Asbestos-Induced Peribronchiolar Cell Proliferation and Cytokine Production Are Attenuated in Lungs of Protein Kinase C-d Knockout Mice

The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)-d knockout (PKCd super(-/-)) mice to demonstrate multiple roles of PKC-d in the development of cell proliferation and inflammation after inhalation of chrysotile asbestos. At 3 days, asbestos-induced peribronchiolar cell proliferation in wild-type mice was attenuated in PKCd super(-/-) mice. Cytokine profiles in bronchoalveolar lavage fluids showed increases in interleukin (IL)-1b, IL-4, IL-6, and IL-13 that were decreased in PKCd super(-/-) mice. At 9 days, microarray and quantitative reverse transcriptase-polymerase chain reaction analysis of lung tissues revealed increased mRNA levels of the profibrotic cytokine, IL-4, hi asbestos-exposed wild-type mice but not PKCd super(-/-) mice. PKCd super(-/-) mice also exhibited decreased lung infiltration of polymorphonuclear cells, natural killer cells, and macrophages in bronchoalveolar lavage fluid and lung, as well as increased numbers of B lymphocytes and plasma cells. These changes were accompanied by elevated mRNA levels of immunoglobulin chains. These data show that modulation of PKC-d has multiple effects on peribronchiolar cell proliferation, proinflammatory and profibrotic cytokine expression, and immune cell profiles in lung. These results also implicate targeted interruption of PKC-d as a potential therapeutic option in asbestos-induced lung diseases.