Keratinocyte growth factor gene transduction ameliorates acute lung injury and mortality in mice.
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.
Baba
Yasuko
Y
Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-000 4, Japan.
Yazawa
Takuya
T
Kanegae
Yumi
Y
Sakamoto
Seiko
S
Saito
Izumu
I
Morimura
Naoto
N
Goto
Takahisa
T
Yamada
Yoshitsugu
Y
Kurahashi
Kiyoyasu
K
D000818:Animals; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000235:genetics*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D018496:Hyperoxia; D007150:Immunohistochemistry; D007249:Inflammation; D019394:Ki-67 Antigen / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000097:blood / Q000139:chemically induced / Q000401:mortality* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D016019:Survival Analysis; D014161:Transduction, Genetic
D016207:Cytokines; D019394:Ki-67 Antigen; D051523:Fibroblast Growth Factor 7