Effects of ceramide inhibition on experimental radiation-induced oral mucositis.

OBJECTIVE: Oral mucositis (OM) is a common toxicity of ionizing radiation (IR), which is used as treatment for head and neck cancer. Ceramide-mediated apoptosis may contribute to the pathogenesis of mucositis. In response to IR or other cellular stresses, ceramide production occurs either by the hydrolytic action of sphingomyelinase (SMase) or de novo via ceramide synthase. STUDY DESIGN: Male golden Syrian hamsters (10 per group) exposed to a single dose of 40 Gy ionizing radiation (day 0) were treated with subcutaneous 0.2 mL injections of either neutral SMase, acidic SMase, or ceramide synthase inhibitor (5 mmol/L glutathione, 5 micromol/L desipramine, or 1 micromol/L fumonisin B1, respectively) from day -1 to day 16. A control group was treated with saline. Two blinded examiners assessed clinical OM development from day 6 to day 26. Two animals per group were killed on days 3, 10, and 16 for immunohistochemical detection of ceramide expression in both the epithelium and in the connective tissue. RESULTS: The group exposed to fumonisin B1 exhibited a statistically significant reduction in mean daily weight gain, mean mucositis score, duration of mucositis, and expression of ceramide in the epithelium on day 3 as well as in the connective tissue on days 10 and 16 relative to control. Immunohistologic analysis also revealed significant differences in ceramide expression on days 3 and 16 for animals treated with glutathione in both the epithelial and connective tissue when compared to the control. CONCLUSIONS: These results suggest that IR triggers early de novo ceramide production and that inhibition of this process attenuates OM on a clinical level.

Caspase-11 is not necessary for chemotherapy-induced intestinal mucositis.

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.