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Historically,
mucositis was thought to be the consequence of activation of herpes
simplex virus 1 by drug or radiation therapy for cancer. This
hypothesis has been refuted, however because herpes virus could
not be uniformly cultured from sites of mucositis and administration
of aggressive, parenteral antiviral medications failed to impact
the incidence, severity, or course of mucositis.
Subsequently,
the mechanism underlying mucositis was thought to be based on
the non-specific tissue-harming effects of chemotherapy or radiation
on the proliferating basal cells of the oral mucosa. It was reasoned
that aggressive cancer therapy resulted in the death of proliferating
cells in the basal epithelium, which resulted in a loss of mucosal
renewal and consequent atrophy and then ulceration. However, a
number of clinical and investigational observations suggested
that other factors also played important pathogenic roles in the
development of mucositis. These observations have led to the conclusion
that mucositis is a biologically complex process in which all
cells of the oral mucosa participate. In the majority of cases,
it seems likely that the initial event is the generation of reactive
oxygen species (free radicals) in response to radiation or chemotherapy.
Subsequently, it seems likely that a number of transcription factors
are activated which result in the expression of a wide variety
of potentially damaging proteins. The release of pro-inflammatory
cytokines likely results in additional tissue changes. Furthermore,
these cytokines may contribute as secondary activators (along
with radiation and chemotherapy) of other tissue-damaging avenues
such as the ceramide pathway. Once ulceration occurs, local oral
bacteria colonize the wound and release cell-wall products into
the mucosa which results in amplification of the tissue destructive
cycle. Ultimately, in the absence of infection, healing occurs
(Sonis
et al., 2000).
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