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Author Notes:

E-mail: ssrini2@emory.edu

Daniel Berg, Editor

Conceived and designed the experiments: BPC SVS SS.

Performed the experiments: BPC VB VLK MVK.

Analyzed the data: BPC VB VLK MVK SVS SS.

Contributed reagents/materials/analysis tools: VLK MVK DPJ ATG SVS SS.

Wrote the paper: BPC SS.

The authors would like to acknowledge Dr. Simon Mwangi, Ph. D; Mallappa Anitha and Irene Joseph for their help.

The authors have declared that no competing interests exist.

Subject:

Research Funding:

This work is supported by CCFA Research Fellowship Awards (B. Chandrasekharan & M. Vijay Kumar), NIH grants KO8 DK067045 and RO3 DK078552 (S.Srinivasan) and DK06411 (S.V. Sitaraman), Digestive Diseases Research Center grant (DK064399).

Targeted Deletion of Neuropeptide Y (NPY) Modulates Experimental Colitis

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Journal Title:

PLoS ONE

Volume:

Volume 3, Number 10

Publisher:

, Pages e3304-e3304

Type of Work:

Article | Final Publisher PDF

Abstract:

Background Neurogenic inflammation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). We examined the role of neuropeptide Y (NPY) and neuronal nitric oxide synthase (nNOS) in modulating colitis. Methods Colitis was induced by administration of dextran sodium sulphate (3% DSS) or streptomycin pre-treated Salmonella typhimurium (S.T.) in wild type (WT) and NPY (NPY−/−) knockout mice. Colitis was assessed by clinical score, histological score and myeloperoxidase activity. NPY and nNOS expression was assessed by immunostaining. Oxidative stress was assessed by measuring catalase activity, glutathione and nitrite levels. Colonic motility was assessed by isometric muscle recording in WT and DSS-treated mice. Results DSS/S.T. induced an increase in enteric neuronal NPY and nNOS expression in WT mice. WT mice were more susceptible to inflammation compared to NPY−/− as indicated by higher clinical & histological scores, and myeloperoxidase (MPO) activity (p<0.01). DSS-WT mice had increased nitrite, decreased glutathione (GSH) levels and increased catalase activity indicating more oxidative stress. The lower histological scores, MPO and chemokine KC in S.T.-treated nNOS−/− and NPY−/−/nNOS−/− mice supported the finding that loss of NPY-induced nNOS attenuated inflammation. The inflammation resulted in chronic impairment of colonic motility in DSS-WT mice. NPY –treated rat enteric neurons in vitro exhibited increased nitrite and TNF-α production. Conclusions NPY mediated increase in nNOS is a determinant of oxidative stress and subsequent inflammation. Our study highlights the role of neuronal NPY and nNOS as mediators of inflammatory processes in IBD.

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©Chandrasekharan et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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