Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents

BMC Gastroenterology

Ronaldo A Ribeiro²  Mariana L Vale²  Rosemeyre S Freire²  Francisco JWS Siqueira²  Roberto CP Lima-Júnior²  Antoniella S Gomes²  Johann V Silva²  Emmanuelle AL Bellaguarda²  Reinaldo B Oriá¹  Gerly AC Brito¹  Renata FC Leitão¹ 

[1] Department of Morphology, Federal University of Ceará, Fortaleza, Brazil;Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, Brazil

关键词: Nφ-Nitro-L-arginine methyl ester;    Aminoguanidine;    Methotrexate;    Nitric oxide synthase;    Nitric oxide;   

Others  :  1113284
DOI  :  10.1186/1471-230X-11-90

 received in 2011-04-26, accepted in 2011-08-16,  发布年份 2011

【 摘 要 】

Background

Methotrexate treatment has been associated to intestinal epithelial damage. Studies have suggested an important role of nitric oxide in such injury. The aim of this study was to investigate the role of nitric oxide (NO), specifically iNOS on the pathogenesis of methotrexate (MTX)-induced intestinal mucositis.

Methods

Intestinal mucositis was carried out by three subcutaneous MTX injections (2.5 mg/kg) in Wistar rats and in inducible nitric oxide synthase knock-out (iNOS^-/-) and wild-type (iNOS^+/+) mice. Rats were treated intraperitoneally with the NOS inhibitors aminoguanidine (AG; 10 mg/Kg) or L-NAME (20 mg/Kg), one hour before MTX injection and daily until sacrifice, on the fifth day. The jejunum was harvested to investigate the expression of Ki67, iNOS and nitrotyrosine by immunohistochemistry and cell death by TUNEL. The neutrophil activity by myeloperoxidase (MPO) assay was performed in the three small intestine segments.

Results

AG and L-NAME significantly reduced villus and crypt damages, inflammatory alterations, cell death, MPO activity, and nitrotyrosine immunostaining due to MTX challenge. The treatment with AG, but not L-NAME, prevented the inhibitory effect of MTX on cell proliferation. MTX induced increased expression of iNOS detected by immunohistochemistry. MTX did not cause significant inflammation in the iNOS^-/- mice.

Conclusion

These results suggest an important role of NO, via activation of iNOS, in the pathogenesis of intestinal mucositis.

【 授权许可】

   
2011 Leitão et al; licensee BioMed Central Ltd.

【 图 表 】

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