Silicosis develops many years after initial exposure to silica particles and is characterized by chronic inflammation, lung fibrosis and ultimately respiratory impairment. There is no effective treatment for silicosis. As a result, patients diagnosed with silicosis are given a dismal prognosis and many patients are still dying of this disease. The biochemical mechanisms behind silicosis are poorly characterized, however oxidants do play a role in disease development. The antioxidant enzyme extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme in the lung extracellular matrix (ECM), protects against other fibrotic lung diseases. Previous studies have correlated the loss of ECSOD with worsening lung injury and a pro-oxidant lung environment. ECSOD overexpression or treatment with SOD-mimetic drugs can prevent this injury. Thus, one component of an effective treatment strategy may be the restoration of the oxidant / antioxidant balance in the lung. Studies show that administration of mesenchymal stem cells (MSCs) can participate in the repair of lung tissue after oxidative injury. However, little is known about the effects of a highly oxidative lung microenvironment on stem cell-mediated tissue repair. Therefore, the investigators hypothesize that silicosis results in a pro-oxidant microenvironment that leads to the reduced efficacy of mesenchymal stem cells to repair lung damage. The investigators will employ a mouse silicosis model whereby MSCs purified from either ECSOD null mice or ECSOD overexpressing mice are administered to animals exposed to silica. The effects of modulating antioxidant levels of both the stem cells and the recipient mice will be determined on the efficacy of the stem cell treatment. When complete, these studies will provide valuable information on the influence of the lung microenvironment on the ability of stem cells to abrogate lung disease. These studies will also begin to address the feasibility of transplanting purified MSCs with augmented antioxidant capabilities into patients with silicotic lung disease as therapy. Lung disease due to silica exposure (silicosis) is a continuing public health problem that has no effective treatment. This project examines the use of adult stem cells along with increased levels of antioxidants in the treatment of silicosis. These studies will help determine the feasibility of using adult stem cells in the treatment of patients with silicosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016000-05
Application #
8299125
Study Section
Special Emphasis Panel (ZES1-JAB-C (R1))
Program Officer
Nadadur, Srikanth
Project Start
2007-09-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$382,428
Indirect Cost
$124,901
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Brass, David M; McGee, Sean P; Dunkel, Mary K et al. (2010) Gender influences the response to experimental silica-induced lung fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 299:L664-71
Ganguly, Koustav; Depner, Martin; Fattman, Cheryl et al. (2009) Superoxide dismutase 3, extracellular (SOD3) variants and lung function. Physiol Genomics 37:260-7