PA vascular remodeling with pulmonary hypertension is a life-threatening complication in infants and children with hypoxic lung diseases. A further understanding of this process is essential to develop new strategies aimed at reducing the severity of pulmonary hypertension in these individuals. Accumulating evidence indicates that reactive oxygen species (ROS), including superoxide (O2-) generated via NADPH oxidase, contribute to vascular remodeling. Extracellular oxidant/antioxidant homeostasis is maintained by the extracellular isoform of superoxide dismutase (EC-SOD), which is highly expressed in the vessel wall. The proposal tests the hypothesis that hypoxia disrupts the balance between the production of extracellular O2- by NADPH oxidase and its clearance by EC-SOD in the PA. We further hypothesize that excess extracellular O2- generated in the hypoxic lung upregulate a hypoxia-inducible and redox-sensitive transcription factor, early growth response-1 (Egr-1), which, in turn, stimulates Egr-1-responsive genes important in causing neonatal chronic hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension.
Aim 1 will use PA segments isolated from chronically hypoxic calves and mice and in vitro pulmonary artery vascular cells isolated from the neonatal calf to evaluate production of reactive oxygen species and expression and activity of EC-SOD.
Aim 2 will use chronically hypoxic mice overexpressing and lacking EC-SOD as well as mice lacking gp91phox subunit of NADPH oxidase to provide in vivo molecular and pharmacologic evidence that extracellular O2- regulates critical hypoxia-responsive genes and contributes to chronic hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension in the developing lung. To complement this model, in Aim 3, we will use the PA adventitial fibroblast isolated from the neonatal calf as a highly relevant model system for in vitro experiments to test the effects of hypoxia-induced extracellular O2- on the expression of the redox-sensitive transcription factor Egr-1. The study of chronic hypoxia as a stimulus for pulmonary vascular remodeling and pulmonary hypertension is compelling, as hypoxia is a common feature of diverse lung diseases. Thus, by advancing our knowledge base and testing new therapeutic approaches in animal models, we will provide a solid foundation for future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for patients with these difficult and serious problems. PROJECT NARRATIVE: Hypoxia complicates severe lung diseases in infants and children, and the development of pulmonary vascular remodeling and pulmonary hypertension in these patients leads to right heart failure, greatly increasing morbidity and mortality. This proposal tests whether an imbalance in production and clearance of extracellular superoxide contributes to the structural remodeling in chronic hypoxic pulmonary hypertension. This proposal will provide the basis for future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for pediatric patients with these difficult and serious problems.
|Hartney, John M; Stidham, Timothy; Goldstrohm, David A et al. (2014) A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution. Circ Cardiovasc Genet 7:659-66|
|Villegas, Leah R; Kluck, Dylan; Field, Carlie et al. (2013) Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasome. Antioxid Redox Signal 18:1753-64|
|Stenmark, Kurt R; Yeager, Michael E; El Kasmi, Karim C et al. (2013) The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 75:23-47|
|Jun, Du; Garat, Chrystelle; West, James et al. (2011) The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells 29:725-35|
|Van Rheen, Zachary; Fattman, Cheryl; Domarski, Shannon et al. (2011) Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling. Am J Respir Cell Mol Biol 44:500-8|
|Hartney, Tanya; Birari, Rahul; Venkataraman, Sujatha et al. (2011) Xanthine oxidase-derived ROS upregulate Egr-1 via ERK1/2 in PA smooth muscle cells; model to test impact of extracellular ROS in chronic hypoxia. PLoS One 6:e27531|
|Majka, Susan; Hagen, Moira; Blackwell, Thomas et al. (2011) Physiologic and molecular consequences of endothelial Bmpr2 mutation. Respir Res 12:84|
|Agrawal, Devendra K; Shao, Zhifei (2010) Pathogenesis of allergic airway inflammation. Curr Allergy Asthma Rep 10:39-48|
|Clarke, Margaret B; Wright, Rachel; Irwin, David et al. (2010) Sustained lung activity of a novel chimeric protein, SOD2/3, after intratracheal administration. Free Radic Biol Med 49:2032-9|
|Takeda, K; Okamoto, M; de Langhe, S et al. (2009) Peroxisome proliferator-activated receptor-g agonist treatment increases septation and angiogenesis and decreases airway hyperresponsiveness in a model of experimental neonatal chronic lung disease. Anat Rec (Hoboken) 292:1045-61|
Showing the most recent 10 out of 11 publications