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Introduction
The breakdown of normal mucosal immunity causes the development of inflammatory bowel disease (IBD), which can be classified as Crohn’s disease (CD) and ulcerative colitis (UC) (1). IBD is a chronically relapsing and remitting condition of unknown origin that exhibits various features of immunological inflammation and affects at least 1 in 1,000 people in western countries. IBD is characterized by inflammation in the intestine, and is associated with diarrhea, occult blood, abdominal pain, weight loss, anemia and leukocytosis. IBD primarily affects young adults, and the disease initially manifests in childhood in 15–25% of cases. Therefore, IBD patients often develop severe symptoms that decrease their quality of life (2). Consequently, there is a need for innovative therapies for IBD.
Current treatments for IBD focus on suppressing inflammation or modulating the immune response using corticosteroids, mercaptopurines, 5-ASA, or monoclonal antibodies against inflammatory cytokines, e.g., the anti-tumor necrosis factor (TNF)-α antibody infliximab (3). However, despite the wide variety of pharmacologic options for patients with IBD, consistent cures and prolonged remissions have yet to be achieved.
Hepatocyte growth factor (HGF) was originally identified (4–7) and cloned (8,9) as a potent mitogen for hepatocytes, but has since been established as a multifunctional cytokine that exhibits mitogenic, motogenic, morphologic, angiogenic, antiapoptotic and organotrophic effects in a variety of tissues (10). HGF is upregulated in inflamed colonic mucosal tissue in patients with CD or UC (11–13), and plasma HGF levels are elevated in animal models of acute colitis (14). In vitro, HGF modulates intestinal epithelial cell proliferation and migration (15), thereby enhancing epithelial cell restitution, which is the initial step of gastrointestinal wound healing. In addition, administration of recombinant human HGF (hHGF) protein reduces the severity of colitis and accelerates colonic mucosal repair in models of TNBS-induced and DSS-induced colitis (16–19), as well as in HLA-B27 transgenic rats with colitis (20). Mukoyama et al (21) showed that the intrarectal administration of an adenoviral (Ad) vector carrying the HGF gene prevented TNBS-induced colitis. Additionally, Hanawa et al (22) demonstrated the attenuation of mouse DSS colitis by naked gene transfer of rat HGF into the liver, and Kanbe et al (23) reported the amelioration of mucosal damage in DSS colitis by the intrarectal administration of the naked HGF gene. In their...