Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodentsReportar como inadecuado

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BMC Gastroenterology

, 11:90

Intestinal disorders


BackgroundMethotrexate 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.

MethodsIntestinal 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.

ResultsAG 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.

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

KeywordsNitric oxide Nitric oxide synthase Methotrexate Aminoguanidine Nφ-Nitro-L-arginine methyl ester Electronic supplementary materialThe online version of this article doi:10.1186-1471-230X-11-90 contains supplementary material, which is available to authorized users.

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Autor: Renata FC Leitão - Gerly AC Brito - Reinaldo B Oriá - Manuel B Braga-Neto - Emmanuelle AL Bellaguarda - Johann V Sil


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