Hepatocyte Growth Factor Facilitates the Repair of Large Colonic Ulcers in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in Rats

Numata, Masatsugu; Ido, Akio; Moriuchi, Akihiro; Kim, Ildeok; Tahara, Yoshihiro; Yamamoto, Shojiro; Hasuike, Satoru; Nagata, Kenji; Miyata, Yukio; Uto, Hirofumi; Tsubouchi, Hirohito

doi:10.1097/01.mib.0000164192.71381.5c

Cited by 30 publications

(36 citation statements)

References 37 publications

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“…Daily subcutaneous injection of Teduglutide, an analogue of GLP-2, has been tried in moderate-to-severe CD patients, which showed potential effect upon mucosal healing [115]. Also, recombinant HGF has been shown to facilitate mucosal repair in a rat colitis model [116]. Human recombinant R-Spondin-1 is another candidate that has been proven to promote proliferation of crypt cells [117].…”

Section: Iecs As Target Cells For the Treatment Of Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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Section: Iecs As Target Cells For the Treatment Of Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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“…In recent years, a number of basic and clinical studies have focused on growth factors and their role in IBD with the objective of developing a novel therapy (31,33,34,42).…”

mentioning

confidence: 99%

Increased expression of midkine in the rat colon during healing of experimental colitis

Yuki

Ishihara²,

Rumi³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Midkine (MK) is a unique growth and differentiation factor that modulates the proliferation and migration of various cells; however, little is known regarding its relationship to intestinal diseases. The aim of this study was to investigate MK expression and its role in dextran sulfate sodium (DSS)-induced colitis in rats. The expressions of MK, receptor-like protein-tyrosine phosphatase (RPTP)-β, and proinflammatory cytokines were examined in rat colonic tissues after the development of DSS-induced colitis using Northern blotting, immunohistochemistry, and laser-capture microdissection (LCM) coupled with RT-PCR. The effects of MK on the migration of intestinal epithelial cells (IEC-6) were also evaluated in vitro using an intestinal wound repair model. MK expression was significantly increased in damaged colonic mucosa, mainly from day 3 to day 5 after the end of DSS administration, with abundant MK immunoreactive signals detected in submucosal fibroblasts. Expressions of proinflammatory cytokines were most strongly induced on day 1, which preceded the augmentation of MK expression. Results of LCM coupled with RT-PCR clearly indicated RPTP-β expression in colonic epithelial cells. The migration assay showed that wound repair in the MK-treated groups was accelerated dose dependently. The present results showed for the first time that intestinal inflammation upregulates the MK-RPTP-β system, which may stimulate mucosal regeneration during the process of healing of colitis. Additional investigations regarding the role of MK may contribute to the development of new options for the treatment of inflammatory bowel diseases.

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“…since HGF is a potent mitogen for hepatocytes, we confirmed before initiating a human trial that repeated doses of intravenous HGF did not accelerate the development of hepatocellular carcinoma in rats fed a choline-deficient, L-amino acid-defined diet (28). We recently reported that treatment with recombinant HGF stimulates the repair of injured intestinal mucosa, leading to amelioration of experimental colitis (12,13). However, repeated doses of HGF may exhibit oncogenic potential; therefore the carcinogenic potential of HGF should be evaluated as precisely as possible before clinical applications of this agent.…”

Section: Discussionmentioning

confidence: 99%

“…4), and consequently inhibited the development of colitis-associated colorectal cancer (Table II). Although HGF ameliorates mucosal injury through its mitogenic and anti-apoptotic effects on colonic epithelial cells (12,13,30), improvement of the microenvironment, which means the reduction of chronic epithelial exposure to proinflammatory cytokines, growth factors and reactive oxygen species throughout repeated cycles of mucosal injury and repair, is considered to be a primary contributor to the prevention of colitis-associated colorectal cancer.…”

Section: Nο Of Tumors ----------------------------------------------mentioning

confidence: 99%

“…HGF activator and HGF activator inhibitor type-1, both HGF-associated molecules involved in the activation of HGF in injured tissues, are associated with colonic mucosal repair (9,10); HGF expression is increased in inflamed colonic mucosal tissues in patients with ulcerative colitis (11). We previously reported that systemic administration of recombinant human HGF ameliorated experimental colitis in rats (12,13). Perturbed homeostasis between luminal antigens (e.g., commensal bacteria) and mucosal immunity serves as a critical determinant in the development of gut inflammation in IBD.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte growth factor ameliorates mucosal injuries leading to inhibition of colon cancer development in mice

Yamaji

Ido

Moriuchi³

et al. 2011

Oncol Rep

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Abstract. Hepatocyte growth factor (HGF), which facilitates the repair of injured mucosa, has the potential to be a new therapeutic agent for inflammatory bowel disease (IBD). However, given that the incidence of colorectal cancer increases continuously with disease duration in patients with IBD, the fact that HGF is a potent mitogen for intestinal epithelial cells may further heighten the risk of bowel cancer in this patient population. In this study, we examined the effects of recombinant HGF on colorectal cancer development in mice with or without experimentally induced colitis. Although HGF stimulated proliferation of colonic epithelial cells in normal mucosa, the development of colorectal cancer induced by repeated injection of azoxymethane (AOM) was significantly inhibited by HGF treatment. In a mouse model of colitis-associated cancer, colorectal cancer frequently developed despite only a single injection of AOM prior to three cycles of dextran sulfate sodium administration. However, HGF treatment significantly facilitated the repair of injured mucosa, leading to inhibition of colorectal cancer development in a dose-dependent manner. Thus, HGF-induced repair of injured mucosa inhibits rather than accelerates the development of colorectal cancer, and these results also suggest the importance of blocking the cycles of mucosal injury and repair to prevent colitis-associated colorectal cancer.

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Hepatocyte Growth Factor Facilitates the Repair of Large Colonic Ulcers in 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis in Rats

Cited by 30 publications

References 37 publications

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Increased expression of midkine in the rat colon during healing of experimental colitis

Hepatocyte growth factor ameliorates mucosal injuries leading to inhibition of colon cancer development in mice

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