Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia
Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia
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DOI：
10.1182/blood-2003-08-2964
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发表时间：
2004-08-15
期刊：
影响因子：
20.3
通讯作者：
Detmar, M
中科院分区：
文献类型：
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作者：
Kunstfeld, R;Hirakawa, S;Detmar, M
血管内皮生长因子-A（VEGF-A）的表达在包括银屑病、迟发型超敏反应（DTH）和类风湿性关节炎在内的几种炎症性疾病中上调。为了直接表征VEGF-A在炎症中的生物学功能，我们评估了在表皮特异性过表达VEGF-A的转基因小鼠的耳皮肤中诱导的实验性DTH反应。VEGF-A转基因小鼠经历了持续超过1个月的显著增加的炎症反应，而野生型小鼠的炎症在7天内恢复到基线水平。VEGF-A转基因小鼠的炎性病变与人类银屑病非常相似，其特征为表皮增生、表皮分化受损以及真皮CD 4（+）T淋巴细胞和表皮CD 8（+）淋巴细胞积聚。令人惊讶的是，VEGF-A还促进淋巴管增殖和扩大，这可能有助于增加炎症反应，因为淋巴管扩大也在人银屑病皮肤病变中检测到。与VEGF受体-1（VEGFR-1）和VEGFR-2阻断抗体联合全身治疗可有效抑制炎症，并缩小淋巴管大小。总之，这些发现揭示了VEGF-A在促进淋巴管扩大、血管通透性过高和白细胞募集中的核心作用，从而导致持续的慢性炎症。抑制VEGF-A的生物活性可能成为抗炎治疗的新途径。(C)2004年，美国血液学会。
Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4(+) T-lymphocytes and epidermal CD8(+) lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. (C) 2004 by The American Society of Hematology.