan, Danica; Dahl, Mar Janna et al. (2016) Effects of preterm birth and ventilation on glomerular capillary growth in the neonatal lamb kidney. J Hypertens 34:1988-97
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Joss-Moore, Lisa A; Hagen-Lillevik, Synneva J; Yost, Calan et al. (2016) Alveolar formation is dysregulated by restricted nutrition but not excess sedation in preterm lambs managed by noninvasive support. Pediatr Res 80:719-728
Joss-Moore, Lisa A; Lane, Robert H; Albertine, Kurt H (2015) Epigenetic contributions to the developmental origins of adult lung disease. Biochem Cell Biol 93:119-27
Albertine, Kurt H (2015) Utility of large-animal models of BPD: chronically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol 308:L983-L1001
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Null, Donald M; Alvord, Jeremy; Leavitt, Wendy et al. (2014) High-frequency nasal ventilation for 21 d maintains gas exchange with lower respiratory pressures and promotes alveolarization in preterm lambs. Pediatr Res 75:507-16
Joss-Moore, Lisa; Carroll, Travis; Yang, Yan et al. (2013) Intrauterine growth restriction transiently delays alveolar formation and disrupts retinoic acid receptor expression in the lung of female rat pups. Pediatr Res 73:612-620

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