The objective of this project is to explore the role of somatic mtDNA mutations in the etiology of interstitial pulmonary fibrosis. Oxidative damage in post mitotic tissues such as the brain, heart and skeletal muscle has been suggested to account for the mutations in mtDNA that accumulate with age. An increase in mtDNA deletions in human lung has recently been reported to occur with age. The aging lung also develops a thickening of the interstitial matrix and a decline in lung function. Mitochondria generate high levels of reactive oxygen species that can damage the nearby mtDNA. Preliminary data suggest that manganese superoxide dismutase is a critical antioxidant enzyme that controls superoxide levels in mitochondria. The relationship between oxidative damage, the accumulation of somatic mtDNA mutations, and mitochondrial dysfunction in the pathogenesis of fibrotic lung disease is virtually unexplored. The hypothesis presented is that chronic oxidative stress causes an accumulation of somatic mtDNA mutations which results in mitochondrial dysfunction in cell populations vital to the maintenance of the interstitial matrix of the lung. To test this hypothesis, proposed studies will: 1) evaluate the role of oxidative stress in the production of somatic mtDNA mutation events and fibroproliferative responses in cultured fibroblasts; 2) study the role of somatic mtDNA mutations in the etiology of pulmonary fibrosis in mice that lack mitochondrial MnSOD; 3) modulate oxidative stress with catalytic antioxidants and correlate effects on somatic mtDNA mutations and fibroproliferative responses in the lung; 4) correlate somatic mtDNA mutations, mitochondrial function, physiologic, biochemical, pathological and morphological responses in the lung as a function of aging. These studies have the potential to further define the etiology of idiopathic pulmonary fibrosis and suggest novel therapeutic approaches to treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059602-04
Application #
6183880
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$269,150
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Day, Brian J (2014) Antioxidant therapeutics: Pandora's box. Free Radic Biol Med 66:58-64
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Velsor, L W; van Heeckeren, A; Day, B J (2001) Antioxidant imbalance in the lungs of cystic fibrosis transmembrane conductance regulator protein mutant mice. Am J Physiol Lung Cell Mol Physiol 281:L31-8
Lewis, W; Copeland, W C; Day, B J (2001) Mitochondrial dna depletion, oxidative stress, and mutation: mechanisms of dysfunction from nucleoside reverse transcriptase inhibitors. Lab Invest 81:777-90

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