Oral mucositis is a common, dose-limiting, acute toxicity of radiation therapy administered for the treatment of cancers of the head and neck. Accumulating data would suggest that the pathogenesis of mucositis is complex and involves the sequential interaction of all cell types of the oral mucosa, as well as a number of cytokines and elements of the oral environment. While a number of studies have reported on gene expression of particular cell types in response to radiation, the overall response of irradiated mucosa has only been evaluated in a limited way. The present study was undertaken to evaluate the expression of a target group of genes using RNA quantification assays and, more broadly, to assess patterns of mucosal gene expression using DNA microarray hybridization. Our results demonstrate the sequential upregulation of a series of genes that, when taken collectively, suggest an intricate functional interaction.
Mucositis is a common, dose-limiting toxicity associated with drug and radiation therapy for cancer. The ulcerative lesions of mucositis serve as systemic portals of entry for the micro-organisms that inhabit the mucosa of the gastrointestinal tract and the oral cavity, often leading to systemic infection. The pathogenesis of mucositis is complex, and consists of varying, sequential interactions between pro-inflammatory cytokines, transcription factors, and pro-apoptotic pathways of the mucosal epithelium and the cells and tissues within the submucosa. A possible mechanism for mucositis injury is the activation of caspases, a family of cysteine proteases. Caspase-11, one of 14 members of this enzymatic family, was studied to determine its role in the development of intestinal mucositis after exposure to melphalan in caspase-11 wild-type (+/+) and knockout (-/-) mice. Immunoblots demonstrated the activation of caspase-11 in duodenal and jejunal samples 24 and 48 h after melphalan administration. No significant differences in the level of intestinal cell death or macrophage infiltration, as measured by TUNEL staining and immunohistochemistry, were present between wildtype (+/+) and knockout (-/-) mice. These findings suggest that while caspase-11 activation occurs in response to melphalan, it does not have a primary role in the pathogenesis of intestinal mucositis.
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