Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-03-29T00:30:04Z No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-03-29T19:38:59Z (GMT) No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) / Made available in DSpace on 2016-03-29T19:38:59Z (GMT). No. of bitstreams: 1 MariaPatriciaOliveiraDaSilvaReinaldo_DISSERT.pdf: 1968663 bytes, checksum: 9310ea8c13185d093751709ea668017c (MD5) Previous issue date: 2015-03-19 / A mucosite intestinal ? a inflama??o e/ou ulcera??o da mucosa do trato gastrointestinal causada pelas terapias antic?ncer. Apresenta histologicamente, atrofia das vilosidades, danos nos enter?citos e infiltra??o de c?lulas inflamat?rias. O metotrexato ? um composto que inibe a dihidrofolato redutase, enzima importante na s?ntese de DNA. ? amplamente utilizado no tratamento de leucemia e outras malignidades. O objetivo deste estudo foi avaliar o efeito da Olmesartana (OLM), um antagonista do receptor da angiotensina II, em um modelo de mucosite intestinal (MMI) induzida por MTX em ratos Wistar. MMI foi induzido atrav?s de inje??o intraperitoneal (i.p.) de MTX (7 mg/kg) durante tr?s dias consecutivos. Os animais foram pr?-tratados com OLM oral a 0.5 mg/kg, 1 mg/kg e 5 mg/kg e com solu??o salina, 30 minutos antes da exposi??o ao MTX durante tr?s dias. Fragmentos de intestino delgado (duodeno, jejuno e ?leo) foram homogeneizados para ensaio de pesquisa das citocinas L-1?, IL-10 e TNF-?, atividade do Malonalde?do (MDA) e da Mieloperoxidase (MPO). Al?m disso, an?lises de imunohistoqu?mica da MMP-2, MMP-9, COX-2, RANK / RANKL e SOCS-1 al?m da an?lise da co-localiza??o da express?o de SOCS-1 pela microscopia confocal foram realizadas. O tratamento com MTX+OLM 5 mg/kg resultou numa redu??o da infiltra??o inflamat?ria da mucosa, ulcera??es, vasodilata??o e ?reas hemorr?gicas (p<0,05), bem como as concentra??es reduzidas de MPO (p<0,001) e as citocinas pr?- inflamat?rias IL-1? e TNF-? (p <0,01). Al?m disso, o tratamento combinado reduziu a express?o de MMP-2, MMP-9, COX-2, RANK e RANKL (p<0,05) e aumentou a express?o citoplasm?tica de SOCS-1 (p<0,05). Nossos achados confirmam o envolvimento de OLM na redu??o da resposta inflamat?ria atrav?s do aumento da sinaliza??o imunossupressora em MMI. Sugerimos tamb?m que o efeito ben?fico do tratamento com a Olmesartana ? especificamente exercida durante o dano atrav?s do bloqueio de citocinas inflamat?rias. / Intestinal Mucositis is inflammation and/or ulceration of mucosa of the gastrointestinal tract caused by anticancer therapies. Histologically, villous atrophy, damage to enterocytes and infiltration of inflammatory cells. Methotrexate (MTX) is a compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. The aim of this study was to evaluate the effect of Olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pretreated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX, for three days. Small intestinal (duodenum, jejunum and ileum) homogenates were assayed for levels of the IL-1?, IL-10 and TNF-? cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX+OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and hemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1? and TNF-? (p<0.01), and increase antiinflammatory cytosine IL-10 (p,0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL (p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signaling in an IMM. We also suggest that the beneficial effect of Olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytosines.