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Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice.

Yuge K, Takahashi T, Khai NC, Goto K, Fujiwara T, Fujiwara H, Kosai K - Int. J. Mol. Med. (2014)

Bottom Line: 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.Owing to its clinical feasibility and potent therapeutic effects, this method may be developed into a clinical therapy for treating IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.

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.

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Related in: MedlinePlus

Effects of adenoviral human hepatocyte growth factor (hHGF) intramuscular gene transduction (IMGT) on inflammatory cytokines in dextran sodium sulfate (DSS)-induced colitis. On day 5 of DSS administration, the expression of inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA). The graphs indicate the level of each cytokine per gram of total colon tissue. The expression of inflammatory cytokines, (A) tumor necrosis factor (TNF)-α, (B) interleukin (IL)-1β, and (C) IL-6 increased after administration of adenoviral HGF IMGT. *P<0.05.
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f9-ijmm-33-05-1064: Effects of adenoviral human hepatocyte growth factor (hHGF) intramuscular gene transduction (IMGT) on inflammatory cytokines in dextran sodium sulfate (DSS)-induced colitis. On day 5 of DSS administration, the expression of inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA). The graphs indicate the level of each cytokine per gram of total colon tissue. The expression of inflammatory cytokines, (A) tumor necrosis factor (TNF)-α, (B) interleukin (IL)-1β, and (C) IL-6 increased after administration of adenoviral HGF IMGT. *P<0.05.

Mentions: The inflammatory cytokine cascade plays an important role in the pathogenesis of DSS-induced colitis. Therefore, we analyzed the cytokine profile of the entire colon by ELISA. In general, we observed upregulation of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the colitic mice (39,40). The expression levels of TNF-α, IL-1β and IL-6 were further increased by hHGF IMGT (Fig. 9).


Intramuscular injection of adenoviral hepatocyte growth factor at a distal site ameliorates dextran sodium sulfate-induced colitis in mice.

Yuge K, Takahashi T, Khai NC, Goto K, Fujiwara T, Fujiwara H, Kosai K - Int. J. Mol. Med. (2014)

Effects of adenoviral human hepatocyte growth factor (hHGF) intramuscular gene transduction (IMGT) on inflammatory cytokines in dextran sodium sulfate (DSS)-induced colitis. On day 5 of DSS administration, the expression of inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA). The graphs indicate the level of each cytokine per gram of total colon tissue. The expression of inflammatory cytokines, (A) tumor necrosis factor (TNF)-α, (B) interleukin (IL)-1β, and (C) IL-6 increased after administration of adenoviral HGF IMGT. *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4020479&req=5

f9-ijmm-33-05-1064: Effects of adenoviral human hepatocyte growth factor (hHGF) intramuscular gene transduction (IMGT) on inflammatory cytokines in dextran sodium sulfate (DSS)-induced colitis. On day 5 of DSS administration, the expression of inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA). The graphs indicate the level of each cytokine per gram of total colon tissue. The expression of inflammatory cytokines, (A) tumor necrosis factor (TNF)-α, (B) interleukin (IL)-1β, and (C) IL-6 increased after administration of adenoviral HGF IMGT. *P<0.05.
Mentions: The inflammatory cytokine cascade plays an important role in the pathogenesis of DSS-induced colitis. Therefore, we analyzed the cytokine profile of the entire colon by ELISA. In general, we observed upregulation of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the colitic mice (39,40). The expression levels of TNF-α, IL-1β and IL-6 were further increased by hHGF IMGT (Fig. 9).

Bottom Line: 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.Owing to its clinical feasibility and potent therapeutic effects, this method may be developed into a clinical therapy for treating IBD.

View Article: PubMed Central - PubMed

Affiliation: Department of Gene Therapy and Regenerative Medicine, Graduate School of Medicine, Gifu University, Gifu 502-1194, Japan.

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.

Show MeSH
Related in: MedlinePlus