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COMP-angiopoietin-1 ameliorates inflammation-induced lymphangiogenesis in dextran sulfate sodium (DSS)-induced colitis model

A. Lee,M. Sung,Won Kim,Y. Jung

Published 2018 in Journal of molecular medicine

ABSTRACT

Alterations in the intestinal lymphatic network are pathological processes as related to inflammatory bowel disease (IBD). In this study, we demonstrated that reduction in inflammation-induced lymphangiogenesis ameliorates experimental acute colitis. A soluble and stable angiopoietin-1 (Ang1) variant, COMP-Ang1, possesses anti-inflammatory and angiogenic effects. We investigated the effects of COMP-Ang1 on an experimental colonic inflammation model. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium (DSS) via drinking water. We determined body weight, disease activity indices, histopathological scores, lymphatic density, anti-ER-HR3 staining, and the expression of members of the vascular endothelial growth factor (VEGF) family and various inflammatory cytokines in the mice. The density of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and VEGFR-3-positive lymphatic vessels increased in mice with DSS-induced colitis. We observed that COMP-Ang1-treated mice showed less weight loss, fewer clinical signs of colitis, and longer colons than Ade-DSS-treated mice. COMP-Ang1 also significantly reduced the density of LYVE-1-positive lymphatic vessels and the disruption of colonic architecture that is normally associated with colitis and repressed the immunoregulatory response. Further, COMP-Ang1 treatment reduced both M1 and M2 macrophage infiltration into the inflamed colon, which involved inhibition of VEGF-C and D expression. Thus, COMP-Ang1, which acts by reducing inflammation-induced lymphangiogenesis, may be used as a novel therapeutic for the treatment of IBD and other inflammatory diseases.Key messagesCOMP-Ang1 decreases inflammatory-induced lymphangiogenesis in experimental acute colitis.COMP-Ang1 improves the symptom of DSS-induced inflammatory response.COMP-Ang1 reduces the expression of pro-inflammatory cytokines in inflamed colon.COMP-Ang1 reduces the expression of VEGFs in inflamed colon.COMP-Ang1 prevents infiltration of macrophages in a DSS-induced colitis model.

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