Keratinocyte growth factor gene transduction ameliorates acute lung injury and mortality in mice
Keratinocyte growth factor gene transduction ameliorates acute lung injury and mortality in mice
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DOI：
10.1089/hum.2006.137
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发表时间：
2007-02-01
影响因子：
4.2
通讯作者：
Kurahashi, Kiyoyasu
中科院分区：
文献类型：
--
作者：
Baba, Yasuko;Yazawa, Takuya;Kurahashi, Kiyoyasu
急性肺损伤（ALI）目前尚无有效的药物治疗方法。由于角质形成细胞生长因子（KGF）促进上皮细胞生长，KGF的气管内给药有可能恢复受损肺的肺组织完整性并改善患者的预后。然而，使用重组KGF蛋白的治疗受限于其短的有效持续时间。因此，我们研究了腺病毒载体介导的KGF基因转导在ALI中的有效性。我们构建了表达小鼠KGF的腺病毒载体（mKGF），并使用MicroSprayer将1.0 × 10（9）空斑形成单位的mKGF cDNA表达（Ad-KGF）和对照（Ad-1 w1）腺病毒载体注入麻醉的BALB/c小鼠体内。三天后，小鼠暴露于> 90%的氧72小时，并检查KGF对高氧诱导的肺损伤的影响。在Ad-KGF组中，KGF在气道上皮细胞中强烈表达，而腺病毒载体滴注引起的细支气管周围和肺泡炎症最小。KGF过表达不仅诱导表面活性蛋白C阳性立方细胞增殖，特别是在终末细支气管和肺泡壁，而且还防止肺损伤，包括肺泡内渗出/出血，白蛋白渗透性增加和肺水肿。KGF转染组的动脉血氧分压和存活率明显高于对照组。这些结果表明，KGF基因转导到气道上皮细胞是一个有前途的潜在治疗ALI。
At present there is no known effective pharmacological therapy for acute lung injury (ALI). Because keratinocyte growth factor (KGF) promotes epithelial cell growth, intratracheal administration of KGF has the possibility of restoring lung tissue integrity in injured lungs and improving patient outcomes. However, treatment using recombinant KGF protein is limited by its short effective duration. Thus, we investigated the effectiveness of intratracheal KGF gene transduction using adenoviral vector in ALI. We constructed an adenoviral vector expressing mouse KGF (mKGF), and 1.0 x 10(9) plaque-forming units of mKGF cDNA-expressing (Ad-KGF) and control (Ad-1w1) adenoviral vector was intratracheally instilled, using a MicroSprayer, into anesthetized BALB/c mice. Three days later, the mice were exposed to > 90% oxygen for 72 hr, and the effect of KGF on hyperoxia-induced lung injury was examined. In the Ad-KGF group, KGF was strongly expressed in the airway epithelial cells, while peribronchiolar and alveolar inflammation caused by adenoviral vector instillation was minimal. The KGF overexpression not only induced proliferation of surfactant protein C-positive cuboidal cells, especially in the terminal bronchiolar and alveolar walls, but also prevented lung injury including intraalveolar exudation/hemorrhage, albumin permeability increase, and pulmonary edema. The arterial oxygen tension and the survival rate were significantly higher in the KGF-transfected group. These findings suggest that KGF gene transduction into the airway epithelium is a promising potential treatment for ALI.