The signaling molecule nitric oxide (NO) is critically involved in airway and vascular function in the developing lung. NO is produced by three isoforms of NO synthase (NOS), neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Our preliminary work in normal baboon fetuses indicates that all three isoforms are expressed in airway epithelium, and that nNOS and eNOS are upregulated during late gestation to optimize NO production in the perinatal period. Bronchopulmonary dysplasia (BPD) is an inflammatory condition which disrupts the development of the preterm human lung, and it is characterized by airway and pulmonary vascular dysfunction. Our initial studies in the baboon BPD model indicate that lung NO production and lung nNOS and eNOS expression are markedly attenuated during the genesis of BPD, and that NO replacement by inhalation (iNO) results in a sustained improvement in oxygenation index. The overall objective of this proposal is to investigate the role of alterations in NOS expression in the pathophysiology of BPD in the baboon model. The primary hypothesis is that pulmonary nNOS and eNOS expression are downregulated during the development of BPD, leading to diminished NO production and abnormal airway and vascular structure and function. The secondary hypothesis is that iNO reverses these abnormalities.
Aim 1 is to define the normal ontogeny and changes in NOS protein and mRNA expression in early BPD, using approaches including laser capture microdissection to evaluate NOS mRNA levels in specific cell types harvested from frozen sections.
Aim 2 is to determine the role of each NOS isoform in airway and vascular function in studies of NOS antagonism in intact animals.
Aim 3 is to reveal the changes in exhaled NO levels with fetal development and BPD, as well as the contribution of each NOS isoform to exhaled NO.
Aim 4 is to determine the effects of iNO on airway and vascular function, on the pulmonary course of early BPD, and on lung histology.
Aim 5 is to determine the mechanisms underlying constitutive nNOS and eNOS gene expression in cultured baboon airway epithelium, and the role of cytokines in their downregulation. The results obtained will increase our knowledge of the role of NO in normally successful postnatal pulmonary adaptation and in the pathophysiology of BPD, thereby possibly leading to novel therapies for this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL063399-04
Application #
6527214
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Berberich, Mary Anne
Project Start
1999-09-01
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$274,657
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Rees, Sandra M; Camm, Emily J; Loeliger, Michelle et al. (2007) Inhaled nitric oxide: effects on cerebral growth and injury in a baboon model of premature delivery. Pediatr Res 61:552-8
Vyas-Read, Shilpa; Shaul, Philip W; Yuhanna, Ivan S et al. (2007) Nitric oxide attenuates epithelial-mesenchymal transition in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 293:L212-21