D’Hondt et al PHASE I: INITIATION DNA and non-DNA damages Generation of oxidative stress and reactive oxygen species PHASE II: MESSAGE GENERATION Upregulation of transcription factors (NF- B) Increased production of IL-1, 2 and 6 Activation of acidic sphyngomyelinases and ceramide synthase PHASE III: SIGNALING AND AMPLIFICATION Positive feedback loops increase cytokine production PHASE IV: ULCERATION Clinically evident erosions Bacterial colonization Additional proinflammatory cytokine secretions PHASE V: HEALING Migration of epithelial cells covering ulcerations Mucosa appears clinically normal Figure 1 Flow chart of the different phases of mucositis development. 162 is responsible for a breakdown in connective tissue and the release of metalloproteinases responsible for more apoptosis. It should be noted that at this time the mucosa still seems clinically normal. Signaling and amplification Signaling and amplification is the third phase. During this period, the release of mediators from the initial injury amplifies the destruction process through activation of positive feedback loops, eg, TNF-α activates NF-κB (Sonis 2002) and sphingomyelinase (Andriea-Abadic and Levade 2002), leading to additional tissue destruction. It is interesting to note that in fractionated radiotherapy, the insult is permanent and feedback loops are constantly activated, blocking the healing process (Sonis 2004). Ulceration Ulceration is the fourth phase. During this period mouth injuries become clinically evident with areas of erosion. Erosions are covered by fibrinous exudates that are also called “pseudomembrane”. The exudate contains oral bacteria. This period frequently coincides with the lowest neutrophil count. Bacterial colonization of the submucosa is present and activates macrophages, leading to new positive feedback and more proinflammatory cytokine secretion. Other cytokines, such as platelet-activating factor (PAF), may play an important role at this stage. It seems that platelet aggregation may worsen oral mucositis (Kuenen et al 2003). High salivary PAF levels are correlated with mucositis severity (McManus et al 1993), and pharmacologic inhibition of platelet aggregation results in reduction of mucositis (Wang et al 2002). Finally, angiogenesis is a late event of mucositis-induced ulcers. Healing Healing is the last phase. During this period, because of some not yet well-characterized signals, epithelial cells directly bordering the site migrate, proliferate, and differentiate. These cells move beneath the pseudomembrane to reconstitute an intact surface. This phenomenon is frequently concomitant with the return of the white blood cell count to normal values. Cells proliferate until the thickness of the mucosa is normal. However, despite the fact that the mucosa appears to be clinically normal, the environment has been altered and does not revert to its original normal state. The patient is at risk of subsequent injury with antineoplasic treatments. Many unanswered questions remain concerning the physiopathology of oral mucositis; for instance, the role of Therapeutics and Clinical Risk Management 2006:2(2)