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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-JAB-C (R1))
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Latoche, Joseph D; Ufelle, Alexander Chukwuma; Fazzi, Fabrizio et al. (2016) Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect 124:1199-207
Lee, Sang-Min; McLaughlin, Joseph N; Frederick, Daniel R et al. (2013) Metallothionein-induced zinc partitioning exacerbates hyperoxic acute lung injury. Am J Physiol Lung Cell Mol Physiol 304:L350-60
Brass, David M; Spencer, Jennifer C; Li, Zhuowei et al. (2012) Innate immune activation by inhaled lipopolysaccharide, independent of oxidative stress, exacerbates silica-induced pulmonary fibrosis in mice. PLoS One 7:e40789
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