La radiothérapie est utilisée seule ou en association avec la chimiothérapie dans le traitement de plus de 50% des cancers. En dépit des progrès techniques dans la balistique, l'irradiation des tissus sains entourant la tumeur et les effets secondaires qui lui sont associés sont une limite à la dose d'irradiation utilisée. Ces effets secondaires, lorsqu'ils concernent le tube digestif, ont un retentissement important sur la qualité de vie des patients et peuvent même engager leur pronostic vital. La compréhension des mécanismes impliqués dans le développement de ces lésions est donc un enjeu majeur dans l'identification de cibles thérapeutiques permettant leur prévention et leur traitement. Durant ma thèse nous avons étudié le rôle des mastocytes dans le développement de la rectite radique in vivo et dans la réponse endothéliale à l'irradiation in vitro. Nos résultats suggèrent un rôle délétère des mastocytes dans le développement de la rectite radique humaine et murine, notamment par l'influence de certains de leurs médiateurs tels que l'histamine et les protéases sur le phénotype des cellules musculaires lisses de la muscularis propria. Le ciblage de certains médiateurs mastocytaires pourrait représenter une nouvelle stratégie thérapeutique pour prévenir et/ou limiter les atteintes radiques digestives. D'autre part, nos travaux montrent que des médiateurs mastocytaires comme l'histamine peuvent exacerber la réponse inflammatoire de l'endothélium à l'irradiation par des mécanismes de signalisation impliquant l'activation de la voie p38 MAPKinase et du facteur de transcription NF-B. L'étude approfondie des voies de signalisation activées lors du développement des lésions radiques pourrait offrir de nouvelles possibilités thérapeutiques dans la gestion des dommages radiques aux tissus sains. / 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-B. The study of intracellular signaling pathways activated during radiation damage development may offer new therapeutic possibilities in the management of healthy tissues radiation damage.

Made available in DSpace on 2015-07-22T20:50:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-24 / Introdução: A coloproctopatia actínica crônica (CAC) é uma complicação reconhecida da radioterapia. O sangramento retal (SR) é a queixa mais comum da CAC e a melhor modalidade de tratamento endoscópico para este sintoma permanece controversa. Objetivo: Comparar a eficácia e a segurança da eletrocauterização bipolar (EB) com a eletrocauterização com plasma de argônio (EPA) no tratamento do SR secundário à CAC. Pacientes e Métodos: Foram incluídos 30 pacientes com SR ativo proveniente da CAC, randomizados em 2 grupos (15 para EB e 15 para EPA) e classificados de acordo com escore de Saunders. A potência foi de 50 W para a EB e de 40 W para a EPA. Todos foram submetidos à colonoscopia inicial para o diagnóstico da lesão e sua extensão e exclusão de outras doenças. O sucesso do tratamento foi definido pela erradicação de todas as telangiectasias. Foram consideradas falhas de tratamento, os casos nos quais sete sessões não foram suficientes para o controle do sangramento. Complicações foram divididas em três diferentes grupos: sensitivas (dor anal, dor abdominal e febre), hemorrágicas (piora do sangramento durante o tratamento e sangramento por úlceras) e anatômico-motoras (afilamento das fezes, estenoses e pseudopólipos). Resultados: A média de idade foi de 67,4 anos (variação de 33 a 82 anos) com 14 mulheres e 16 homens. Não houve diferença estatística significante entre os grupos no número de sessões (p = 0,313). Não houve diferença significativa em relação às complicações sensitivas (p = 0,245), hemorrágicas (p = 0,169) ou anatômico-motoras (p = 0,700) entre os grupos. Entretanto, a incidência total de complicações foi significativamente maior no grupo EB. Somente uma falha terapêutica foi observada em cada grupo (p = 1,000). Também não houve diferença significativa na recidiva (p = 1,000). Pacientes em uso de aspirina necessitaram de um número maior de sessões para cessação do SR (p = 0,036) e para erradicação das telangiectasias (p = 0,047). Conclusões: A EPA e a EB apresentaram semelhanças em relação à eficácia no tratamento da coloproctopatia actínica crônica hemorrágica. Contudo, a EPA é mais segura que a EB. / Introduction: Chronic radiation coloproctopathy (CRCP) is a well-recognized complication of radiotherapy. Rectal bleeding is the most common symptom of radiation injury and the optimal endoscopic treatment of bleeding due to CRCP is still controversial. Aim: To compare the efficacy and safety of bipolar eletrocauterization (BEC) and argon plasma eletrocauterization (APE) in the management of bleeding from CRCP. Methods: Thirty patients with active bleeding from telangiectasias were enrolled, randomized into two groups (15 BEC and 15 APE) and classified according to Saunders score. Power settings were 50 W for BEC and 40 W for APE. Initial treatment was performed after a complete colonoscopy to rule out synchronous lesions and follow-up was performed with flexible sigmoidoscopies. Success was defined as eradication of all telangiectasias. Failure was defined whenever more than seven sessions or other therapies were necessary for treatment of bleeding. Complications were divided into three different groups: sensory (anal pain, abdominal pain and/or fever), hemorrhagic (worsening of bleeding during treatment, bleeding from ulcers) and anatomic/motor (tapered feces, stenosis and/or pseudopolyps). Results: Mean age was 67.4 years (range 33-82), with 14 women and 16 men. There was no significant difference regarding the number of sessions in both groups (p = 0.313). There were no significant differences regarding sensory (p = 0.245) hemorrhagic (p = 0.169) or anatomic/motor (p = 0.700) complications between both groups. However, the overall complication rate was significantly higher in EB group (p = 0.020). Only one failure was observed in each group (p = 1.000). There was also no significant difference regarding relapse (p = 1.000) Conclusions: BEC and APE are equally effective in patients with bleeding telangiectasias from CRCP. Nevertheless, APE is safer than EB. / TEDE / BV UNIFESP: Teses e dissertações