Radiation therapy is used alone or in combination with chemotherapy in more than 50% of cancer treatments. Despite recent advances in treatment delivery such as dose-sculpting techniques, irradiation of healthy tissues surrounding the tumor and the associated side effects limit the radiation amount used. Those side effects when concerning the gastrointestinal tract have profound repercussions on patient’s quality of life and may even engage their vital prognosis. The comprehension of the mechanisms implicated in the development of these lesions is thus a major stake in the identification of therapeutic targets allowing their prevention and treatment. During my PhD, we studied the role of mast cells in the development of radiation proctitis in vivo and in the endothelial response to irradiation in vitro. Our results suggest that mast cells have a deleterious role in the development of human and murine radiation proctitis, in particular by the influence of some of its mediators such as histamine and proteases on the phenotype of the smooth muscle cells of the muscularis propria. Targeting mast cells’mediators may represent new therapeutic tools to prevent and/or limit digestive radiation damage. Other shares our work shows that mast cells mediators such as histamine can exacerbate the endothelial inflammatory response to irradiation by mechanisms involving the activation of the p38MAPKinase pathway and the transcription factor NF-κB. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage.