Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice

Abstract

Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SRalpha promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes.

Effect of rectal administration of rebamipide on dextran sulfate sodium-induced colitis: Role of hepatocyte growth factor

“…In our recent work, the regulated genes by HGF in DSS-induced colitis were examined [18]. The genes which were increased over 5-fold by HGF were 284 genes in experiment 1 and 205 genes in experiment 2, respectively [18].…”

“…5-Aminosalicylic acid (5-ASA) and corticosteroids have been used for the chronic phase as well as acute phase. Although these agents are effective in many patients, therapy is effective for experimental colitis in mice [17,18]. These data suggest that intestinal mucosal healing is stimulated by the HGF/c-Met signaling system.…”

“…The histologic findings of DSS-induced colitis were composed of epithelial destruction, remarkable infiltration of inflammatory cells, and submucosal edema [18]. In the present study, we especially focused on ongoing inflammation, and grading system was performed previously described [23].…”

Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease

“…The importance of HGF has been confirmed by the intrarectal administration of HGF-expressing adenovirus in TNBStreated mice, which leads to significant improvements in mucosal damage [48] . The same group has also demonstrated the therapeutic effects of naked gene therapy of HGF in the DSS-induced colitis model [49] . Taking these results together, HGF gene delivery may be very useful as a therapeutic strategy for human IBD.…”

“…Migration inhibitory factor [114] , LIX [115] , L-18 [33] , CCR5 [116] , IL-1 [117] Adhesion molecules CD98 [118] , β2 integrins (CD18/11a) [83] , Integrin α1β1 [81] , VCAM-1 [119] Transcriptional factors STAT3 [74] Toll like receptors and ligands CpG motifs [92] , Flagellin/TLR5 [90] Enzymes Chitinase 3-like-1 [102] , Carbonic anhydrase Ⅳ [100] , Eosinophil peroxidase [120] , Caspase-1 [105] Hormones Adiponectin [112] , Resistin-like molecule β [121] , Leptin [113] , Osteopontin [122] , Activins [123] Others Galanin-1 receptor [124] Regulatory factors Categories Factors (References) T cells γδT cells [23,24] Cytokines/chemokines BFGF [51] , FGF2 [125] , TGF-α [46] , TFF2 [53] , ITF [54] , HGF [47,49] Transcription factors SOCS3 [74] , Nrf2 [126] , PPARγ [76,77] , PPARδ [76] Adhesion molecules B2 integrins (CD11β) [83] Receptors TLR4 [87] , PG receptor EP-4 [95] , Pregnane X Receptor [127] Enzymes COX-2 [94,96] , COX-1 [94] , Matrix metalloproteinase-2 …”