The role of matrix metalloproteinases and their inhibitors in irinotecan-induced oral mucositis: an animal model.

Background: Chemotherapy-induced oral mucositis is defined as damage of oral mucosa caused by unwanted detrimental effects of the cytotoxic chemotherapy. Oral mucositis presents as widespread painful ulcerations and erythematous eruptions and occurs in between 40-100% of all patients undergoing chemotherapy. Currently, there are no standard treatments available to prevent oral mucositis and the consequences on health care systems remain extensive. Research into the pathogenesis of oral mucositis has shown a complex underlying process, involving several overlapping biological events in the epithelium and submucosal layers. However, this pathogenesis is still not fully understood. A group of proteolytic enzymes called matrix metalloproteinases (MMPs) have been recently postulated to play a part in mediating the damaging process seen in oral mucositis. It is well established that MMPs and their naturally existing inhibitors (tissue inhibitors of metalloproteinases; TIMPs) maintain a balanced level in normal physiological status of oral mucosa. Their dysregulated balance underlies some pathophysiological aspects of several diseases including some diseases of the oral and gastrointestinal mucosae. These mucosal diseases include ulcerative colitis, Crohn‟s disease, recurrent aphthous stomatitis and oral lichen planus. However, as MMPs and TIMPs have not been well studied in oral mucositis, this formed the basis of this thesis. Hypothesis and Aims of the thesis: If MMPs and TIMPs are involved in the pathogenesis of oral mucositis, their tissue levels will change following the administration of cytotoxic chemotherapy. This may correlate to any histopathological changes in the oral mucosa. This thesis aimed to investigate the morphological changes and the tissue expression levels of MMP-2, -3 -9 and TIMP-1 within the oral cavity in a well-established pre-clinical animal model of chemotherapy-induced oral mucositis. Results and Discussion: The findings presented in this thesis demonstrate epithelium thickness reduces without obvious ulceration in the oral mucosa very early after chemotherapy administration. Maximum atrophy is observed 60 min following chemotherapy in both dorsal and ventral surfaces of the tongue. This reduction in epithelial thickness is associated with significant up-regulation of MMP-2, -3 and -9 and down-regulation of TIMP-1 in all layers of the oral mucosa. MMP-9 is also up-regulated at later time point. These findings support previous evidence that oral mucositis involves changes in the submucosa before it is clinically evident. The early reduction in epithelial thickness confirms similar findings reported in earlier studies of oral mucositis in rat buccal mucosa. The up-regulation of MMP-2, -3, -9 and down-regulation of TIMP-1 coincided with the previously described early up-regulation of transcription factors and pro-inflammatory cytokines in oral mucosa, suggesting a relationship between their up-regulation/down-regulation and the release of these factors and cytokines. Furthermore, the different patterns of expression demonstrated by MMP-2, -3, -9 suggest that these MMPs are involved in various aspects of the 5-phase model of OM pathophysiology including initiation of inflammatory response and tissue injury, recruitment of other mediators of OM and restoration of oral mucosa to normal physiological status. Conclusion: This thesis has provided evidence that MMPs play a key role in the aetiology of oral mucositis. Research in this area needs to be directed towards studying other relevant MMPs and also towards interventional therapies aiming to target MMP-2, -3 and -9 to prevent or reduce the severity of oral mucositis, as well as to promote faster healing of OM lesions. This will help provide an optimum treatment outcomes provided to cancer patients and improve the quality of life during and after their treatment.

Author dc:creator

• Al-Azri, Abdul Rahman

Advisors dc:contributor.advisor

• Logan, Richard Martin
• Gibson, Rachel Jane
• Keefe, Dorothy Mary Kate

• oral mucositis; matrix metalloproteinases; MMPs; tissuee inhibitors of metalloproteinase; TIMPs; irinotecan

Handle dc:identifier.uri

http://hdl.handle.net/2440/81399

OAI identifier oai:identifier

oai:digital.library.adelaide.edu.au:2440/81399