Certain particulate hexavalent chromium [Cr(VI)] compounds are human respiratory carcinogens and are associated with fibrosis, fibrosarcomas, adenocarcinomas and squamous cell carcinomas of the lung. Although Cr(VI) is a well documented carcinogen, little is known about the pathologic injury, immune responses and survival signaling that contribute to the development of lung cancers. The overaching objective of this dissertation research was to examine the nexus between tissue injury, inflammation, and genotoxic death/survival signaling as a key determinant of early Cr(VI) oncogenesis. To explore this nexus we developed an in vivo model of intranasal inhalation of particulate chromate in BALB/c mice and utilized an in vitro model of Cr(VI)-induced death resistance. Dysregulation of the survival signaling kinase Akt was observed in vitro in cells resistant to Cr(VI) induced death where expression and activation of Akt was upregulated after Cr(VI) exposure. Despite this upregulation of Akt, inhibition of the pathway did not support a role for Akt in the Cr(VI)-induced death resistance. This lack of a role for Akt was confirmed under conditions of Akt upregulation and Cr(VI) exposure. Furthermore, the results suggest a potential pro-apoptotic function of Akt in hTERT-expressing fibroblasts. Studies from our novel in vivo model of particulate Cr(VI) inhalation revealed that a single dose of Cr(VI) induced bronchiolar cell apoptosis, toxic mucosal injury and inflammation that progressed into a pneumonitis. Repeated exposure to Cr(VI) induced a chronic inflammatory response characterized in the airways by an immediate influx of neutrophils after each Cr(VI) exposure, and subsequent infiltration of macrophages. Cr(VI)-induced chronic injury and inflammation was apparent in lung tissue with toxic mucosal injury, peribronchial inflammation, and development of a pneumonitis dominated by lymphocytes and macrophages. The acute and chronic injury and inflammation correlated with airways immunoreactive for phosphorylation of Akt. Furthermore, repetitive Cr(VI) exposure resulted in epithelial cells expressing the proliferation marker Ki-67 and a reactive hyperproliferative response among epithelial cells lining airways. Taken together, we suggest that these early disease processes of injury and inflammation induced by Cr(VI) promote a microenvironment that may participate in the initiation and promotion of neoplastic cells and contribute over time to Cr(VI) carcinogenesis.
|Advisor:||Patierno, Steven R.|
|Commitee:||Ceryak, Susan M., Constant, Stephanie L., Kennedy, Katherine A., Lee, Norman H., Noonan, Frances, O'Brien, Travis J.|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 69/07, Dissertation Abstracts International|
|Subjects:||Occupational safety, Oncology|
|Keywords:||Carcinogenesis, Death resistance, Hexavalent chromium, Inflammation, Lung injury|
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