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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.
| Identifer | oai:union.ndltd.org:IBICT/oai:repositorio.ufrn.br:123456789/20121 |
| Date | 19 March 2015 |
| Creators | Reinaldo, Maria Patr?cia Oliveira da Silva |
| Contributors | 01847881459, http://lattes.cnpq.br/1903940945895093, Leit?o, Renata Ferreira de Carvalho, 43088139304, http://lattes.cnpq.br/5213035069793195, Ara?jo, Aurigena Antunes de, 83806059420, http://lattes.cnpq.br/3531154240424211, Ara?jo J?nior, Raimundo Fernandes de |
| Publisher | Universidade Federal do Rio Grande do Norte, SEM PROGRAMA, UFRN, Brasil |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Source | reponame:Repositório Institucional da UFRN, instname:Universidade Federal do Rio Grande do Norte, instacron:UFRN |
| Rights | info:eu-repo/semantics/openAccess |
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