Oxidative stress and reactive oxygen species signaling are now recognized to have a critical role in the pathogenesis of pulmonary hypertension (PH). The sole extracellular enzymatic defense against superoxide (O2 -) is the antioxidant extracellular superoxide dismutase (EC-SOD or SOD3). Though EC-SOD constitutes a small fraction of total SOD activity in most tissues, it is the most abundant SOD isoform in arteries. In preliminary data and the few human studies to date, EC-SOD expression and activity are decreased in endstage PH. Loss of EC-SOD activity in animal models of PH worsens outcome, though the mechanisms are poorly understood. We hypothesize that EC-SOD localized to the pulmonary artery (PA) wall is critical to the protection against vascular inflammation and remodeling because it prevents extracellular redox-sensitive events in the matrix that can activate important signaling pathways in PA cells. We will test this hypothesis using novel mouse models, primary PASMC and macrophages, potent molecular tools and a targeted EC-SOD replacement.
Our first Aim will test the contribution of insufficient vascular EC-SOD to the development of PH; and whether its prominent vascular localization can be translated into a more effective therapeutic strategy by targeting EC-SOD replacement to the PA. We will test mouse strains with a generalized loss of EC-SOD versus a preferential loss of vascular EC-SOD, measure redox state, inflammation, pulmonary vascular remodeling and PH;and test if the effects can be reversed by targeted EC-SOD replacement.
Our second Aim will test if insufficient vascular EC-SOD, as a result of impaired scavenging of extracellular O2 -, activates TGF- β;and if this is responsible for ERK1/2 activation, Egr-1 expression and the subsequent changes in growth, inflammation and synthetic properties of PASMC.
This aim will use in vivo and in vitro models to systematically test if low vascular EC-SOD, increases O2 --dependent activation of the key growth factor,TGF-β, and if this is responsible for ERK1/2-dependent up-regulation of the transcription factor, early growth response-1, leading to changes in the growth, inflammatory, and synthetic properties of PASMC in PH. In the third Aim, we will test if low vascular EC-SOD results in oxidative fragmentation of matrix component, HA, leading to NLRP3 inflammasome activation in macrophages.
This aim will focus on a specific matrix component, hyaluronan, susceptible to superoxide-mediated fragmentation and implicated in PH.
The aim will test if insufficient vascular EC-SOD leads to oxidative fragmentation of hyaluronan and its activation of the NLRP3 inflammasome, a protein platform that processes pro-inflammatory cytokines IL-1βand IL-18 in macrophages. This proposal provides direct translational relevance by establishing the foundation to develop novel antioxidant therapies appropriately targeted to a specific vascular compartment. These findings will have important implications in a wide range of lung diseases to ultimately improve health outcome for patients with these serious problems.
Hypoxia complicates severe lung diseases, and the development of pulmonary vascular remodeling and pulmonary hypertension in these patients leads to right heart failure, greatly increasing morbidity and mortality. Loss of a key vascular antioxidant enzyme, extracellular superoxide dismutase, promotes structural remodeling and inflammation in chronic hypoxic pulmonary hypertension. This proposal will provide the basis for the development of novel therapeutic antioxidant strategies and future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for pediatric and adult 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