title: Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice.
abstract: Inflammatory bowel disease (IBD) severely affects the quality of life of patients. At present, there is no clinical solution for this condition; therefore, there is a need for innovative therapies for IBD. Hepatocyte growth factor (HGF) exerts various biological activities in various organs. However, a clinically applicable and effective HGF-based therapy for IBD has yet to be developed. In this study, we examined the therapeutic effect of injecting an adenoviral vector encoding the human HGF gene (Ad.HGF) into the hindlimbs of mice with dextran sodium sulfate (DSS)-induced colitis. Plasma levels of circulating human HGF (hHGF) were measured in injected mice. The results showed that weight loss and colon shortening were significantly lower in Ad.HGF-infected mice as compared to control (Ad.LacZ-infected) colitic mice. Additionally, inflammation and crypt scores were significantly reduced in the entire length of the colon, particularly in the distal section. This therapeutic effect was associated with increased cell proliferation and an antiapoptotic effect, as well as a reduction in the number of CD4+ cells and a decreased CD4/CD8 ratio. The levels of inflammatory, as well as Th1 and Th2 cytokines were higher in Ad.HGF-infected mice as compared to the control colitic mice. Thus, systemically circulating hHGF protein, produced by an adenovirally transduced hHGF gene introduced at distal sites in the limbs, significantly ameliorated DSS-induced colitis by promoting cell proliferation (i.e., regeneration), preventing apoptosis, and immunomodulation. Owing to its clinical feasibility and potent therapeutic effects, this method may be developed into a clinical therapy for treating IBD.
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yuge
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Ngin Cin
authors.initials: NC
authors.lastname: Khai
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Food Science, Kyoto Women's University, Kyoto 605-8501, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Kosai
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000628:therapy*; D016264:Dextran Sulfate / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D017228:Hepatocyte Growth Factor; D016264:Dextran Sulfate