Karlsen Tine V, Reikvam Tore, Tofteberg Anne, Nikpey Elham, Skogstrand Trude, Wagner Marek, Tenstad Olav, Wiig Helge
From the Department of Biomedicine, University of Bergen, Norway (T.V.K., T.R., A.T., E.N., T.S., M.W., O.T., H.W.); and Departments of Medicine (E.N.) and Pathology (M.W.), Haukeland University Hospital, Bergen, Norway.
Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2128-2135. doi: 10.1161/ATVBAHA.117.309883. Epub 2017 Sep 21.
Lymphatic vessels play an important role in body fluid, as well as immune system homeostasis. Although the role of malfunctioning or missing lymphatics has been studied extensively, less is known on the functional consequences of a chronically expanded lymphatic network or lymphangiogenesis.
To this end, we used K14-VEGF-C (keratin-14 vascular endothelial growth factor-C) transgenic mice overexpressing the vascular endothelial growth factor C in skin and investigated the responses to inflammatory and fluid volume challenges. We also recorded interstitial fluid pressure, a major determinant of lymph flow. Transgenic mice had a strongly enhanced lymph vessel area in skin. Acute inflammation induced by lipopolysaccharide and chronic inflammation by delayed-type hypersensitivity both resulted in increased interstitial fluid pressure and reduced lymph flow, both to the same extent in wild-type and transgenic mice. Hyperplastic lymphatic vessels, however, demonstrated enhanced transport capacity after local fluid overload not induced by inflammation. In this situation, interstitial fluid pressure was increased to a similar extent in the 2 strains, thus, suggesting that the enhanced lymph vessel area facilitated initial lymph formation. The increased lymph vessel area resulted in an enhanced production of the chemoattractant CCL21 that, however, did not result in augmented dendritic cell migration after induction of local skin inflammation by fluorescein isothiocyanate.
An expanded lymphatic network is capable of enhanced chemoattractant production, and lymphangiogenesis will facilitate initial lymph formation favoring increased clearance of fluid in situations of augmented fluid filtration.
淋巴管在体液以及免疫系统稳态中发挥重要作用。尽管功能失常或缺失的淋巴管的作用已得到广泛研究，但对于慢性扩张的淋巴管网络或淋巴管生成的功能后果却知之甚少。
为此，我们使用了在皮肤中过表达血管内皮生长因子C的K14-VEGF-C（角蛋白14血管内皮生长因子C）转基因小鼠，并研究了其对炎症和液体容量挑战的反应。我们还记录了间质液压力，这是淋巴流动的一个主要决定因素。转基因小鼠皮肤中的淋巴管面积显著增加。脂多糖诱导的急性炎症和迟发型超敏反应诱导的慢性炎症均导致间质液压力升高和淋巴流动减少，野生型和转基因小鼠的变化程度相同。然而，增生性淋巴管在非炎症诱导的局部液体过载后显示出增强的运输能力。在这种情况下，两种品系的间质液压力升高程度相似，因此表明淋巴管面积的增加促进了初始淋巴形成。淋巴管面积的增加导致趋化因子CCL21的产生增加，然而，在异硫氰酸荧光素诱导局部皮肤炎症后，这并未导致树突状细胞迁移增加。
扩张的淋巴管网络能够增强趋化因子的产生，淋巴管生成将促进初始淋巴形成，有利于在液体滤过增加的情况下提高液体清除率。
