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Exploring the administration route of HGF-expressing adenoviral vector (Ad-HGF) and low but local HGF-expression plasmid vector with macroaggregated albumin/polyethyleneiminV(MAA-PEI) for the clinically effective HGF gene transfer therapy.

探索HGF表达腺病毒载体(Ad-HGF)和低但局部HGF表达质粒载体与大聚集白蛋白/聚乙烯亚胺V(MAA-PEI)的给药途径，以用于临床有效的HGF基因转移治疗。

基本信息

批准号：
12557056
负责人：
NUKIWA Toshihiro
金额：
$ 8.45万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Hepatocyte growth factor (HGF) is a multi-organ regeneration factor including the anti-apoptotic, angiogenic, proliferative, and morphogenic activity functioning not only in liver but kidney or lung. In the current investigation, in order to apply the HGF gene transfer in the clinical setting for acute lung injury (ALI) and lung fibrosis, we have explored (1) the use of high-expression but antigenic adenoviral vector in the context of administration route, and (2) the use of low-expression but local and non-inflammatory plasmid vector in mouse model. Although high HGF protein was detected by intratracheal Ad-HGF administration, the bleomycin induced ALI and fibrosis persisted with reduced HGF effect. In contrast, in spite of the fact that only fraction of HGF was delivered to the lung by the way of intraperitoneal of intravenous administration of Ad-HGF, the bleomycin induced ALI and fibrosis had been suppressed through repression of both alveolar epithelial cell apoptosis and TGF-b expression. When MAA-PEI was introduced to mix plasmid HGF vector for local HGF expression in the lung, the expression efficiency increased by 10 fold (1 ug plasmid) compared with naked plasmid vector, and the duration of HGF expression prolonged for more than 10 days. Furthemore the concentration of HGF in the lung was only one thousandth of the amount yielded by Ad-HGF, the bleomycin induced ALI and fibrosis was efficiently suppressed. Taken together, while high HGF expression and suppression of lung inflammation was obtained using non-tracheal Ad-HGF administration in the bleomycin induced ALI and fibrosis, local, non-inflammatory and repeatable feature of HGF plasmid/MAA-PEI indicates a possible modality for clinical application in ALI or fibrosis.

肝细胞生长因子（HGF）是一种多器官再生因子，包括抗凋亡，血管生成，增殖和形态发生活性，不仅在肝脏，而且在肾脏或肺中发挥作用。在目前的研究中，为了将HGF基因转移应用于急性肺损伤（ALI）和肺纤维化的临床环境中，我们探索了（1）在给药途径的背景下使用高表达但具有抗原性的腺病毒载体，以及（2）在小鼠模型中使用低表达但局部和非炎性的质粒载体。虽然肝内注射Ad-HGF可检测到高水平的HGF蛋白，但博来霉素诱导的ALI和纤维化持续存在，而HGF作用降低。相反，尽管通过腹腔内或静脉内施用Ad-HGF仅将部分HGF递送至肺，但通过抑制肺泡上皮细胞凋亡和TGF-β表达，博来霉素诱导的ALI和纤维化已被抑制。将MAA-PEI引入混合质粒HGF载体进行肺局部表达，表达效率比裸质粒载体提高10倍（1 μ g质粒），表达持续时间延长10 d以上。而且肺内HGF浓度仅为Ad-HGF的千分之一，能有效抑制博莱霉素诱导的ALI和肺纤维化。综上所述，虽然使用非气管Ad-HGF给药在博来霉素诱导的ALI和纤维化中获得了高HGF表达和肺部炎症抑制，但HGF质粒/MAA-PEI的局部、非炎症和可重复的特征表明了在ALI或纤维化中临床应用的可能模式。