VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes
VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes
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DOI：
10.1182/blood-2007-01-066811
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Detmar, Michael
中科院分区：
文献类型：
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作者：
Halin, Cornelia;Tobler, Nadja E.;Detmar, Michael
淋巴管生成参与肿瘤细胞转移，并在慢性炎症性疾病中起主要作用。为了研究淋巴管生成在炎症中的作用，我们诱导并维持小鼠耳中的迟发型超敏反应（DTH），然后通过定量荧光激活细胞分选（FACS）和免疫荧光分析炎症组织和引流淋巴结（LN）中的淋巴管生成。长期的炎症诱导淋巴管内皮细胞的数量显着增加，不仅在发炎的耳朵，但也在耳引流耳淋巴结。全身给予血管内皮生长因子（VEGF）-A中和抗体可有效阻断炎症诱导的淋巴管生成。令人惊讶的是，组织炎症特异性诱导LN淋巴管生成，但不诱导LN血管生成。这些发现解释了VEGF-A的蛋白和mRNA水平的分析，这表明，VEGF-A在炎症的耳朵表达在高的mRNA和蛋白水平，但表达增加，只有在蛋白水平的激活LN。淋巴结中炎症诱导的淋巴管生成与淋巴结B淋巴细胞的存在无关，如B细胞缺陷小鼠所示。我们的数据表明，慢性炎症积极诱导淋巴管生成的淋巴结，这是远程控制，在炎症部位产生的淋巴管生成因子。
Lymphangiogenesis is involved in tumor cell metastasis and plays a major role in chronic inflammatory disorders. To investigate the role of lymphangiogenesis in inflammation, we induced and maintained delayed-type hypersensitivity (DTH) reactions in the ears of mice and then analyzed the resulting lymphangiogenesis in the inflamed tissue and draining lymph nodes (LNs) by quantitative fluorescence-activated cell sorting (FACS) and by immunofluorescence. Long-lasting inflammation induced a significant increase in the number of lymphatic endothelial cells, not only in the inflamed ears but also in the ear-draining auricular LNs. Inflammation-induced lymphangiogenesis was potently blocked by systemic administration of a vascular endothelial growth factor (VEGF)-A neutralizing antibody. Surprisingly, tissue inflammation specifically induced LN lymphangiogenesis but not LN angiogenesis. These findings were explained by analysis of both VEGF-A protein and mRNA levels, which revealed that VEGF-A was expressed at high mRNA and protein levels in inflamed ears but that expression was increased only at the protein level in activated LNs. Inflammation-induced lymphangiogenesis in LNs was independent of the presence of nodal B lymphocytes, as shown in B cell-deficient mice. Our data reveal that chronic inflammation actively induces lymphangiogenesis in LNs, which is controlled remotely, by lymphangiogenic factors produced at the site of inflammation.