Baba Yasuko, Yazawa Takuya, Kanegae Yumi, Sakamoto Seiko, Saito Izumu, Morimura Naoto, Goto Takahisa, Yamada Yoshitsugu, Kurahashi Kiyoyasu
Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-000 4, Japan.
Hum Gene Ther. 2007 Feb;18(2):130-41. doi: 10.1089/hum.2006.137.
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.
目前，对于急性肺损伤（ALI）尚无已知有效的药物治疗方法。由于角质形成细胞生长因子（KGF）可促进上皮细胞生长，气管内给予KGF有可能恢复受损肺组织的完整性并改善患者预后。然而，使用重组KGF蛋白进行治疗受到其有效持续时间短的限制。因此，我们研究了使用腺病毒载体进行气管内KGF基因转导在ALI治疗中的有效性。我们构建了一种表达小鼠KGF（mKGF）的腺病毒载体，并使用微量喷雾器将1.0×10⁹ 个噬斑形成单位的表达mKGF cDNA的腺病毒载体（Ad-KGF）和对照腺病毒载体（Ad-1w1）气管内滴注到麻醉的BALB/c小鼠体内。三天后，将小鼠暴露于>90%的氧气中72小时，并检测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的过表达不仅诱导了表面活性蛋白C阳性立方体细胞的增殖，特别是在终末细支气管和肺泡壁中，而且还预防了包括肺泡内渗出/出血、白蛋白通透性增加和肺水肿在内的肺损伤。KGF转染组的动脉血氧张力和存活率显著更高。这些发现表明，将KGF基因转导至气道上皮是一种有前景的ALI潜在治疗方法。
