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Reorganization of alveolar capillaries in pulmonary fibrosis by gene trasfection of Hepatocyte Growth Factor

肝细胞生长因子基因转染对肺纤维化肺泡毛细血管的重组

基本信息

批准号：
14570534
负责人：
EBINA Masahito
金额：
$ 2.24万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Hepatocyte growth factor (HGF), a pluripotent mediator with anti-fibrotic effects, is a candidate gene therapy for idiopathic pulmonary fibrosis for which current therapy is minimally effective. We examined human 11(hHGF) gene transfer by a unique gene delivery system using macroaggregated albumin-polyethylenimine conplex (MM-PEI). which induces lung specific gene expression without causing inflammation. lntravenous administration of MAA-PEI with 1 μg pCAG.hHGF (MAA-PEI+pCAG.hHGF) to C57BL/6 mice induced a level of hHGF expression in the lung equal to 10 μg of pCAG.hHGF alone, prolonged its expression only in the lung, and reduced the hHGF express ion in other organs. In situ RT-PCR revealed hHGF production in endothelial cells, alveolar macrophages, and alveolar epithelial cells, but not in airway epithelial cells. Inflammatory cytokines (TNF-α and IL-6) and collagen synthesis in the lungs after bleomycin injury were statistically decreased by MAA-PEI+pCAG.hHGF injection. Since regeneration of alveolar epithelial cells and capillary endothelial cells by bone marrow-derived stem cells after bleomycin-induced injury was unaffected by HGF, the primary anti-inflammatory and anti-fibrotic mechanism of HGF after lung injury is likely to be the inhibition of apoptosis, as suggested by in vitro experiments. These results indicate that this novel HGF gene transfer system may have promising clinical applications.

肝细胞生长因子（HGF）是一种具有抗纤维化作用的多能介质，是治疗特发性肺纤维化的候选基因治疗，目前的治疗效果最低。我们研究了人11（hHGF）基因转移的独特的基因传递系统，使用大分子聚集的白蛋白-聚乙烯亚胺复合物（MM-PEI）。其诱导肺特异性基因表达而不引起炎症。C57 BL/6小鼠静脉注射MAA-PEI+pCAG·hHGF（MAA-PEI+pCAG·hHGF）1 μg，10 μg，原位RT-PCR显示hHGF在内皮细胞、肺泡巨噬细胞和肺泡上皮细胞中产生，但不在气道上皮细胞中产生。MAA-PEI+pCAG、hHGF注射组肺组织中炎性细胞因子（TNF-α、IL-6）和胶原合成均明显减少。由于骨髓来源的干细胞在博来霉素诱导的损伤后对肺泡上皮细胞和毛细血管内皮细胞的再生不受HGF的影响，因此体外实验表明，HGF在肺损伤后的主要抗炎和抗纤维化机制可能是抑制细胞凋亡。这些结果表明，这种新的HGF基因转移系统可能具有良好的临床应用前景。