Figures for:
The Pathobiology of Mucositis

[Nat Rev Cancer 4(4):277-284, 2004. © 2004 Nature Publishing Group]

Figure 1.  The oral mucosa.
The oral mucosa is comprised of stratified squamous epithelium that overlies the lamina propria, which consists of fibroblasts and connective tissue, small blood vessels (capillaries), inflammatory cells (macrophages) and extracellular matrix (ECM). The epithelium of the movable mucosa (which makes up the cheeks, inner aspects of the lips, ventral surface of the tongue, floor of the mouth and soft palate) is not keratinized, in contrast to the dorsal tongue, hard palate and gingiva. Although all the tissues of the mouth are susceptible to radiation-induced mucositis, only the movable mucosa develops chemotherapy-induced injury. The oral epithelium, like the skin, is a constantly renewing tissue in which proliferating cells in the basal layer produce daughter cells that then migrate to the surface.

Figure 2.  Primary damage response and signal amplification.
Radiation- or chemotherapy-induced mucositis is initiated by direct injury to basal epithelial cells and cells in the underlying tissue. DNA-strand breaks can result in cell death or injury. Non-DNA injury is initiated through a variety of mechanisms, some of which are mediated by the generation of reactive oxygen species. Radiation and chemotherapy are effective activators of several injury-producing pathways in endothelia, fibroblasts and epithelia. In these cells, the activation of transcription factors such as nuclear factor-κB (NF-κB) and NRF2 leads to the upregulation of genes that modulate the damage response. Immune cells (macrophages) produce pro-inflammatory cytokines, such as tumour-necrosis factor-α (TNF-α) and interleukin 6, which causes further tissue injury. These signalling molecules also participate in a positive-feedback loop that amplifies the original effects of radiation and chemotherapy. For example, TNF-α activates NF-κB and sphingomyelinase activity in the mucosa, leading to more cell death. In addition, direct and indirect damage to epithelial stem cells results in a loss of renewal capacity. As a result, the epithelium begins to thin and patients start to experience the early symptoms of mucositis.

Figure 3.  Ulceration and healing.
a | About 10 days after the administration of stomatotoxic chemotherapy, or at cumulative radiation doses of about 30 Gy, the integrity of the epithelium disintegrates and ulceration occurs. The ulcerative phase is extremely painful, as the protective barrier that overlies the nerve endings in the lamina propria is eliminated. Oral bacteria colonize the ulcer, where they release cell-wall products that penetrate into the connective tissue to stimulate the release of other cytokines. The inflammatory infiltrate is most robust during the ulcerative stage and consists of macrophages, plasma and mast cells. Depending on the bone-marrow status of the patient, neutrophils might also be present. The ulcer can be covered by a fibrinous, bacteria-laden exudate that is referred to as a 'pseudomembrane'. b | In most cases, spontaneous healing occurs about 2-3 weeks after the cessation of radiotherapy or by 3 weeks after the administration of chemotherapy. The epithelium migrates from the wound margins as a consequence of signals from mesenchymal cells and extracellular matrix (ECM), which determine proliferation, migration and differentiation.

Figure 4.  Signal amplification during mucositis.
Chemotherapy (CT) and radiation therapy (RT) activate the transcription factor nuclear factor-κB (NF-κB) in epithelial, endothelial and mesenchymal cells and macrophages, leading to the upregulation of genes and the production of pro-inflammatory cytokines, such as tumour-necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). These cytokines amplify the primary signal or may activate NF-κB in other cells, which results in the transcription of genes encoding mitogenactivated protein kinase (MAPK), cyclooxegenase 2 (COX2) and tyrosine-kinase signalling molecules. These signalling pathways lead to activation of matrix metalloproteinases (MMPs) 1 and 3 in cells of the epithelium and lamina propria, which ultimately results in tissue injury.