Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice
Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice
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DOI：
10.4049/jimmunol.175.2.1224
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Nakanishi, Y
中科院分区：
文献类型：
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作者：
Hamada, N;Kuwano, K;Nakanishi, Y
血管内皮生长因子（VEGF）是一种具有促炎作用的血管生成因子。Flt-1是VEGF的特异性受体之一，可溶性Flt-1 （sflt-1）与VEGF结合并竞争性地抑制其与受体的结合。我们研究了VEGF在博莱霉素诱导的小鼠肺炎的病理生理学中的作用，使用了一种新的治疗策略，包括将sflt-1基因转染到骨骼肌中作为抗VEGF治疗的生物工厂。基因转移后3-14天，血清sflt-1水平显著升高。在气管内灌注博来霉素前3天或后7天转染sflt-1基因，可使炎症细胞数量减少，支气管肺泡灌洗液蛋白浓度降低，14天时血管性血癌因子表达降低。转染sflt-1基因也可在14天后减轻肺纤维化和细胞凋亡。由于炎症细胞浸润开始于3天，随后发生间质纤维化，因此VEGF可能不仅在炎症早期，而且在纤维化晚期都具有促炎、诱导通透性和血管生成因子的重要作用。此外，从临床应用的角度来看，该方法可能有利于治疗肺损伤和纤维化，因为它不需要使用病毒载体或中和Ab。
Vascular endothelial growth factor (VEGF) is an angiogenesis factor with proinflammatory roles. Flt-1 is one of the specific receptors for VEGF, and soluble flt-1 (sflt-1) binds to VEGF and competitively inhibits it from binding to the receptors. We examined the role of VEGF in the pathophysiology of bleomycin-induced pneumopathy in mice, using a new therapeutic strategy that comprises transfection of the sflt-1 gene into skeletal muscles as a biofactory for anti-VEGF therapy. The serum levels of sflt-1 were significantly increased at 3-14 days after the gene transfer. Transfection of the sflt-1 gene at 3 days before or 7 days after the intratracheal instillation of bleomycin decreased the number of inflammatory cells, the protein concentration in the bronchoalveolar lavage fluid and with von Willebrand factor expression at 14 days. Transfection of the sflt-1 gene also attenuated pulmonary fibrosis and apoptosis at 14 days. Since the inflammatory cell infiltration begins at 3 days and is followed by interstitial fibrosis, it is likely that VEGF has important roles as a proinflammatory, a permeability-inducing, and an angiogenesis factor not only in the early inflammatory phase but also in the late fibrotic phase. Furthermore, this method may be beneficial for treating lung injury and fibrosis from the viewpoint of clinical application, since it does not require the use of a viral vector or neutralizing Ab.