Journal
FREE RADICAL RESEARCH
Volume 46, Issue 12, Pages 1427-1436Publisher
INFORMA HEALTHCARE
DOI: 10.3109/10715762.2012.732698
Keywords
colitis; nitric oxide; inflammation; neutrophil; ICAM-1; P-selectin
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Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Development of Advanced Measurement and Analysis Systems from the Japan Science and Technology Agency (JST)
- Japan Society for the Promotion of Science [19004]
- Grants-in-Aid for Scientific Research [23790049] Funding Source: KAKEN
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Nitric oxide (NO) is thought to be a key molecule in the progression of ulcerative colitis and experimental colitis induced by dextran sodium sulfate (DSS). However, the detrimental effect of DSS-induced NO production on the colonic mucosa is incompletely understood. Increases in the expression of adhesion molecules in the vascular endothelium and activated neutrophils (thereby releasing injurious molecules such as reactive oxygen species) are reportedly associated with the pathogenesis of DSS-induced colitis. We investigated if the detrimental effect of NO production on the colonic mucosa was attributable to the activation of neutrophil infiltration by NO in mice with DSS-induced colitis. NO2-/NO3- content in the middle and distal colon was increased on days 5 and 7, but alterations in the proximal colon were not observed. Myeloperoxidase (MPO) activity and expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) were significantly increased in the entire colon, whereas TNF-alpha levels were significantly increased only in the middle and distal colon on day 7. The pathology of colitis and increases in colonic MPO activity, P-selectin, ICAM-1, and TNF-alpha levels were suppressed by the inducible NO synthase (iNOS)-specific inhibitor aminoguanidine and NO scavenger c-PTIO, whereas all but TNF-alpha levels were increased by the non-specific NOS inhibitor L-NAME. These findings suggest that iNOS-derived NO increases TNF-alpha levels in the middle and distal colon and increased TNF-alpha levels induce expression of P-selectin and ICAM-1, thereby promoting the infiltration of activated neutrophils, which leads to damage to colonic tissue.
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