The formation of scars within the lungs (pulmonary fibrosis) frequently leads to shortness of breath, disability and even death. Occupational exposure to organic or inorganic dusts are well-known to cause pulmonary fibrosis. The etiology of many cases of lung fibrosis remains unknown, or idiopathic, but it is thought that occupational and environmental exposure to particulates may be responsible for upwards of 25% of these idiopathic cases. Unfortunately, current medical treatment is frequently ineffective in halting or reversing lung fibrosis. The overall purpose of this study is to better understand the basic mechanism of lung scarring so that physicians will some day be able to intervene in the pulmonary scarring process and thereby prevent suffering and postpone death. A common structural feature of lung fibrosis is an increase in the number of cells called fibroblasts. A scar is formed when fibroblasts move into a wound and proliferate. Fibroblast proliferation and chemotaxis are mediated by growth factors and cytokines. Platelet-derived growth factor (PDGF) is a potent fibroblast growth factor and chemoattractant, which binds to lung fibroblast surface receptors to generate secondary messengers that stimulate cell growth. Although PDGF expression is upregulated at the site of fibroproliferative lung lesions, it remains to be demonstrated whether or not PDGF is actually directing fibroproliferation during lung fibrogenesis. The hypothesis is that disruption of PDGF receptor signal transduction will significantly inhibit the development of lung fibrogenesis. To test this hypothesis, two strategies directed at disrupting PDGF receptor signal transduction in lung fibroblasts in vitro and in vivo will be employed. The first approach will utilize a newly-developed tyrosine kinase inhibitor that is selective for PDGF receptors, whereas the second approach will use dominant-negative PDGF receptor constructs to inhibit murine lung fibroblast proliferation. It is expected that the information derived from employing these two strategies will be complementary. In concert, these experiments will define for the first time the key role PDGF plays in the pathogenesis of pulmonary fibrosis and help answer whether future research should be directed toward blocking the activity of PDGF to treat lung fibrosis in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES010046-01A1
Application #
6194060
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Mastin, Patrick
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$222,750
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Zhuo, Ying; Hoyle, Gary W; Shan, Bin et al. (2006) Over-expression of PDGF-C using a lung specific promoter results in abnormal lung development. Transgenic Res 15:543-55
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