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(American Journal of Pathology. 2007;170:140-151.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060381

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

Arti Shukla^*, Karen M. Lounsbury, Trisha F. Barrett^*, Joanna Gell^*, Mercedes Rincon, Kelly J. Butnor^*, Douglas J. Taatjes^*, Gerald S. Davis, Pamela Vacek, Keiichi I. Nakayama^¶, Keiko Nakayama^¶, Chad Steele^|| and Brooke T. Mossman^*

From the Departments of Pathology,^* Pharmacology, Medicine, and Medical Biostatistics, University of Vermont, Burlington, Vermont; the Pediatric Pulmonary Division,|| Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania; and the Department of Molecular Genetics,^¶ Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)- knockout (PKC^–/–) mice to demonstrate multiple roles of PKC- 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 PKC^–/– mice. Cytokine profiles in bronchoalveolar lavage fluids showed increases in interleukin (IL)-1ß, IL-4, IL-6, and IL-13 that were decreased in PKC^–/– 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, in asbestos-exposed wild-type mice but not PKC^–/– mice. PKC^–/– 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- 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- as a potential therapeutic option in asbestos-induced lung diseases.

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