Hepatocyte growth factor accelerates restitution of intestinal epithelial cells

Nishimura, Shuji; Takahashi, M; Ota, Shinichi; Hirano, Minoru; Hiraishi, Hideyuki

doi:10.1007/s005350050066

Cited by 43 publications

(19 citation statements)

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“…Methotrexate exerts its toxicity by directly inhibiting DNA synthesis, leading to a reduction of mitosis in the crypts and shortening of the villi (Trier, 1962;Altmann, 1974), followed by proliferative recovery phase after the damage (Taminiau et al, 1980). Previous in vivo studies have demonstrated that HGF plays an important role in gastric ulcer repair, and in vitro studies have shown that HGF stimulates intestinal cell proliferation and restitution (Kinoshita et al, 1997;Goke et al, 1998;Nishimura et al, 1998). Despite these reports, limited in vivo studies have been undertaken to investigate the role of HGF in intestinal growth and repair (Kato et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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Summary Chemotherapy or radiotherapy often cause mucosal damage in the gut (gut mucositis) in cancer patients. As a step to investigate mechanisms underlying subsequent intestinal repair, we have examined the expression profiles of hepatocyte growth factor (HGF) and its receptor c-met, two molecules previously implicated in tissue repair, in comparison to the histopathological and proliferative changes in a rat model of methotrexate-induced small intestinal mucositis. Histological analysis of the intestinal specimens revealed crypt loss and villus atrophy with damage maximal on day 5 after methotrexate injection, and normalization of mucosal structure commencing on day 6. Crypt cell proliferation was decreased dramatically on day 3, normalized on day 4 and up-regulated on days 5 and 6. HGF and c-met protein/mRNA expression was up-regulated between days 4 and 7, with the mRNA co-localizing to the crypt and lower villus epithelium. Therefore, following methotrexate injection, a decrease in crypt cell proliferation preceded histological damage, and conversely, crypt cell hyperproliferation preceded mucosal regeneration. Up-regulation of HGF and c-met coincided with crypt hyperproliferation and mucosal recovery, suggesting a role for HGF in intestinal repair following acute injury. The crypt epithelial localization of HGF and c-met implies an autocrine or paracrine mechanism of HGF action. All these procedures were approved by the Animal Ethics Committee of the Women's and Children's Hospital, Adelaide, Australia. Histopathological analysis of intestinal damage and repairTransverse sections (4 µm in thickness) of paraffin-embedded proximal jejunal specimens were stained with haematoxylin and eosin (H&E) and examined with a light microscope. A semi-quantitative histological assessment of intestinal damage was utilized to obtain an overall score of damage severity. A total score for the sample was derived from the sum of scores for 11 histopathological criteria as we have previously described (Howarth et al, 1996), including villus fusion and stunting (atrophy), disruption of brush border and surface enterocytes, disappearance of goblet cells, reduction in numbers of mitotic figures, crypt loss/architectural disruption, disruption or distortion of crypt cells, crypt abscess formation, infiltration of polymorphonuclear cells and lymphocytes and dilatation of lymphatics and capillaries. For each criterion, a score was given to represent a mild (score 1), moderate (2), severe (3), or no (0) changes. Quantitative histological analyses were also conducted to measure the changes in crypt depth and villus height in the jejunal specimens over the time course. Microscopic images were acquired and analysed. For each animal, the height and depth of ten villi and crypts respectively were measured at three tissue levels, each separated by 100 µm, and means of the 30 measurements were calculated for each animal. Although histological damage prevented accurate measurements of villus and crypt lengths in some regions, in the jejunal ...

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Section: Discussionmentioning

confidence: 99%

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

et al. 2000

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“…Several studies have described increased serum HGF levels in animals with experimental colitis (Dignass et al, 1994;Takahashi et al, 1995b;Matsuo et al, 1997;Nishimura et al, 1998;Ortega-Cava et al, 2002). In the present study, c-Met tyrosine phosphorylation was also observed in colonic tissue of rats with DSS-induced colitis in the absence of HGF treatment, suggesting that endogenous rat HGF was also induced.…”

Section: Hgf Facilitates Mucosal Repair In Dss-induced Colitis 149mentioning

confidence: 98%

“…HGF activator (HGFA) and HGF activator inhibitor type-1, HGF-associated molecules involved in the activation of HGF in injured tissues, are associated with colonic mucosal repair (Itoh et al, 2000;Kataoka et al, 2000b). Additionally, HGF expression was reported to be up-regulated in inflamed colonic mucosal tissue in patients with ulcerative colitis , and plasma HGF levels are increased in animal models of acute colitis (Dignass et al, 1994;Takahashi et al, 1995b;Matsuo et al, 1997;Nishimura et al, 1998;Ortega-Cava et al, 2002). Recombinant human HGF will soon be available for administration to patients with severe liver disease.…”

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confidence: 99%

Hepatocyte Growth Factor Facilitates Colonic Mucosal Repair in Experimental Ulcerative Colitis in Rats

Tahara¹,

Ido²,

Yamamoto³

et al. 2003

J Pharmacol Exp Ther

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Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration, serving as a critical regulator of intestinal wound healing. In this study, we examined the effect of administration of recombinant human HGF on colonic mucosal damage in vivo. Acute colitis was induced in rats by feeding with 5% dextran sulfate sodium (DSS) for 7 days, and colitis was subsequently maintained by feeding with 1% DSS. On the 5th day of DSS administration, osmotic pumps releasing recombinant human HGF (200 g/day) were implanted into the peritoneum of the rats. Continuous intraperitoneal delivery of HGF led to both increased serum human HGF levels and c-Met tyrosine phosphorylation within the colonic mucosa. Compared with mock-treated rats, those administered human HGF showed a reduction in colitis-associated weight loss, large intestinal shortening, and improved colonic erosions. Enhanced epithelial regeneration and cellular proliferation were observed in rats treated with recombinant human HGF. The weights of the liver, kidneys, and spleen were not affected by HGF administration. These results indicate that HGF administration accelerates colonic mucosal repair in rats with DSS-induced colitis and suggest that recombinant human HGF may be a useful therapeutic tool to facilitate intestinal wound healing in patients with ulcerative colitis.

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“…Moreover, previous studies demonstrated that HGF/SF can stimulate both esophageal and gastrointestinal epithelial growth in primary cultures (Fukamachi et al, 1994;Takahashi et al, 1995). HGF/SF was also shown to enhance both intestinal mucosal repair and function in vivo (Kato et al, 1997a(Kato et al, , 1997bNishimura et al, 1998). Furthermore, it was shown recently that HGF/SF stimulated gastrointestinal tyrosine kinase activity, which colocalizes with c-Met in the brush border membrane of enterocytes (Sunitha et al, 1999 Recently, we described some of the consequences of inappropriate expression of HGF/SF using transgenic mice in which expression of a mouse HGF/SF cDNA was regulated by the mouse metallothionein (MT) gene promoter and 5'/3' genomic flanking sequences as a model system.…”

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confidence: 97%

Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

Takayama

Takagi

LaRochelle

et al. 2001

Laboratory Investigation

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SUMMARY:Hepatocyte growth factor/scatter factor (HGF/SF) can stimulate growth of gastrointestinal epithelial cells in vitro;however, the physiological role of HGF/SF in the digestive tract is poorly understood. To elucidate this in vivo function, mice were analyzed in which an HGF/SF transgene was overexpressed throughout the digestive tract. Nearly a third of all HGF/SF transgenic mice in this study (28 of 87) died by 6 months of age as a result of sporadic intestinal obstruction of unknown etiology. Enteric ganglia were not overtly affected, indicating that the pathogenesis of this intestinal lesion was different from that operating in Hirschsprung's disease. Transgenic mice also exhibited a rectal inflammatory bowel disease (IBD) with a high incidence of anorectal prolapse. Expression of interleukin-2 was decreased in the transgenic colon, indicating that HGF/SF may influence regulation of the local intestinal immune system within the colon. These results suggest that HGF/SF plays an important role in the development of gastrointestinal paresis and chronic intestinal inflammation. HGF/SF transgenic mice may represent a useful model for the study of molecular mechanisms associated with a subset of IBD and intestinal pseudo-obstruction. Moreover, our data identify previously unappreciated side effects that may be encountered when using HGF/SF as a therapeutic agent. (Lab Invest 2001, 81:297-305).H epatocyte growth factor/scatter factor (HGF/ SF) was first identified as a highly potent hepatocyte mitogen (Gohda et al, 1988;Nakamura et al, 1989) but is now known as a multifunctional cytokine based on its ability to stimulate proliferation, movement, and/or morphogenesis of a broad spectrum of cultured epithelial cells expressing the tyrosine kinase receptor encoded by the c-met proto-oncogene (Gherardi and Stoker, 1991;Montesano et al, 1991;Rosen et al, 1994;Rubin et al, 1991;Vande Woude, 1992;Zarnegar and Michalopoulos, 1995). HGF/SF is produced in cells of mesenchymal origin, whereas c-met is expressed in adult and embryonic epithelium, implicating HGF/SF-Met signal transduction pathways as important in the epithelial-mesenchymal interaction that occurs during embryogenesis, tissue organization, and organogenesis. Gene targeting studies have shown that HGF/SF-Met signaling is required for the normal development of liver, skeletal muscle, and placenta Schmidt et al, 1995;Uehara et al, 1995).In the fetal digestive tract, c-met transcripts were found in the epithelia of the intestinal anlagen and the villi, whereas the distribution of HGF/SF RNA showed dynamic changes during mouse development by in situ hybridization (Sonnenberg et al, 1993). Immunohistochemical analysis of temporal expression revealed that both HGF/SF and c-Met could be detected between 7 and 8 weeks of gestation in human fetal digestive tissues (Kermorgant et al, 1997). These results suggest that HGF/SF-Met signaling participates in digestive system morphogenesis. Moreover, previous studies demonstrated that HGF/SF can stimulate both esophageal ...

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Hepatocyte growth factor accelerates restitution of intestinal epithelial cells

Cited by 43 publications

References 19 publications

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Increased expression of HGF and c-met in rat small intestine during recovery from methotrexate-induced mucositis

Hepatocyte Growth Factor Facilitates Colonic Mucosal Repair in Experimental Ulcerative Colitis in Rats

Ulcerative Proctitis, Rectal Prolapse, and Intestinal Pseudo-Obstruction in Transgenic Mice Overexpressing Hepatocyte Growth Factor/Scatter Factor

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