The development and inflammatory features of radiotherapy-induced glossitis in rats

Abstract

Objectives: To improve the existing animal models (mice, rats, and hamsters) for radiotherapy-induced oral mucositis (RTOM), thereby establishing a radiotherapy-induced glossitis (RTG) Sprague-Dawley (SD) rat model. Study Design: A lead device was designed to limit radiation exposure to a 1×1 cm2 area of a rat's dorsal anterior tongue with a single 30Gy of X-ray radiation. The general conditions of the irradiated rats, such as body-weight and behavior, were observed. The oral mucositis index (OMI) of the RTG rats were measured daily. Histological changes of the irradiated tongue tissues were assayed by H&E staining. Results and Conclusion: No significant changes were clinically observed 3 to 4 days after irradiation. At 5 to 6 day, punctuation and confluenced redness of the mucosa were observed. The small blood vessels became more extensive, engorged, thin vessel walls. More infiltrating cells were observable, necrosis and exfoliation of the squamous cells appeared, and the formation of an ulcerative lesion could be observed. Seven to 15 days, the exfoliated epithelial layer was observed to have formed an ulcerative lesion, then aggravated ulcerative lesions consisting of pseudomembranous filament exudates could be observed. The structure of the epithelium had become completely disintegrated, forming deep, microscopic ulcerative lesions. Twenty-one days, the periphery of the ulcer was observed to have begun to heal, and granulation tissue could be observed at the bottom of the ulceration. At 35 days after irradiation, the epithelial structure presented again, but the epithelium was very thin. An RTG animal model was successfully established in SD rats, which provides a new research platform for the study of RTOM pathogenesis.

Establishment of an X-ray Irradiation-Induced Glossitis Model in Rats: Biphasic Elevation of Proinflammatory Cytokines and Chemokines

“…It decreased between days 7 and 10 associated with decrease in the amounts of food consumption and water intake, and then gradually recovered to normal (data not shown). Although the delayed occurrence of oral mucositis has been reported in previous studies (Murphy et al, 2008;Mangoni et al, 2009;Li et al, 2011), this is the first report to demonstrate delayed weight loss. The cause of this delayed weight loss is considered to be decreased food consumption as a result of oral mucositis, as food consumption and water intake decreased in parallel with the degree of tongue damage.…”

“…The timing to appearance of ulceration following radiation exposure should be associated with the cell cycle of lingual epithelial cells (Vissink et al, 2003), in which X-ray irradiation-induced DNA damage arrests cell proliferation. In the previous study of Li et al (2011), the maximal glossitis score was observed 14 days after irradiation, related to the fusion of pre-existing ulcers. The discrepancy in timing of ulceration between the current study and previous study might be due to differences in dosage and techniques of X-ray exposure.…”

“…The pathologic progression of mucositis has been described as consisting of five phases: initiation, upregulation and generation of messenger signals, signaling and amplification, ulceration, and healing (Sonis, 2004). Histologic investigations have been reported in previous studies (Kitagawa et al, 2008;Li et al, 2011), but time-dependent alterations of pathologic and molecular status during the five phases are still largely unknown. In this study, we also investigated tongue gene expression, focusing on proinflammatory cytokines and chemokines that are believed to play a pivotal role in triggering inflammation and development of the tissue damage seen in radiation-induced oral mucositis; we also performed quantitative evaluation of macroscopic injury.…”

“…In addition to mouse and hamster models, rat radiation models have recently been developed and reported (Cassatt et al, 2002;Rezvani and Ross, 2004;Yeoh et al, 2007;Kitagawa et al, 2008;Li et al, 2011). An advantage of rat models is the size of the tongue, which can be handled and quantified more easily than that of the mouse.…”

“…An advantage of rat models is the size of the tongue, which can be handled and quantified more easily than that of the mouse. In rat irradiation models (Li et al, 2011), oral mucositis was induced by direct X-ray irradiation of the tongue, fixed outside the body with adhesive tape, an approach that carries a high risk of causing artifactual damage during the procedure. Instead of the tongue, the buccal mucosa is sometimes selected as the site for induction of oral mucositis by X-ray irradiation.…”