Gene expression of keratinocyte and hepatocyte growth factors during the healing of rat gastric mucosal lesions

Kinoshita, Yoshikazu; Nakata, Hirohisa; Hassan, Sazzad; Asahara, Masahiro; Kawanami, Chiharu; Matsushima, Yumi; Naribayashi-Inomoto, Yoko; Cai, Ping; Dai, Min; Nakamura, Akira; Chiba, Tsutomu

doi:10.1016/0016-5085(95)90564-2

Cited by 83 publications

(64 citation statements)

References 26 publications

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“…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). In the present study, we have demonstrated up-regulation of both HGF and c-met during the repair of the small intestinal mucosa following methotrexate-induced damage in the rat, similar to that observed during the healing of gastric ulcers (Tsujii et al, 1994;Kinoshita et al, 1995;Schmassmann et al, 1997b). The transient up-regulation in HGF mRNA and protein from days 4 to 6, peaking on day 5 coincides with the timing of hyperproliferation during the repair of the intestine.…”

Section: Discussionsupporting

confidence: 72%

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: Discussionsupporting

confidence: 72%

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

et al. 2000

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“…Furthermore, KSOS is a soluble derivative of sucralfate (7), and when growth factors are bound to it, the resulting complex en hances DNA synthesis of the cells (8). The RGM 1 cells (14,15) used in the present study can detect the action of growth factors and cytokines; actually, epidermal growth factors (EGF), basic fibroblast growth factor, transform ing growth factor (TGF) alpha, hepatocyte growth factor and interleukin-1 enhance the DNA synthesis (ref. 14 and O. Furukawa et al, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Effects of Sucralfate and Its Components on Acid- and Pepsin-Induced Damage to Rat Gastric Epithelial Cells.

1997

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ABSTRACT-Wehave established models of cell damage induced by acid and pepsin using rat gastric epithelial cells (RGMI). In the present study, the effects of aluminum hydroxide [AI(OH)3] and potassium sucrose octasulfate (KSOS), which are components of sucralfate, and sucralfate on cell damage and peptic activity of pepsin were examined. Pretreatment of cells with sucralfate (0.1-3 mg/ml) or Al(OH)3 (0.1-1 mg/ml) for 2 hr prevented both acid (pH 4.0) and pepsin (pH 4.5) induced cell damage. However, KSOS (0.1-1 mg/ml) did not show any effects on two different types of cell damage. The peptic activity of pepsin at pH 4.5 was about 10010 of that at pH 2.0. Sucralfate and KSOS slightly inhibited peptic activity at pH 4.5. Al(OH)3 inhibited peptic activity by approximately 50010; however, no concentration-dependent pattern was observed. Pepstatin (0.003-0.1 mg/ml), a specific inhibitor of pepsin, inhibited the peptic activity in a concentration-dependent manner. Here, we confirmed that sucralfate and Al(OH)3 have cytoprotective effects against acid and pepsin-induced cell damage. The mechanism behind the cytoprotective effects of sucralfate seems to relate to adhesion of the cell surface and neutralization of hydrogen ion by aluminum that prevents the penetration of hydrogen ions into the cells.

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“…In addition, basic fibroblast growth factor (bFGF) that is synthesized by cells of mesodermal origin was shown to improve the healing of gastroduodenal ulcerations due to enhancement of angiogenesis in the ulcer bed [6, 7]. Another growth factor, hepatocyte growth factor (HGF) binds to upregulated Met/HGF receptor on epithelial cells in the ulcer margin and contributes to the epithelial-mesenchymal interaction during ulcer healing [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Effect of Local Application of Growth Factors on Gastric Ulcer Healing and Mucosal Expression of Cyclooxygenase-1 and -2

Brzozowski

Konturek

et al. 2001

Digestion

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Background/Aims: Ulcer healing involves expression of various growth factors such as epidermal growth factor (EGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) at the ulcer margin, but the influence of EGF, HGF and bFGF applied locally with or without neutralizing anti-EGF, HGF and bFGF antibodies or cyclooxygenase (COX)-1 and COX-2 inhibitors on ulcer healing and the expression of COX-1 and COX-2 during ulcer healing have only been studied a little. Methods: Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm²) received a submucosal injection of either (1) vehicle (saline), (2) EGF, (3) HGF, and (4) bFGF with or without antibodies against EGF, HGF and bFGF or indomethacin (2 mg/kg/day i.p.), a nonspecific inhibitor of COX, or NS-398 (10 mg/kg/day i.g.) and Vioxx (5 mg/kg/day i.g.), both highly specific COX-2 inhibitors. A separate group of animals with chronic gastric fistulas was also used to assess gastric secretion during ulcer healing with and without growth factors. Each growth factor and specific antibody against EGF, HGF and bFGF (100 ng/100 µl each) were injected just around the ulcer immediately after ulcer induction and this local injection was repeated on day 2 following anesthesia and laparotomy. On days 13 and 21, the ulcer area was determined by planimetry, gastric blood flow (GBF) at the ulcer margin was examined by the H₂-gas clearance technique, and mucosal generation of PGE₂ and the gene expression of COX-1 and COX-2 in the non-ulcerated and ulcerated gastric mucosa were assessed. Gastric ulcers healed progressively within 21 days after induction and this effect was accompanied by a significant increase in GBF at the ulcer margin and in the expression of COX-2 in the ulcer area. Local treatment with EGF, HGF and bFGF produced a significant decrease in gastric acid secretion and significantly accelerated the rate of ulcer healing and raised GBF at the ulcer margin causing further significant upregulation of COX-2 but not COX-1 expression in the ulcerated mucosa. The acceleration of ulcer healing and hyperemia at the ulcer margin exhibited by locally applied EGF, HGF and bFGF were similar to those obtained with systemic administration of these growth factors. HGF applied submucosally, upregulated COX-2 expression and this was significantly attenuated by concurrent treatment with antibody against this peptide. Anti-EGF and anti-bFGF antibodies completely abolished the acceleration of the ulcer healing and hyperemia at the ulcer margin induced by these growth factors. Indomethacin and both COX-2 inhibitors significantly prolonged ulcer healing, while suppressing the generation of PGE₂ in non-ulcerated and ulcerated gastric mucosa and GBF at the ulcer margin. The acceleration of ulcer healing by EGF, HGF and bFGF and the accompanying rise in GBF at the ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx. Conclusions: (1) Growth factors...

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Gene expression of keratinocyte and hepatocyte growth factors during the healing of rat gastric mucosal lesions

Cited by 83 publications

References 26 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

Effects of Sucralfate and Its Components on Acid- and Pepsin-Induced Damage to Rat Gastric Epithelial Cells.

Effect of Local Application of Growth Factors on Gastric Ulcer Healing and Mucosal Expression of Cyclooxygenase-1 and -2

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