Roles of hepatocyte growth factor and its receptor Met during gastric ulcer healing in rats

Schmassmann, Adrian; Stettler, C; Poulsom, Richard; Tarasova, Nadya I.; Hirschi, Claudia; Flogerzi, Beatrice; Matsumoto, Kunio; Nakamura, Toshikazu; Halter, F

doi:10.1016/s0016-5085(97)70005-2

Cited by 79 publications

(76 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 73%

“…HGF is a potent morphogen, motogen and mitogen for a diverse variety of epithelial cells (Schmassmann et al, 1997a). Previous studies have demonstrated the mRNA and protein expression of HGF and c-met in various tissues, including the developing digestive tissues (Wang et al, 1994;Kermorgant et al, 1997) and the normal adult stomach, small intestine and colon (Di Renzo et al, 1991;Prat et al, 1991;Wolf et al, 1991).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2000

View full text Add to dashboard Cite

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 ...

show abstract

Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

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

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Recently, a number of studies have shown that HGF could have crucial roles in the repair and regeneration of various epithelial tissues (22)(23)(24). HAI-1 would contribute to this process via the regulation of pericellular HGFA activity that is critical in the activation of HGF (Fig.…”

Section: Figmentioning

confidence: 99%

“…HGFA is secreted as an inactive single-chain 96-kDa zymogen (pro-HGFA) and is activated by thrombin in injured tissues via a cleavage at the bond between Arg 407 and Ile 408 resulting in a two-chain heterodimeric form (5-7). The active form of HGFA efficiently activates the single-chain precursor form of HGF bound to the extracellular matrix (6,7,21), and the activated HGF in turn facilitates the repair and regeneration of a variety of injured tissues through binding to the c-Met receptor expressed in epithelial and endothelial cells (1,2,(22)(23)(24). Thus, it is important to investigate the regulation of HGF activation in the injured tissue in which HGFA and HAIs could be critically involved.…”

mentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Specific Cell Surface Binding Protein of Hepatocyte Growth Factor Activator (HGFA) and Regulates HGFA Activity in the Pericellular Microenvironment

Kataoka¹,

Shimomura²,

Kawaguchi³

et al. 2000

Journal of Biological Chemistry

118

157

View full text Add to dashboard Cite

Hepatocyte growth factor activator (HGFA) is responsible for proteolytic activation of the precursor form of hepatocyte growth factor in injured tissues. To date, two specific inhibitors of HGFA have been identified, namely HGFA inhibitor type 1 (HAI-1) and type 2 (HAI-2)/placental bikunin (PB). Both inhibitors are first synthesized as integral membrane proteins having two Kunitz domains and a transmembrane domain, and are subsequently released from cell surface by shedding. Here we show that an active form of HGFA is specifically complexed with membrane-form HAI-1, but not with HAI-2/PB, on the surface of epithelial cells expressing both inhibitors. This binding required the enzyme activity of HGFA. The selective binding of HGFA to the cell surface HAI-1 was further confirmed in an engineered system using Chinese hamster ovary cells, in which only the cells expressing HAI-1 retained exogenous HGFA. The binding of HGFA to HAI-1 was reversible, and no irreversible modifications affecting the enzyme activity occurred during the binding. Importantly, HAI-1 and the HGFA⅐HAI-1 complex were quickly released from the cell surface by treatment with phorbol 12-myristate 13-acetate or interleukin 1␤ accompanying the generation of 58-kDa fragments of HAI-1, which are less potent against HGFA, as well as significant recovery of HGFA activity in the culture supernatant. This regulated shedding was completely inhibited by BB3103, a synthetic zinc-metalloproteinase inhibitor. We conclude that HAI-1 is not only an inhibitor but also a specific acceptor of active HGFA, acting as a reservoir of this enzyme on the cell surface. The latter property appears to ensure the concentrated pericellular HGFA activity in certain cellular conditions, such as tissue injury and inflammation, via the up-regulated shedding of HGFA⅐HAI-1 complex. These findings shed light on a novel function of the integral membrane Kunitz-type inhibitor in the regulation of pericellular proteinase activity.

show abstract

“…It was frequently reported that nonsteroidal anti-inflammatory drugs delay healing of experimental gastric ulcers by arresting epithelial proliferation in the margins of ulcers, interfering with reepithelialization, and inhibiting angiogenesis in the granulation tissue. [1][2][3][4] Although the cellular and molecular mechanisms of ulcer healing have been extensively studied, [5][6][7][8][9] the PG-dependent mechanisms involved in the healing of surgical wounds remain virtually unexplored.…”

mentioning

confidence: 99%

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

Kamoshita

Ikeda

Fujita

et al. 2006

The American Journal of Pathology

View full text Add to dashboard Cite

E-type prostaglandins have been reported to be proangiogenic in vivo. Thus, we examined prostaglandin receptor signaling relevant to wound-induced angiogenesis. Full-thickness skin wounds were created on the backs of mice, and angiogenesis in wound granulation tissues was estimated. Wound closure and re-epithelization in EP3 receptor knockout mice (EP3 ؊/؊ ) were significantly delayed compared with their wild-type (WT) mice, whereas those in EP1 ؊/؊ , EP2 ؊/؊ , and EP4 ؊/؊ were not delayed. Wound-induced angiogenesis estimated with CD31 immunohistochemistry in EP3 ؊/؊ mice was significantly inhibited compared with that in WT mice. Immunoreactive vascular endothelial growth factor (VEGF) in wound granulation tissues in EP3 ؊/؊ mice was markedly less than that in WT mice. Wound closure in WT mice was delayed significantly by VEGF neutralizing antibody compared with control IgG. Wound-induced angiogenesis and wound closure were significantly suppressed in EP3 ؊/؊ bone marrow transplantation mice compared with those in WT bone marrow transplantation mice. These were accompanied with the reductions in accumulation of VEGF-expressing cells in wound granulation tissues and in mobilization of VEGF receptor 1-expressing leukocytes in peripheral circulation. These results indicate that the recruitment of EP3-expressing cells to wound granulation tissues is critical for surgical wound healing and angiogenesis via up-regulation of VEGF. (Am J Pathol

show abstract

Roles of hepatocyte growth factor and its receptor Met during gastric ulcer healing in rats

Cited by 79 publications

References 7 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 Activator Inhibitor Type 1 Is a Specific Cell Surface Binding Protein of Hepatocyte Growth Factor Activator (HGFA) and Regulates HGFA Activity in the Pericellular Microenvironment

Recruitment of a Prostaglandin E Receptor Subtype, EP3-Expressing Bone Marrow Cells Is Crucial in Wound-Induced Angiogenesis

Contact Info

Product

Resources

About