Extracellular superoxide dismutase (EC-SOD) is the most abundant extracellular antioxidant enzyme in the lung. However its biological role in both the neonatal and adult lung, during health and disease, is poorly understood. In the lung, EC-SOD has been primarily localized to alveolar type II epithelial cells as well as to pulmonary vascular smooth muscle. Thus, EC-SOD has positioned itself to likely play an important role in both pulmonary vascular biology as well as in alveolar epithelial homeostasis. We have previously shown that the mouse lung has the highest tissue expression of EC-SOD. Further enhancing EC-SOD levels using transgenic mice overexpressing human EC-SOD in type II alveolar epithelial cells resulted in attenuation of lung injury in models of oxidative stress. The long-term goal of this project is to understand the basic biochemistry and molecular pathobiology and regulation of EC-SOD in the lung. Towards this goal, we have proposed the following specific aims: (1) Identify, map, and functionally characterize the murine EC-SOD promoter and transcriptional regulatory elements. (2) Characterize the distribution and differential gene expression pattern of various EC-SOD mRNA isoforms under normal and oxidative stress conditions. (3) Critically evaluate EC-SOD expression during lung development. (4) Test the hypothesis that reduced EC-SOD expression in premature lungs predisposes to the development of hyperoxic-induced bronchopulmonary dysplasia and that overexpression protects against its development. We expect that data derived from these studies will further our understanding of basic mechanisms involved in regulating EC-SOD expression in the lung and underlie the basis for rational development of future studies utilizing transgenic mice technology, targeted against pulmonary and cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064894-04
Application #
6654859
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Berberich, Mary Anne
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$308,000
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Zelko, Igor N; Stepp, Marcus W; Folz, Rodney J (2013) A bioluminescent transgenic mouse model: real-time in vivo imaging of antioxidant EC-SOD gene expression and regulation by interferon gamma. Gene 530:75-82
Zelko, Igor N; Stepp, Marcus W; Vorst, Alan L et al. (2011) Histone acetylation regulates the cell-specific and interferon-ýý-inducible expression of extracellular superoxide dismutase in human pulmonary arteries. Am J Respir Cell Mol Biol 45:953-61
Zelko, Igor N; Folz, Rodney J (2010) Extracellular superoxide dismutase attenuates release of pulmonary hyaluronan from the extracellular matrix following bleomycin exposure. FEBS Lett 584:2947-52
Zelko, Igor N; Mueller, Michael R; Folz, Rodney J (2010) CpG methylation attenuates Sp1 and Sp3 binding to the human extracellular superoxide dismutase promoter and regulates its cell-specific expression. Free Radic Biol Med 48:895-904
Zelko, Igor N; Mueller, Michael R; Folz, Rodney J (2008) Transcription factors sp1 and sp3 regulate expression of human extracellular superoxide dismutase in lung fibroblasts. Am J Respir Cell Mol Biol 39:243-51
Liu, John Q; Zelko, Igor N; Erbynn, Efua M et al. (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290:L2-10
Liu, John Q; Yang, Dennis; Folz, Rodney J (2006) A novel bronchial ring bioassay for the evaluation of small airway smooth muscle function in mice. Am J Physiol Lung Cell Mol Physiol 291:L281-8
Liu, John Q; Erbynn, Efua M; Folz, Rodney J (2005) Chronic hypoxia-enhanced murine pulmonary vasoconstriction: role of superoxide and gp91phox. Chest 128:594S-596S
Liu, John Q; Zelko, Igor N; Folz, Rodney J (2004) Reoxygenation-induced constriction in murine coronary arteries: the role of endothelial NADPH oxidase (gp91phox) and intracellular superoxide. J Biol Chem 279:24493-7
Liu, John Q; Folz, Rodney J (2004) Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. Am J Physiol Lung Cell Mol Physiol 287:L111-8

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