Persistent pulmonary hypertension of the newborn (PPHN) is a serious clinical problem that affects up to 10% of infants admitted to the Neonatal Intensive Care Unit, and occurs when pulmonary vascular resistance does not decrease normally during the transition to air breathing at birth. We have utilized a fetal lamb model of PPHN to study the vascular changes associated with PPHN, and to determine how these changes might interfere with the normal pulmonary vascular transition. Our preliminary data in PPHN lambs strongly suggest: 1) a central role for reactive oxygen species (ROS) in the pathogenesis of PPHN;2) that hyperoxia enhances production of ROS by mitochondrial and cytosolic sources, which increase vascular reactivity, and 3) that the PPHN lamb is particularly vulnerable to the effects of hyperoxia, responding with exaggerated increases in ROS and vascular dysfunction. We hypothesize We propose three specific aims to further our knowledge of the pathogenesis and therapeutic opportunities for PPHN: 1. Determine abnormalities of vascular mitochondrial and cytosolic ROS production specific to PPHN. 2. Determine the effect of hyperoxia on ROS production in the PPHN vasculature. 3. Determine the effects of therapeutic strategies targeted at reducing ROS production in specific cellular compartments. An improved understanding of the mechanistic basis for this syndrome will potentially identify novel clinical approaches to managing the vascular dysfunction that characterizes PPHN. Such therapies could dramatically improve immediate and long-term clinical outcomes, while substantially reducing the health care costs associated with this syndrome.

Public Health Relevance

We expect our studies to improve our understanding of the causes of persistent pulmonary hypertension, a serious medical condition that affects 10% of infants admitted for neonatal intensive care. Our research should lead to therapies that reduce oxygen toxicity, improve immediate and long- term clinical outcomes, and substantially reduce the health care costs associated with this syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054705-18
Application #
8511773
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Lin, Sara
Project Start
1995-08-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
18
Fiscal Year
2013
Total Cost
$447,755
Indirect Cost
$72,168
Name
University of California Davis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T et al. (2015) Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn. Front Pharmacol 6:47
Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T et al. (2015) Cyclic stretch stimulates mitochondrial reactive oxygen species and Nox4 signaling in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 309:L196-203
Farrow, Kathryn N; Steinhorn, Robin H (2015) Pulmonary hypertension in premature infants. Sharpening the tools of detection. Am J Respir Crit Care Med 191:12-4
Heilman, Rachel P; Lagoski, Megan B; Lee, Keng Jin et al. (2015) Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice. Am J Physiol Heart Circ Physiol 308:H1575-82
Lee, Keng Jin; Berkelhamer, Sara K; Kim, Gina A et al. (2014) Disrupted pulmonary artery cyclic guanosine monophosphate signaling in mice with hyperoxia-induced pulmonary hypertension. Am J Respir Cell Mol Biol 50:369-78
Perez, Marta; Wedgwood, Stephen; Lakshminrusimha, Satyan et al. (2014) Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulm Circ 4:71-81
Wedgwood, Stephen; Steinhorn, Robin H (2014) Role of reactive oxygen species in neonatal pulmonary vascular disease. Antioxid Redox Signal 21:1926-42
Ball, Molly K; Waypa, Gregory B; Mungai, Paul T et al. (2014) Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med 189:314-24
Lakshminrusimha, Satyan; Steinhorn, Robin H (2013) Inodilators in nitric oxide resistant persistent pulmonary hypertension of the newborn. Pediatr Crit Care Med 14:107-9
Wedgwood, Stephen; Lakshminrusimha, Satyan; Czech, Lyubov et al. (2013) Increased p22(phox)/Nox4 expression is involved in remodeling through hydrogen peroxide signaling in experimental persistent pulmonary hypertension of the newborn. Antioxid Redox Signal 18:1765-76

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