Original Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 28, 2011; 17(36): 4076-4089
Published online Sep 28, 2011. doi: 10.3748/wjg.v17.i36.4076
Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis
Malgorzata Zwolinska-Wcislo, Tomasz Brzozowski, Agata Ptak-Belowska, Aneta Targosz, Katarzyna Urbanczyk, Slawomir Kwiecien, Zbigniew Sliwowski
Malgorzata Zwolinska-Wcislo, Gastroenterology and Hepatology Clinic, Jagiellonian University Medical College, 31-531 Cracow, Poland
Tomasz Brzozowski, Agata Ptak-Belowska, Aneta Targosz, Slawomir Kwiecien, Zbigniew Sliwowski, Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland
Katarzyna Urbanczyk, Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland
Author contributions: Zwolinska-Wcislo M designed the study, performed the majority of the experiments and helped with writing of the manuscript; Ptak-Belowska A and Targosz A measured the plasma levels of cytokines, the generation of mucosal prostaglandins and assessed the expression of cytokines in the colonic tissue using molecular techniques; Urbanczyk K performed the histological evaluation of the colonic mucosa; Kwiecien S performed experiments in rats and measured the colonic blood flow; Sliwowski Z evaluated the lesion score, colonic tissue weight and MPO activity; Brzozowski T designed the study, wrote the manuscript and worked on the revised version of this paper.
Supported by The financial grant K/PBW/000067 of the Polish Ministry of Science and Higher Education
Correspondence to: Dr. Tomasz Brzozowski, Professor, Chairman, Department of Physiology, Jagiellonian University Medical College, 16 Grzegorzecka Street, 31-531 Cracow, Poland. mpbrzozo@cyf-kr.edu.pl
Telephone: +48-12-4211006 Fax: +48-12-4222014
Received: February 21, 2011
Revised: June 15, 2011
Accepted: June 22, 2011
Published online: September 28, 2011

AIM: To determine the effect of non-selective cyclooxygenase (COX) inhibitors, selective COX-2 inhibitors and nitric oxide (NO)-releasing aspirin in the healing of ulcerative colitis.

METHODS: Rats with 2,4,6 trinitrobenzenesulfon-ic acid (TNBS)-induced colitis received intragastric (ig) treatment with vehicle, aspirin (ASA) (a non-selective COX inhibitor), celecoxib (a selective COX-2 inhibitor) or NO-releasing ASA for a period of ten days. The area of colonic lesions, colonic blood flow (CBF), myeloperoxidase (MPO) activity and expression of proinflammatory markers COX-2, inducible form of nitric oxide synthase (iNOS), IL-1β and tumor necrosis factor (TNF)-α were assessed. The effects of glyceryl trinitrate (GTN), a NO donor, and 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-​tetramethyl-1H-imidazolyl-1-oxy-3-oxide, onopotassium salt (carboxy-PTIO), a NO scavenger, administered without and with ASA or NO-ASA, and the involvement of capsaicin-sensitive afferent nerves in the mechanism of healing the experimental colitis was also determined.

RESULTS: Rats with colitis developed macroscopic and microscopic colonic lesions accompanied by a significant decrease in the CBF, a significant rise in colonic weight, MPO activity and plasma IL-1β and TNF-α levels. These effects were aggravated by ASA and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), but not celecoxib and counteracted by concurrent treatment with a synthetic prostaglandin E2 (PGE2) analog. Treatment with NO-ASA dose-dependently accelerated colonic healing followed by a rise in plasma NOx content and CBF, suppression of MPO and downregulation of COX-2, iNOS, IL-1β and TNF-α mRNAs. Treatment with GTN, the NO donor, significantly inhibited the ASA-induced colonic lesions and increased CBF, while carboxy-PTIO or capsaicin-denervation counteracted the NO-ASA-induced improvement of colonic healing and the accompanying increase in the CBF. These effects were restored by co-treatment with calcitonin gene related peptide (CGRP) and NO-ASA in capsaicin-denervated animals.

CONCLUSION: NO-releasing ASA, in contrast to ASA, COX-1 inhibitors, and SC-560, accelerated the healing of colitis via a mechanism involving NO mediated improvement of microcirculation and activation of sensory nerves releasing CGRP.

Keywords: Nitric oxide-releasing aspirin, Colitis, Cyclo-oxygenase-2, Aspirin, Celecoxib, Colonic blood flow, Interleukin-1β, Tumor necrosis factor-α