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.
| Shan, Bin; Hagood, James S; Zhuo, Ying et al. (2010) Thy-1 attenuates TNF-alpha-activated gene expression in mouse embryonic fibroblasts via Src family kinase. PLoS One 5:e11662 |
| Shan, Bin; Morris, Cindy A; Zhuo, Ying et al. (2007) Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J Mol Cell Cardiol 42:517-25 |
| 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 |
| Lasky, J A; Ortiz, L A (2001) Antifibrotic therapy for the treatment of pulmonary fibrosis. Am J Med Sci 322:213-21 |
