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.
|El Kasmi, Karim C; Vue, Padade M; Anderson, Aimee L et al. (2018) Macrophage-derived IL-1?/NF-?B signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 9:1393|
|Ni, Kevin; Gill, Amar; Tseng, Victor et al. (2018) Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury. Respir Res 19:107|
|Haeger, Sarah M; Liu, Xinyue; Han, Xiaorui et al. (2018) Epithelial Heparan Sulfate Contributes to Alveolar Barrier Function and Is Shed during Lung Injury. Am J Respir Cell Mol Biol 59:363-374|
|Sherlock, Laurie G; Trumpie, Ashley; Hernandez-Lagunas, Laura et al. (2018) Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia. Antioxidants (Basel) 7:|
|Delaney, Cassidy; Sherlock, Laurie; Fisher, Susan et al. (2018) Serotonin 2A receptor inhibition protects against the development of pulmonary hypertension and pulmonary vascular remodeling in neonatal mice. Am J Physiol Lung Cell Mol Physiol 314:L871-L881|
|Garcia, Anastacia M; Allawzi, Ayed; Tatman, Philip et al. (2018) R213G polymorphism in SOD3 protects against bleomycin-induced inflammation and attenuates induction of proinflammatory pathways. Physiol Genomics 50:807-816|
|Gaurav, Rohit; Varasteh, Jason T; Weaver, Michael R et al. (2017) The R213G polymorphism in SOD3 protects against allergic airway inflammation. JCI Insight 2:|
|Hernandez-Saavedra, Daniel; Swain, Kalin; Tuder, Rubin et al. (2017) Redox Regulation of the Superoxide Dismutases SOD3 and SOD2 in the Pulmonary Circulation. Adv Exp Med Biol 967:57-70|
|D'Alessandro, Angelo; Nozik-Grayck, Eva; Stenmark, Kurt R (2017) Identification of Infants at Risk for Chronic Lung Disease at Birth. Potential for a Personalized Approach to Disease Prevention. Am J Respir Crit Care Med 196:951-952|
|Rashid, Jahidur; Patel, Brijeshkumar; Nozik-Grayck, Eva et al. (2017) Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH). J Control Release 250:96-106|
Showing the most recent 10 out of 44 publications