Orientadores: João Jose Fagundes, Claudio Saddy Rodrigues Coy / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T03:47:45Z (GMT). No. of bitstreams: 1 Ayrizono_MariadeLourdesSetsuko_D.pdf: 4568393 bytes, checksum: 41569c5ce061c5dcb69f8392fef8364c (MD5) Previous issue date: 2005 / Resumo: Plastia intestinal é uma alternativa cirúrgica no tratamento da estenose da doença de Crohn, principalmente em doentes com ressecções intestinais prévias ou múltiplos segmentos acometidos. O objetivo do trabalho consistiu na análise retrospectiva das complicações e do seguimento dos doentes operados por esta técnica. Foram estudados 28 doentes com estenoses do intestino delgado, ileocecais ou em anastomoses ileocólicas, submetidos à plastias intestinais, no período de setembro de 1991 a maio de 2004, pelo Serviço de Coloproctologia, da Disciplina de Moléstias do Aparelho Digestivo da UNICAMP. Dezesseis doentes (57,1%) eram do sexo masculino, com média etária de 33,3 anos (16-54). Dezesseis tinham antecedente de cirurgia para doença de Crohn, sendo em 13, ressecções intestinais. Foram realizadas 116 plastias (média de 4,1/doente), sendo 94 (81%) à Heineke-Mikulicz, 15 (13%) à Finney e sete (6%) ileocoloplastias látero-Iaterais. Três doentes foram submetidos a plastias em dois procedimentos cirúrgicos e dois, em três cirurgias. Dezoito doentes (64,3%) realizaram ressecções intestinais concomitantes à plastia, sendo 15 enterectomias (53,6%), duas ileotiflectomias (7,1%) e uma enterectomia associada à ileotiflectomia (3,6%). Foram observadas 14 complicações em sete doentes (25%), e um óbito (3,6%). Ocorreram duas complicações gerais (14,3%), em dois doentes (7,1%) e oito complicações locais precoces (57,1%), em sete doentes (25%). Ocorreram três deiscências de plastias (10,7% dos doentes), mas analisando-se por plastias realizadas, este índice foi de 2,6% (3/116). Dois doentes (7,1%), apresentaram peritonite não relacionada a plastia, sendo uma por lesão inadvertida de alça de delgado e outra secundária à deiscência da anastomose ileocólica. Foram observadas ainda, duas infecções da ferida operatória (14,3%), em dois doentes (7,1%), e uma hemorragia digestiva (3,6%). Complicações locais tardias foram em número de quatro (28,6%), em dois doentes (7,1%). Ambos apresentaram associação de hérnia incisional e fístula êntero-cutânea. O tempo médio de internação foi de 12,4 dias. No seguimento médio de 58,1 meses, 17 doentes (63%), apresentaram recidiva das cólicas abdominais, após três a 48 meses das plastias e dois doentes (7,4%), evoluíram com fistulas êntero-cutâneas, após dois e 19 meses, respectivamente. Onze doentes (40,7%) foram submetidos a novas cirurgias para realização de outras plastias ou ressecções intestinais, sendo que dois deles foram reoperados duas vezes e um, três vezes. Observaram-se quatro recidivas (3,5%) em local de plastia prévia, em três doentes (11,1%). Das recidivas, três (20%), foram na plastia do tipo Finney e uma no Heineke-Mikulicz (1,1%). Atualmente, 19 doentes estão assintomáticos ou oligossintomáticos, a grande maioria com uso de medicação. Em conclusão, as plastias apresentam baixos índices de complicações, principalmente no quesito deiscência, apesar das suturas serem realizadas no intestino doente. Pode-se inferir ainda que propiciam alívio dos sintomas. Uma vez que muitos doentes com doença de Crohn necessitarão de várias cirurgias ao longo da vida, as plastias constituem uma alternativa eficaz, pois podem aliviar os sintomas obstrutivos e também evitar ressecções intestinais extensas e suas conseqüências / Abstract: Strictureplasty is an altemative surgical procedure for Crohn' s disease, particulary in patients with previous resections or many intestinal stenosis. The aim of this tudy was to analyze surgical complications and clinical follow-up in patients submitted to strictureplasty secondary to Crohn' s disease. Twenty-eight patients (57,1% male, mean age 33,3 years, range 16-54 years) with Crohn's disease and intestinal stenosis (small bowel, ileocecal region and ileocolic anastomosis) were submitted to strictureplasty,at one institution,betweenseptember1991and may2004. Sixteeenpatients had previous surgical procedures for Crohn's disease and 13 with intestinal resections. The mean follow-up was 58,1 months. A total of 116 strictureplasties were done (94 Heineke-Mikulicz - 81%, 15 Finney - 13%, seven side-to-side ileocolic strictureplasty - 6%). Three patients were submitted to strictureplasty at two different surgical procedures and two in three procedures. Regarding to strictureplasty, postoperative complication rate was 57,1%, with three suture leaks (10,7%) and late was present in two patients, both with incisional hemial and enterocutaneous fistulas (28,6%). Patients remainded hospitalized during a medium time of 12,4 days. Clinical and surgical recurrence rates were 63~ and 41%, respectively. Among the patients submitted to another surgery, two patients had two more operations and one had three. Recurrence rate at strictureplasty site was observed in 3,5%, being Finney techinique the commonest one. Presently, 19 patients had been asymptomatic with the majority of them under medical therapy. In conclusion, strictureplasties have low complicating rates, in spite of having been done at compromised site, with long term pain relief. Considering the clinical course of Crohn' s disease, with many patients being submitted to intestinal resections, strictureplasties should be considered as an effective surgical treatment to spare long intestinal resections / Doutorado / Cirurgia / Doutor em Cirurgia

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La Broncho-Pneumopathie chronique obstructive (BPCO) est un problème majeur en santé publique puisque ce sera la 3ème cause de mortalité en 2020. Il s'agit d'une maladie inflammatoire chronique du poumon se traduisant par une obstruction progressive des bronches, partiellement ou non réversible, incluant bronchite chronique, hypersécrétion de mucus et emphysème. L'atteinte ne se limite pas au poumon et affecte d'autres organes dont le tube digestif en favorisant la maladie de Crohn. Le premier facteur de risque impliqué dans le développement de cette maladie est l’exposition à la fumée de cigarette qui induit un stress oxydatif au sein du poumon responsable d'une inflammation chronique et du développement de la BPCO. L'interleukine-17 joue un rôle essentiel dans ce processus en contrôlant l'inflammation et l'altération de la fonction respiratoire. L'objectif de cette thèse est de comprendre les facteurs contrôlant cette réponse IL-17 afin de proposer ensuite de nouvelles voies thérapeutiques. Dans la première partie, nous nous sommes focalisés sur le stress oxydatif et à son impact sur les cellules de l’immunité innée. Ensuite, nous abordons le rôle d'un facteur immunorégulateur, l'IL-10, et à son interférence avec le microbiote digestif. Cela nous a amené à nous intéresser aux lésions digestives associées au tabagisme. Un modèle murin d’exposition chronique à la fumée de cigarette a été développé afin de reproduire la physiopathologie de la BPCO. Concernant l'impact du stress oxydatif, nous avons étudié le rôle des cellules iNKT (cellules ayant un puissant potentiel dans l’immunorégulation et dans l’inflammation) qui sont activées par ce type de stress. Les cellules iNKT sont rapidement recrutées et activées au sein du poumon suite à l’exposition à la fumée de cigarette. En utilisant des souris déficientes, nous avons montré l’importance de ces cellules dans la physiopathologie de la BPCO. Cette pathogénicité est dépendante de la production de l’interleukine-17 par ces cellules et est initiée par le stress oxydatif sur les cellules épithéliales pulmonaires et les cellules dendritiques qui activent les cellules iNKT.Dans la seconde partie du projet, l’IL-10 intervient notamment dans le contrôle de l'inflammation afin d’éviter le développement de réponses immunologiques exacerbées dans certains contextes. Dans les poumons exposés à la fumée de cigarette, la production d’IL-10 est augmentée et la déficience pour cette cytokine entraîne une augmentation de la réponse Th17 et du déclin de la fonction pulmonaire. Une dysbiose (altération du microbiote) est observée avec la fumée de cigarette et la déficience à l'IL-10. De plus, une déplétion des bactéries Gram+ par antibiothérapie permet de limiter le développement de la réponse IL-17 et de l'atteinte pulmonaire soulignant l'importance du microbiote. En conclusion, nous avons identifié le stress oxydatif et l'IL-10 comme facteurs intervenant dans la réponse IL-17 associé à la BPCO. Ce travail souligne également le rôle du microbiome comme un organe à part entière et la modulation de ce dernier pourrait aboutir à l'identification de nouvelles voies thérapeutiques. / Chronic Obstructive Pulmonary Disease (COPD) is a major health problem which is going to become the third leading cause of death worldwide by 2020. COPD is characterized by a chronic inflammation of the airways causing progressive bronchial obstruction, with no completely reversible airflow limitation, including chronic bronchitis, mucus hypersecretion and emphysema. The pathology is not limited to the airways and can affect others organs including the gastro-intestinal tract promoting Crohn disease. Cigarette smoke exposure is the most important risk factor for developing COPD. Exposure to cigarette smoke induces a strong burden of reactives oxygen species and this oxidative stress is responsible for a chronic inflammation and the development of COPD. Interleukin (IL)-17 plays a critical role in controlling process of inflammation and lung function decline.The aim of this thesis is the understanding which factors are controlling the IL-17 response in order to propose new therapeutic approaches.In the first part, we focused on oxidative stress and its impact on innate immune cells. Then we addressed the role of an immunoregulatory factor, the interleukin (IL)-10, and its interference with intestinal microbiota. This part lead us to study intestinal damages linked to cigarette smoking.To mimic the physiopathology of COPD, we set up a mouse model of chronic exposure to cigarette smoke. Concerning the impact of oxidative stress, we investigated the role of iNKT cells (cells with a crucial potent role in immunoregulation and inflammation) activated by this type of stress. iNKT cells rapidly accumulate and be activated within the lungs of cigarette smoke exposed mice. Using deficient mice, we demonstrated that these cells strongly contribute to the COPD pathogenesis. This pathogenicity is iNKT cells-produced IL-17 dependant and initiated by the effect of oxidative stress on airway epithelial cells and dendritic cells activating iNKT.In the second part of the work, IL-10 interferes notably in the inflammation control in order to avoid exacerbated immunological responses development in some contexts. In cigarette smoke exposed lungs, IL-10 production is up-regulated and the deficiency for this cytokine leads to an increased Th17 response and to lung function decline. An altered microbiota (named dysbiosis) is observed with cigarette smoke exposure and IL-10 deficiency. Moreover, Gram+ bacteria depletion using antibiotics is able to limit the IL-17 response development and the lung function decline highlighting the crucial role for microbiota.To conclude, we identified two factors, oxidative stress and IL-10, implicated in IL-17 response linked to COPD. This work also underlines the role of microbioma as a whole organ and the modulation of this microbioma could result in new therapeutic ways identification in COPD.