Microangiopathy triggers, and inducible nitric oxide synthase exacerbates dextran sulfate sodium-induced colitis

• Published in: Laboratory investigation Vol. 95; no. 7; pp. 728 - 748
• Main Authors: Saijo, Hiroki, Tatsumi, Norifumi, Arihiro, Seiji, Kato, Tomohiro, Okabe, Masataka, Tajiri, Hisao, Hashimoto, Hisashi
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.07.2015; Nature Publishing Group US; Nature Publishing Group
• Subjects: 38; 692/420/256/2516; 82/51; 82/80; Actins - metabolism; Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Butylscopolammonium Bromide; Capillaries - pathology; Capillary Permeability; Colitis - chemically induced; Colitis - enzymology; Colitis - pathology; Colon - blood supply; Colon - pathology; Dextran Sulfate; Disease Models, Animal; Enteric Nervous System - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Intestinal Mucosa - pathology; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Mice, Inbred C57BL; Microcirculation; Nitric Oxide Synthase Type II - metabolism; Pathology; Peripherins - metabolism; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; research-article; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2015.60

Ulcerative colitis (UC) is a representative clinical manifestation of inflammatory bowel disease that causes chronic gastrointestinal tract inflammation. Dextran sulfate sodium (DSS)-induced colitis mice have been used to investigate UC pathogenesis, and in this UC model, disturbance and impairment of the mucosal epithelium have been reported to cause colitis. However, how DSS sporadically breaks down the epithelium remains unclear. In this study, we focused on the colonic microcirculation and myenteric neurons of DSS-induced colitis. Moreover, we examined the potential of myenteric neurons as a target to prevent exacerbation of colitis. Fluorescent angiographic and histopathological studies revealed that DSS administration elicited blood vessel disruption before epithelial disorders appeared. Ischemic conditions in the lamina propria induced inducible nitric oxide synthase (iNOS) expression in myenteric neurons as colitis aggravated. When neuronal activity was inhibited with butylscopolamine, neuronal iNOS expression decreased, and the exacerbation of colitis was prevented. These results suggested that DSS-induced colitis was triggered by microcirculatory disturbance in the mucosa, and that excessive neuronal excitation aggravated colitis. During remission periods of human UC, endoscopic inspection of the colonic microcirculation may enable the early detection of disease recurrence, and inhibition of neuronal iNOS expression may prevent the disease from worsening.