Asbestos and silica, are occupationally-associated particulates capable of inducing pulmonary fibrosis. The alveolar macrophage (AM) is hypothesized to play a central role in the development of particulate-induced fibrosis due to its ability to release a spectrum of effector molecules (eg., superoxide anion, cytokines) that can modulate the function of a number of lung cells including stimulation of fibroblast proliferation and collagen formation. The overall goal of the research is to define the molecular events, from initial particulate binding to effector expression, that characterizes the AM response to fibrogenic particulates and potential involvement of the immune System in fibrogenesis. The first hypothesis to be tested is that fibrogenic particulates interact with surface receptors to alter intracellular pathways that characterize the AM response to these particulates in contrast to non-fibrogenic particulates. This response should be consistent with the potential for release of inflammatory mediators. This hypothesis will be tested by: 1. Evaluating the involvement of specific macrophage receptors for their ability to mediate particulate binding and macrophage stimulation. 2. Characterizing intracellular pathways activated by fibrogenic particulates. 3. Examining the role of stress protein induction in the AM response to particulates. 4. Examining potential mechanisms of AM priming by particulates. The second hypothesis to be tested is that AM from asbestotic and silicotic patients are activated due to either the establishment of an inflammatory environment (immune system mediated) or the presence of altered AM in these patients. The second hypothesis will be tested by: 1. Molecular characterization of the macrophages from fibrotic patients including expression of stress proteins. 2. Examination of lymphocyes, their subsets and state of activation. The purpose of this project is to test these specific hypotheses in order to obtain a description of a potential mechanism of induction of fibrotic disease by silica and asbestos and quite possibly other fibrotic agents. This knowledge will facilitate the development of strategies to block/arrest this process.
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