Causes and Pathology of Mucositis

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Mucositis

(in vitro studies)

Defention: One of the most debilitating side effects of radiotherapy and chemotherapy treatment. It is characterized by both inflammation and cell loss in the epithelial barrier. Mucositis is a very complex condition: it develops as a series of dynamic interactions that begin in the epithelium but in a later stage involves other tissue mucosal components like the endothelium, extracellular matrix and connective tissue. It is a frequent reason to postpone chemotherapy treatment ultimately leading towards a higher mortality in cancer patients.

The pathobiology can be described in five stages: initiation, message generation, signal amplification, ulceration and healing.

5 stages:

Initiation phase: The initiation phase follows immediately after exposure to radiation or chemotherapy. The treatments cause the production of reactive oxygen species (ROS). These are free radicals that cause DNA strands in epithelium cells to break. Thus arising reversible and irreversible DNA damage.

Message generation phase: In the message generation phase different transcription factors are activated. The most important is nuclear factor-kappa B (NF-κB), this is a regulatory molecule that controls nearly 200 genes of which that encode pro-inflammatory cytokines and cell adhesion molecules. The increase in synthesis of cytokines and other enzymes causes an increase in apoptosis of epithelial cells and fibroblasts.

Signaling and amplification phase: One of the pro -inflammatory cytokines produced is tumor necrosis factor alpha (TNF-α), this molecule damages the cells but also increases the activity of NF-κB. With as result a positive feedback loop that causes amplification of injury that also continues after the cancer therapy. Until now there is little manifestation of symptoms.

Ulceration phase: The real problems begin when there is penetration through the epithelium into the submucosa. There is the beginning of an ulcer and on the ulcer surface oral bacteria colonize. The bacteria produce toxins and inflammatory cytokines in reaction with macrophages. This phase is responsible for the most symptoms occurring in mucositis. The ulceration can result in complications like bacteremia (infection of blood with bacteria) and sepsis. Ulceration associated with mucositis also increases the risk for viridans streptococcal bacteremia, septicemia and systematic infection.

Healing phase: Healing can occur spontaneous or can be improved by therapy. Epithelial cells which are under control of the extracellular matrix move, migrate, grow and differentiate to form a wound.

This cycle of stages can be repeated several times in different sites on the oral mucosa throughout the course of therapy.

The role of bacteria in oral mucositis

According to this five phase model the oral microbiota play no role in the pathobiology of mucositis. However research has implicated a role for the commensal microbiota in several inflammatory diseases like inflammatory bowel disease. ( as we saw in the previous lesson about crohn disease). It’s likely that the commensal bacteria also play a role in this inflammatory disease : mucositis. Commensal microbiota might have a beneficial effect on the development of oral mucositis, they might offer protection against its development. There are five pathways in the development of mucositis that are potentially influenced by the commensal oral microbiota:

Influencing the inflammatory process

The resident bacteria cause a constant state of low grade inflammation. They guarantee the presence of ligands for TLR such as peptidoglycaan and LPS. This ensures an activation of the downstream signaling pathways resulting in a low grade inflammation. Paradoxically, commensal bacteria are also capable to suppress more severe inflammatory responses. Multiple bacteria are capable of decreasing NFkB activation, resulting in less production of inflammatory cytokines. This can be...
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