Inhalation of silica in mining, sandblasting and quarrying occupations results in serious, potentially life threatening, pulmonary inflammatory and fibrotic pathologies including acute and chronic (nodular pulmonary fibrosis) silicosis. Thus the first objective of this proposal is to determine the mechanisms underlying silica-induced pulmonary inflammation and fibrosis, particularly the role of the cytokine transforming growth factor beta 1(TGfb1). TGFb is strongly implicated in pulmonary fibrosis induced by silica and other agents. The second objective is to develop novel gene-based therapeutic strategies for treatment of these fibrotic pathologies. The hypothesis will be tested that activated TGFb is a key mediator of crystalline silica-mediated fibrosis, and if inhibited a fibrotic outcome can be prevented. Two different anti-TGFb strategies will be utilized. The first will involve adenoviral vector mediated overexpression of the core protein of the proteoglycan decorin in mouse lung. Decorin is a physiological inhibitor of active TGFb. The second strategy will exploit the inhibitory nature of the pre-proportion of the TGFb molecule itself, termed the LAP. Transgenic mice over-expressing LAP under control of the lung specific SP- C promoter will be used, and should produce prolonged inhibition of active TGFb. Unlike crystalline silica, amorphous silica induces inflammation, but not fibrogenesis. It is hypothesized that this is related to failure of amorphous silica to upregulate active TGFb. The concept will be tested that over-expression of low levels of active TGFb, in the context of ongoing amorphous silica-induced injury and inflammation, will drive silica-mediated inflammation to fibrogenesis. Assessment will also be made of the ability this inflammatory milieu itself to activate latent TGFb. Finally, to further address the mechanisms of inflammation and fibrogenesis induced by different silicas, their potential to activate fibroblasts in vitro will be examined. The PI of this project has just been recruited as faculty to the Depts. of Medicine and Environmental Medicine. She is committed to an academic career, and will spend 80% of her time in research studies. She has had previous training in inflammation, fibrogenesis and gene transfer, and now plans to expand her studies to investigate environmental and occupational lung disease. To achieve this she wishes to obtain additional training in environmental toxicology, and the role of the immune system in fibroblast activation. The environment in Rochester has a critical mass of international experts in these areas, whose interests are aligned with those of the PI. They will collaborate with the PI, and form her advisory committee. In conjunction with a formal education program me this should allow her to successfully develop as an independent investigator, while yielding new insights into the pathogenesis and treatment of fibrotic pathologies.
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