title: Olmesartan decreased levels of IL-1β and TNF-α, down-regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model.
abstract: Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. 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 pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1β, IL-10 and TNF-α 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 haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1β (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine 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 signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines.
authors.affiliation: Post graduation program Health Science/Department of Morphology, UFRN, Natal, RN, Brazil; Post graduation program in Functional and Structural Biology/UFRN, Natal, RN, Brazil; Department of Morphology/UFRN, Natal, RN, Brazil.
authors.forename: Raimundo Fernandes
authors.initials: RF
authors.lastname: de Araújo
authors.affiliation: Post graduation program in Functional and Structural Biology/UFRN, Natal, RN, Brazil; Department of Morphology/UFRN, Natal, RN, Brazil.
authors.forename: Maria Patrícia Oliveira da Silva
authors.initials: MP
authors.lastname: Reinaldo
authors.affiliation: Post graduation program in Pharmacology/Department of Morphology/UFC, Fortaleza, CE, Brazil.
authors.forename: Gerly Anne de Castro
authors.initials: GA
authors.lastname: Brito
authors.affiliation: Department of Morphology/UFRN, Natal, RN, Brazil; Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: Pedro de França
authors.initials: Pde F
authors.lastname: Cavalcanti
authors.affiliation: Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Freire
authors.affiliation: Edmond and Lily Safra International Institute of Neuroscience of Natal (ELS-IINN), Natal, RN, Brazil.
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: de Moura Freire
authors.affiliation: Department of Biophysics and Pharmacology, UFRN, Natal, RN, Brazil.
authors.forename: Caroline Addison Xavier
authors.initials: CA
authors.lastname: de Medeiros
authors.affiliation: Department of Biophysics and Pharmacology, UFRN, Natal, RN, Brazil; Post graduation program Public Health/Department of Biophysics and Pharmacology/UFRN, Natal, RN, Brazil; Post graduation program in Pharmaceutical Science/UFRN, Natal, RN, Brazil.
authors.forename: Aurigena Antunes
authors.initials: AA
authors.lastname: de Araújo
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016470:Bacteremia / Q000188:drug therapy; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D007964:Leukocytosis / Q000188:drug therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008727:Methotrexate / Q000633:toxicity; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D007093:Imidazoles; D053583:Interleukin-1beta; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C437965:olmesartan; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008727:Methotrexate