Hepatocyte Growth Factor Accelerates the Wound Repair of Cultured Gastric Mucosal Cells

Watanabe, Sumio; Hirose, Miyoko; Wang, Xian‐En; Maehiro, K.; Murai, Toshio; Kobayashi, Osamu; Nagahara, Akihito; Sato, Nobuhiro

doi:10.1006/bbrc.1994.1394

Cited by 75 publications

(46 citation statements)

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“…Studies from other laboratories have confirmed our findings (10). It has also been shown lately that HGF not only accelerates repair of gastric epithelial cells, but also protects against ethanol-induced gastric epithelial disruption (11).…”

Section: Introductionsupporting

confidence: 88%

Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.

Takahashi¹,

Ota²,

Hata³

et al. 1996

J. Clin. Invest.

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Although the clinical efficacy of prostaglandins (PGs), especially on gastric mucosal injuries induced by nonsteroidal antiinflammatory drugs, is widely appreciated, their mechanism of action, apart from acid suppression, is quite unclear. In this study, we have established a primary culture system of human gastric fibroblasts and clearly demonstrated that PGs strongly induce the expression of hepatocyte growth factor (HGF) in the fibroblasts, which is mediated by PGE specific receptor, EP2 or EP4. Since HGF facilitates repair and protection of gastric epithelial cells in a paracrine manner, it is assumed that some of the beneficial effects of PGs may be mediated by HGF. To confirm this assumption, we established a simplified in vitro culture gastric mucosal model which consists of gastric epithelial cells and gastric fibroblasts. Using the model, we performed a round wound restitution assay. PGE1 remarkably accelerated restitution which was completely inhibited by anti-HGF antibody, indicating that the action was mediated by HGF. To confirm these in vitro data, we further demonstrated that HGF mRNA expression is downregulated at the edges of nonsteroidal antiinflammatory drug-induced gastric ulcers where PGs should be depleted. In summary, we proposed that gastric fibroblasts are newly recognized targets of PGs, and HGF produced by human gastric fibroblasts may be a key factor for anti-ulcer action of PGs in the stomach. ( J. Clin. Invest. 1996. 98:2604-2611.)

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Section: Introductionsupporting

confidence: 88%

Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.

Takahashi¹,

Ota²,

Hata³

et al. 1996

J. Clin. Invest.

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“…In the present study, we examined the capacity of HGF/SF to modulate keratinocyte metalloproteinase production. Although HGF/SF is known to stimulate keratinocyte migration and proliferation (24,25) and to promote wound healing in several in vitro models (47)(48)(49), this is the first report of its ability to regulate matrix metalloproteinase expression in any cell type in a physiologic setting.…”

Section: Discussionmentioning

confidence: 89%

Mechanisms of Hepatocyte Growth Factor Stimulation of Keratinocyte Metalloproteinase Production

Dunsmore¹,

Rubin

Kovacs³

et al. 1996

Journal of Biological Chemistry

105

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Matrix metalloproteinases participate in normal physiologic processes; however, their overproduction has been associated with connective tissue destruction in a variety of pathological states. Migrating basal keratinocytes transiently express collagenase-1 during normal cutaneous reepithelialization. However, the overexpression of both collagenase-1 and stromelysin-1 has been associated with the pathogenesis of chronic nonhealing ulcers. Aberrant expression of metalloproteinases in inflammation is mediated, at least in part, by soluble factors. Since hepatocyte growth factor/scatter factor (HGF/SF) has been reported to promote keratinocyte migration and proliferation, key events in wound repair, and since HGF/SF is produced by dermal fibroblasts and its c-Met receptor is expressed by basal keratinocytes in wounded skin, we have studied the effects of HGF/SF upon keratinocyte metalloproteinase expression. We have found that HGF/SF can stimulate keratinocyte collagenase-1 and stromelysin-1 production in a dose-dependent and matrix-dependent manner. Expression of 92-kDa gelatinase was not affected by HGF/SF. We determined that HGF/SF regulation of collagenase-1 expression is transcriptionally mediated and requires tyrosine kinase and protein kinase C activaties. HGF/ NK1, a naturally occurring, truncated form of HGF/SF, also stimulates collagenase-1 production, but much less efficiently than does the parent molecule. However, HGF/NK2, another HGF/SF splice variant, as well as heparin, potently inhibit HGF/SF-induced collagenase-1 synthesis. These results indicate that HGF/SF and its naturally occurring splice variants have diverse biological effects on keratinocytes and suggest an additional mechanism whereby HGF/SF may regulate keratinocyte function during wound repair.Matrix metalloproteinases are a gene family of zinc-dependent enzymes with the collective capacity to degrade virtually all extracellular matrix components (1). At present, the matrix metalloproteinase gene family consists of three interstitial collagenases (2-4), three stromelysins (5-7), two gelatinases (8, 9), matrilysin (10), metalloelastase (11, 12), and two membrane-type metalloproteinases (13,14). With the notable exception of matrilysin (15, 16), matrix metalloproteinases are not constitutively expressed in normal tissues. Their expression is induced, however, in a variety of physiologic and pathologic conditions, including cutaneous wound repair.Collagenase-1 (MMP-1) 1 and stromelysin-1 (MMP-3) are two matrix metalloproteinases produced by keratinocytes in response to skin injury (17,18,22). These enzymes exhibit distinct substrate specificities and spatial localization within a wound. Collagenase-1 is capable of degrading fibrillar collagens (types I and III), abundant constituents of the dermal matrix, whereas stromelysin-1 degrades basement membrane components such as laminin and proteoglycans. Collagenase-1 is invariably produced by the migrating front of basal keratinocytes in both acute and chronic wounds (17)(18)(19)(20) and is marke...

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“…Later induction events correlate with HGF-induced epithelial and endothelial cell migration and morphogenesis, including increased production of transcription factor ETS1 (Fafeur et al, 1997), urokinase-type plasminogen activator (u-PA), and its receptor (Pepper et al, 1992), and the zinc ®nger protein slug (Savagner et al, 1997). The HGFstimulated proliferation and migration of keratinocytes that is thought to occur during wound healing Gohda et al, 1994;Watanabe et al, 1994;Nusrat et al, 1994;Sponsel et al, 1994), is accompanied by the induction of collagenase (matrix metalloproteinase 1; MMP-1; Dunsmore et al, 1996;Fafeur et al, 1997) and stromelysin-1 (MMP-3; Dunsmore et al, 1996). These induction events may be coordinated with the HGF-stimulated induction of plasminogen activator inhibitor-1, resulting in appropriate spatial and temporal inhibition of matrix proteolysis (Pepper et al, 1992;Wojta et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Induction of tissue inhibitor of metalloproteinases-3 is a delayed early cellular response to hepatocyte growth factor

Castagnino

Soriano²,

Montesano³

et al. 1998

Oncogene

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Hepatocyte Growth Factor Accelerates the Wound Repair of Cultured Gastric Mucosal Cells

Cited by 75 publications

References 0 publications

Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.

Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach.

Mechanisms of Hepatocyte Growth Factor Stimulation of Keratinocyte Metalloproteinase Production

Induction of tissue inhibitor of metalloproteinases-3 is a delayed early cellular response to hepatocyte growth factor

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