Production and Activation of Hepatocyte Growth Factor during the Healing of Rat Gastric Ulcers

Kinoshita, Yoshikazu; Kishi, Kiyohiko; Asahara, Masahiro; Matsushima, Yumi; Wang, He Yao; Miyazawa, Keiji; Kitamura, Naomi; Chiba, Tsutomu

doi:10.1159/000201448

Cited by 27 publications

(17 citation statements)

References 14 publications

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“…This hypothesis may agree with the fact that the cells which expressed HAI-1 protein in this study are susceptible to HGF/SF. For example, HGF/SF is an important mitogen for the gastric, bile duct, and renal tubule epithelium (Kawaida et al 1994;Takahashi et al 1995;Matsumoto and Nakamura 1996;Kinoshita et al 1997) and Schwann cells (Kranoselsky et al 1994). However, another important target of HGF/SF, hepatocytes, did not express HAI-1 protein, and bronchial and alveolar epithelia, which are also susceptible to HGF/SF (Ohmichi et al 1996), expressed a very low level of HAI-1 protein.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

Kataoka

Suganuma

Shimomura

et al. 1999

J Histochem Cytochem.

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109

135

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SUMMARYWe used a specific monoclonal antibody to human hepatocyte growth factor activator inhibitor type 1 (HAI-1) in immunohistochemical procedures to determine the distribution and localization of HAI-1 in human tissues. In normal adult tissues, HAI-1 was predominantly expressed in the simple columnar epithelium of the ducts, tubules, and mucosal surface of various organs. In all cases, HAI-1 was localized predominantly on the cellular lateral (or basolateral) surface. By contrast, hepatocytes, acinar cells, endocrine cells, stromal mesenchymal cells, and inflammatory cells were hardly stainable with the antibody, and stratified squamous epithelium showed only faint immunoreactivity on the surface of cells of the basal layer. In the gastrointestinal tract, the surface epithelium was strongly stained. RNA blot analysis confirmed the presence of specific mRNA transcript in the gastrointestinal mucosa, and in situ hybridization revealed that HAI-1 mRNA showed a similar cellular distribution pattern. Although HAI-1 was not expressed in normal hepatocytes, strong immunoreactivity was observed on the epithelium of pseudo-bile ducts and on the surface of scattered hepatocytes in fulminant hepatitis. The enhanced expression was also noted in regenerating tubule epithelial cells of the kidney after infarction. We conclude that HAI-1 is preferentially expressed in the simple columnar epithelium of the mucosal surface and duct, that the predominant localization of HAI-1 is the cell surface, and that the expression of HAI-1 can be modulated by tissue injury and regeneration.

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Section: Discussionmentioning

confidence: 99%

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

Kataoka

Suganuma

Shimomura

et al. 1999

J Histochem Cytochem.

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109

135

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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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“…HGF is reported to exist in various organs, liver, kidney and lung. [27][28][29] In vitro experiments revealed that, when organ injury occurs, HGF is activated and thus plays an important role in organ regeneration and tissue repair. [30][31][32][33] The activated form of HGF was also detected clinically in the ascitic fluid of patients Figure 3 The suppression of GB-d1 migration by AdCMV.NK4 infection.…”

Section: Discussionmentioning

confidence: 99%

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model

Tanaka

Sasaki

et al. 2004

Cancer Gene Ther

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Gallbladder cancer cells are stimulated by hepatocyte growth factor (HGF) in vitro and in vivo. We constructed an adenovirus vector, AdCMV.NK4, carrying the HGF antagonist HGF/NK4 (NK4) and evaluated whether or not this vector can suppress the peritoneal implantation of gallbladder cancer in a novel peritoneal injury mouse model. A human gallbladder cancer cell line (GBd1) and human peritoneal mesothelial cells infected with the adenovirus vector produced a substantial level of NK4 protein. An invasion of GB-d1 cells was determined by a coculture with AdCMV.NK4-infected human mesothelial cells in vitro. Both the invasion and migration of GB-d1 cells were dramatically inhibited by this vector in a multiplicity of infection (MOI)-dependent manner. GB-d1 cells were intraperitoneally injected into the nude mice with peritoneal injury, followed by either AdCMV.NK4 or a control vector (AdCMV.LacZ). The incidence and the size of the metastatic tumor drastically decreased by AdCMV.NK4 (MOI 100: n ¼ 4, Po.0001). Real-time PCR analysis revealed a transient elevation of mouse HGF mRNA expression at the peritoneal injury sites. AdCMV.NK4 has been suggested to induce the inhibition of the implantation and growth of gallbladder cancer cells in vivo through its anti-HGF activity, and the use of NK4 gene transfer could be an effective modality for preventing peritoneal metastasis of gallbladder cancer.

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Production and Activation of Hepatocyte Growth Factor during the Healing of Rat Gastric Ulcers

Cited by 27 publications

References 14 publications

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

Distribution of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) in Human Tissues: Cellular Surface Localization of HAI-1 in Simple Columnar Epithelium and Its Modulated Expression in Injured and Regenerative Tissues

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

Gallbladder cancer treatment using adenovirus expressing the HGF/NK4 gene in a peritoneal implantation model

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