Abstract
Inflammatory bowel disease (IBD) is characterized by inflammation, angiogenesis, and lymphangiogenesis. Artemisinin (Art), a chemical compound isolated from Artemisia annua L. (sweet wormwood), has several biochemical properties including antibacterial, anticancer, anti-inflammation, and anti-angiogenesis effects. We investigated the effects of Art on inflammation-induced lymphangiogenesis in a dextran sulfate sodium (DSS)-induced mouse acute colitis model. The mice were orally administered Art for 7 days before being evaluated using the disease activity index (DAI) and documenting colonic inflammatory changes, colon edema, microvessel density, lymphatic vessel density (LVD), proinflammatory cytokine levels, and vascular endothelial growth factor (VEGF)-C and VEGF-D/VEGF receptor (VEGFR)-3 mRNA expression levels in colon tissue. Art reduced DSS-induced lymphatic vessel endothelial hyaluronan receptor-1-positive LVD. Art also reduced the symptoms of colitis, improved tissue histology, and relieved inflammatory edema in mice affected by colitis. In addition, Art decreased the infiltration of immunomodulatory cells and inflammatory cytokines, which involved reduction of VEGF-C, -D, and VEGFR-3 expression. Taken together, our findings suggest that Art ameliorates inflammation-driven lymphangiogenesis in an experimental colitis mouse model via the VEGF-C/VEGFR-3 signaling pathway, implicating this pathway as a potential target for the treatment of IBD.
Highlights
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic inflammatory disorders, arising as a result of the interaction between environmental and genetic factors leading to immunological responses and inflammation [1,2]
Our findings suggest that Art ameliorates inflammation-driven lymphangiogenesis in an experimental colitis mouse model via the Vascular endothelial growth factor (VEGF)-C/VEGF receptor (VEGFR)-3 signaling pathway, implicating this pathway as a potential target for the treatment of IBD
Vascular endothelial growth factor (VEGF)-C and VEGF-D are related to VEGF receptor (VEGFR)-3 through lymphatic vessels and lymphangiogenesis
Summary
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic inflammatory disorders, arising as a result of the interaction between environmental and genetic factors leading to immunological responses and inflammation [1,2]. Meaningful increases in blood and lymphatic vessel density (LVD) have been demonstrated in an experimental colitis mouse model [6,7]. Patients with IBD consistently show enlargement or dilation of the mucosa resulting from lymphatic obstruction and submucosal edema [8]. Vascular endothelial growth factor (VEGF)-C and VEGF-D are related to VEGF receptor (VEGFR)-3 through lymphatic vessels and lymphangiogenesis. Enhancing inflammatory lymphangiogenesis by VEGF-C aggravated intestinal inflammation in experimental colitis mice [9,10]. Sato et al [2]
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