No one has yet proven which of the potential mediators of interstitial pulmonary fibrosis (IPF) play a mechanistic role in the disease. We have developed a well-characterized model of IPF by exposing rats or mice to chrysotile asbestos fibers for brief period and elucidating the features of the disease process. It has been postulated that combinations of peptide growth factors are the central mediators of IPF. The practical problem in this regard is that lung cells are known to produce a multitude of growth factors, cytokines and inflammatory agents. Our data point to two peptide growth factors as key in the development of interstitial pulmonary fibrosis. One is platelet-derived growth factor (PDGF), the most potent mesenchymal cell mitogen known, the other is transforming growth factor beta (TGFbeta), the most powerful stimulator of extracellular matrix deposition by the same cells. Our central hypothesis stats: After insult by a fibrogenic agent, the isoforms of PDGF and TGFbeta are key determinants mediating the proliferative and fibrogenic components of the consequent interstitial pulmonary fibrosis. Using in situ hybridization, immunochemistry and Northern analysis, this hypothesis will be addressed by asking whether or not consequent to a 3- hr exposure to asbestos, fibers, genes encoding these factors are upregulated during the fiber translocation and macrophage migration phase of the disease, subsequently during the proliferative phase of the disease (4-72 hrs. post-inhalation) and during the progressive (fibrogenic) phase (4 days-6 months post-exposure). We wail learn if the mRNAs encoding these factors are upregulated in EPITHELIAL, MACROPHAGE (alveolar and interstitial), MESENCHYMAL and VASCULAR cell populations. If our hypothesis is correct, control animals exposed to air or to non- fibrogenic carbonyl-iron particles will exhibit no upregulation of mRNAs encoding PDGF and TGFBeta since they show no fibrogenesis. Furthermore, it is not known if these or any factor released at the alveolar surface by macrophages or epithelium can actually reach the interstitial target cell population which must be stimulated for IPF to ensue. This important issue will be approached using our in vitro co- culture system.
The Specific Aims ask whether or not under normal conditions and after treatment with non-fibrogenic iron particles, both PDGF and TGFBeta are intact alveolar epithelium. It is postulated that asbestos deposition causes injury to epithelium through fiber toxicity and oxygen radical production by activated macrophages, thus allowing passage of the growth factors to the connective tissue compartment where they mediate mesenchymal cell proliferation and extracellular matrix deposition, the hallmarks of IPF. In order to develop therapeutic strategies for interstitial lung disease it will be essential to establish which molecules are the key mediators of disease and are expressed in the disease process.
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