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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.

de Araújo RF, Reinaldo MP, Brito GA, Cavalcanti Pde F, Freire MA, de Moura Freire MA, de Medeiros CA, de Araújo AA - PLoS ONE (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

MTX and OLM effects on leukocyte density.MTX alone and MTX-OLM 5 mg/kg reduced leukocyte density (**p<.001 and *** p<0.001, respectively vs. Negative control), indeed, the and MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX).
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pone-0114923-g003: MTX and OLM effects on leukocyte density.MTX alone and MTX-OLM 5 mg/kg reduced leukocyte density (**p<.001 and *** p<0.001, respectively vs. Negative control), indeed, the and MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX).

Mentions: We observed significant leukopenia in animals treated with MTX (p<0.001) and MTX-OLM 5 mg/kg (p<0.001, Fig. 3) with number of leukocytes less than 2000/mm3 cells, indeed, the MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX), Fig. 3. The blood culture results were negative for all groups, indicating the absence of bacteraemia (data not shown).


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.

de Araújo RF, Reinaldo MP, Brito GA, Cavalcanti Pde F, Freire MA, de Moura Freire MA, de Medeiros CA, de Araújo AA - PLoS ONE (2014)

MTX and OLM effects on leukocyte density.MTX alone and MTX-OLM 5 mg/kg reduced leukocyte density (**p<.001 and *** p<0.001, respectively vs. Negative control), indeed, the and MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4273993&req=5

pone-0114923-g003: MTX and OLM effects on leukocyte density.MTX alone and MTX-OLM 5 mg/kg reduced leukocyte density (**p<.001 and *** p<0.001, respectively vs. Negative control), indeed, the and MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX).
Mentions: We observed significant leukopenia in animals treated with MTX (p<0.001) and MTX-OLM 5 mg/kg (p<0.001, Fig. 3) with number of leukocytes less than 2000/mm3 cells, indeed, the MTX-OLM 5 mg/kg resulted in an even stronger reduction effect than MTX alone (##p<.01 vs. MTX). OLM 5 mg/kg increased leukocyte density significantly (###p<.001 vs. MTX), Fig. 3. The blood culture results were negative for all groups, indicating the absence of bacteraemia (data not shown).

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus