The role of PDGF in pulmonary fibrosis and lung development
Description
Platelet-derived growth factor (PDGF) regulates proliferation, chemotaxis and differentiation of connective tissue cells during embryogenesis and possibly in disease states such as pulmonary fibrosis. To assess the effects of PDGF on lung development and pulmonary fibrosis in vivo, transgenic mice were generated in which expression of the human PDGF-A or -B gene was targeted to distal lung epithelium under control of the human surfactant protein C (SPC) promoter In SPC-PDGFB transgenic mice, overexpression of PDGF-B resulted in an abnormal lung structure in both adult and juvenile mice, including enlarged airspaces, inflammation, and fibroproliferative lesions. The severity of this phenotype varied significantly on C57BL/6, SJL and B6SJL hybrid backgrounds and progressed with age. To determine the effect of overexpression of PDGF-B on the progression of pulmonary fibrosis, transgenic and nontransgenic mice were challenged with three different fibrotic agents, including bleomycin, silica, and asbestos. Lung fibrosis induced by bleomycin and silica was similar in SPC-PDGFB mice and nontransgenic mice. Asbestos induced more pronounced fibrotic lesions 2 days to 8 weeks after multiple asbestos exposures, but fibrotic lesions examined 10 months after multiple asbestos exposures were similar in transgenic and nontransgenic mice. These studies suggest that PDGF stimulates inflammation and fibroblast proliferation in acute fibroproliferative lesions but other factors are required for end-stage lesions to develop Overexpression of PDGF-A in transgenic mice from the SPC promoter resulted in perinatal lethality caused by respiratory failure. To examine the effects of PDGF-A during lung development, SPC-PDGFA embryos were obtained on embryonic days (E) 16.5 and 18.5. Transgene message was detected throughout epithelial cells of the terminal respiratory buds but not in bronchioles and blood vessels. Lungs of SPC-PDGFA transgenic mice were larger and more solid than those of their nontransgenic littermates. The weights of whole lung and heart en bloc, and of the left lung of transgenic mice were heavier than those of nontransgenic embryos on E16.5. Histologic analysis of transgenic lungs showed a dramatic increase in mesenchymal cells and terminal buds on both E16.5 and E18.5 with a decrease in conducting airways and airspaces of respiratory buds. The cellular proliferation rate in transgenic lung was higher than that in wild-type littermates on E16.5. In transgenic embryos, progression to the saccular stage of lung development was blocked and elastin deposition was impaired. The results of these studies indicate that the downregulation of PDGF-A expression, which normally occurs during progression to the saccular stage, is required for development of a functional lung. The studies reported here, in contrast to many experiments with cultured cells, suggest that PDGF-A can have more potent effects in vivo than PDGF-B