Inhaled particulates such as asbestos damage lung epithelial cells which in turn, triggers a compensatory proliferative response and ultimately fibroproliferative lung diseases. The cell signaling events that mediate this constellation of events in the various lung cell types are not fully known. However, our preliminary data in animal and cell culture models demonstrate that asbestos-induced activation of protein kinase C (PKC) is an early event in asbestos-associated outcomes. Furthermore, certain effects of asbestos, including some that are functionally related to proliferation, injury and changes in gene expression, are PKC-dependent. PKCs are a family of Ser/Thr kinases with selective functions. Thus, we propose to determine which PKC isoforms are activated by asbestos and which PKC isoforms modify activities of MAPKs and AP-1 dependent gene expression. These studies will provide mechanistic information on asbestos-mediated signaling events. Finally, we propose to generate animals that are genetically altered to have decreased functional PKCdelta in lung epithelial cells. These animals will be used in inhalation studies to specifically evaluate the role of PKCdelta in epithelial cell proliferation and fibroproliferative disease. Using asbestos as a model, these studies have broader implications for the role of individual PKCs in other types of lung pathologies as well.
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