Korea Food Research Institute, 245, Nongsaengmyeong-ro, Iseo-myeon, Wanju_Gun, Jeollabuk-do, 55365, Republic of Korea.
Department of Internal Medicine, Division of Nephrology, Chonbuk National University Medical School, Jeonju, Republic of Korea.
J Mol Med (Berl). 2018 May;96(5):459-467. doi: 10.1007/s00109-018-1633-x. Epub 2018 Apr 2.
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.
COMP-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.
肠道淋巴管网络的改变与炎症性肠病（IBD）有关，是一种病理过程。在这项研究中，我们证明了减少炎症诱导的淋巴管生成可改善实验性急性结肠炎。一种可溶性且稳定的血管生成素-1（Ang1）变体，COMP-Ang1，具有抗炎和血管生成作用。我们研究了 COMP-Ang1 对实验性结肠炎症模型的影响。通过饮用 3%葡聚糖硫酸钠（DSS）在小鼠中诱导实验性结肠炎。我们测定了小鼠的体重、疾病活动指数、组织病理学评分、淋巴管密度、抗 ER-HR3 染色以及血管内皮生长因子（VEGF）家族成员和各种炎症细胞因子的表达。DSS 诱导结肠炎小鼠的淋巴管内皮透明质酸受体 1（LYVE-1）和 VEGFR-3 阳性淋巴管密度增加。我们观察到，与 Ade-DSS 治疗的小鼠相比，COMP-Ang1 治疗的小鼠体重减轻更少、结肠炎临床症状更少、结肠更长。COMP-Ang1 还显著降低了 LYVE-1 阳性淋巴管的密度和与结肠炎相关的结肠结构的破坏，并抑制了免疫调节反应。此外，COMP-Ang1 治疗减少了 M1 和 M2 巨噬细胞浸润到炎症结肠，这涉及到 VEGF-C 和 D 表达的抑制。因此，通过减少炎症诱导的淋巴管生成起作用的 COMP-Ang1 可用于治疗 IBD 和其他炎症性疾病的新型治疗方法。
COMP-Ang1 可减少实验性急性结肠炎中的炎症诱导性淋巴管生成。COMP-Ang1 改善 DSS 诱导的炎症反应的症状。COMP-Ang1 减少了炎症结肠中促炎细胞因子的表达。COMP-Ang1 减少了炎症结肠中 VEGFs 的表达。COMP-Ang1 可防止巨噬细胞在 DSS 诱导的结肠炎模型中的浸润。
