The long-term objectives are to better understand the progression of events leading to the development of bronchopulmonary dysplasia (BPD) in premature neonates requiring mechanical ventilation, and to test the efficacy of retinoid treatments in preventing the development of BPD. The premature lung is structurally immature and is subject to injury at the cellular and architectural levels when subjected to the mechanical forces of ventilation. Stretch-mediated injury blocks the normal developmental pattern of the neonatal lung and results in loss of gas-exchange capacity. Previous studies have shown that the structural protein elastin is required for alveolar development and is abnormally assembled into fibers in the BPD lung, and that the alveolar myofibroblast phenotype and distribution is altered in BPD. Retinoids are currently being tested in human trials for efficacy in abating lung injury in the ventilated premature neonate at risk for BPD, and are known to regulate elastin gene expression in the developing lung. The first specific aim of this proposal is to test the efficacy of retinoids in attenuating the development of BPD in the baboon model of BPD, and to determine the effects of retinoids on elastic fiber deposition and assembly in the ventilated premature neonate. This model offers highly controlled treatment regimens and therefore can be used to critically test therapeutic modalities. Preterm baboon fetuses delivered at 125 d of gestation will be assigned to retinoid treatment or vehicle and then subjected to the standard treatments for 6-14 days. Physiologic indices, morphometric analysis of lung structure, and molecular analyses of elastic fiber assembly and injury will be used to assess retinoid effects.
The second aim i s to determine the effects of other experimental treatments on alveolar myofibroblast distribution and elastic fiber assembly, as we propose these are important indices of alveolar development.
The third aim i s to use gene array technology to identify changes in gene expression resulting from mechanical ventilation, and to """"""""mine"""""""" gene expression profiles with the goal of developing a molecular signature for BPD.
This aim will also identify genes with expression profiles associated with alveolar development, and downstream targets of specific therapies for BPD. These studies will be highly interactive within the Consortium and provide gene expression data for the scientific community at large.
