Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Dec 1;98(11):2604–2611. doi: 10.1172/JCI119080

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

M Takahashi 1, S Ota 1, Y Hata 1, Y Mikami 1, N Azuma 1, T Nakamura 1, A Terano 1, M Omata 1
PMCID: PMC507719  PMID: 8958224

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (660.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bastien L., Sawyer N., Grygorczyk R., Metters K. M., Adam M. Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype. J Biol Chem. 1994 Apr 22;269(16):11873–11877. [PubMed] [Google Scholar]
  2. Ben-Av P., Crofford L. J., Wilder R. L., Hla T. Induction of vascular endothelial growth factor expression in synovial fibroblasts by prostaglandin E and interleukin-1: a potential mechanism for inflammatory angiogenesis. FEBS Lett. 1995 Sep 18;372(1):83–87. doi: 10.1016/0014-5793(95)00956-a. [DOI] [PubMed] [Google Scholar]
  3. Coleman R. A., Grix S. P., Head S. A., Louttit J. B., Mallett A., Sheldrick R. L. A novel inhibitory prostanoid receptor in piglet saphenous vein. Prostaglandins. 1994 Feb;47(2):151–168. doi: 10.1016/0090-6980(94)90084-1. [DOI] [PubMed] [Google Scholar]
  4. Eberhart C. E., Coffey R. J., Radhika A., Giardiello F. M., Ferrenbach S., DuBois R. N. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994 Oct;107(4):1183–1188. doi: 10.1016/0016-5085(94)90246-1. [DOI] [PubMed] [Google Scholar]
  5. Giardiello F. M., Hamilton S. R., Krush A. J., Piantadosi S., Hylind L. M., Celano P., Booker S. V., Robinson C. R., Offerhaus G. J. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313–1316. doi: 10.1056/NEJM199305063281805. [DOI] [PubMed] [Google Scholar]
  6. Giovannucci E., Rimm E. B., Stampfer M. J., Colditz G. A., Ascherio A., Willett W. C. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med. 1994 Aug 15;121(4):241–246. doi: 10.7326/0003-4819-121-4-199408150-00001. [DOI] [PubMed] [Google Scholar]
  7. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med. 1994 Mar;96(3):274–281. doi: 10.1016/0002-9343(94)90153-8. [DOI] [PubMed] [Google Scholar]
  8. Kargman S. L., O'Neill G. P., Vickers P. J., Evans J. F., Mancini J. A., Jothy S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res. 1995 Jun 15;55(12):2556–2559. [PubMed] [Google Scholar]
  9. Katsuyama M., Nishigaki N., Sugimoto Y., Morimoto K., Negishi M., Narumiya S., Ichikawa A. The mouse prostaglandin E receptor EP2 subtype: cloning, expression, and northern blot analysis. FEBS Lett. 1995 Sep 25;372(2-3):151–156. doi: 10.1016/0014-5793(95)00966-d. [DOI] [PubMed] [Google Scholar]
  10. Katsuyama M., Sugimoto Y., Namba T., Irie A., Negishi M., Narumiya S., Ichikawa A. Cloning and expression of a cDNA for the human prostacyclin receptor. FEBS Lett. 1994 May 9;344(1):74–78. doi: 10.1016/0014-5793(94)00355-6. [DOI] [PubMed] [Google Scholar]
  11. Levi S., Goodlad R. A., Lee C. Y., Stamp G., Walport M. J., Wright N. A., Hodgson H. J. Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing. Lancet. 1990 Oct 6;336(8719):840–843. doi: 10.1016/0140-6736(90)92341-e. [DOI] [PubMed] [Google Scholar]
  12. Matsumoto K., Okazaki H., Nakamura T. Novel function of prostaglandins as inducers of gene expression of HGF and putative mediators of tissue regeneration. J Biochem. 1995 Feb;117(2):458–464. doi: 10.1093/jb/117.2.458. [DOI] [PubMed] [Google Scholar]
  13. Matsumoto K., Okazaki H., Nakamura T. Up-regulation of hepatocyte growth factor gene expression by interleukin-1 in human skin fibroblasts. Biochem Biophys Res Commun. 1992 Oct 15;188(1):235–243. doi: 10.1016/0006-291x(92)92375-8. [DOI] [PubMed] [Google Scholar]
  14. McCarthy D. M. Mechanisms of mucosal injury and healing: the role of non-steroidal anti-inflammatory drugs. Scand J Gastroenterol Suppl. 1995;208:24–29. doi: 10.3109/00365529509107758. [DOI] [PubMed] [Google Scholar]
  15. Muscat J. E., Stellman S. D., Wynder E. L. Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer. 1994 Oct 1;74(7):1847–1854. doi: 10.1002/1097-0142(19941001)74:7<1847::aid-cncr2820740704>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  16. Nakamura T., Nishizawa T., Hagiya M., Seki T., Shimonishi M., Sugimura A., Tashiro K., Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440–443. doi: 10.1038/342440a0. [DOI] [PubMed] [Google Scholar]
  17. Ota S., Terano A., Hiraishi H., Mutoh H., Nakada R., Hata Y., Shiga J., Sugimoto T. A monolayer culture of gastric mucous cells from adult rabbits. Gastroenterol Jpn. 1990 Feb;25(1):1–7. doi: 10.1007/BF02785323. [DOI] [PubMed] [Google Scholar]
  18. Regan J. W., Bailey T. J., Pepperl D. J., Pierce K. L., Bogardus A. M., Donello J. E., Fairbairn C. E., Kedzie K. M., Woodward D. F., Gil D. W. Cloning of a novel human prostaglandin receptor with characteristics of the pharmacologically defined EP2 subtype. Mol Pharmacol. 1994 Aug;46(2):213–220. [PubMed] [Google Scholar]
  19. Robert A. Cytoprotection by prostaglandins. Gastroenterology. 1979 Oct;77(4 Pt 1):761–767. [PubMed] [Google Scholar]
  20. Roth S., Agrawal N., Mahowald M., Montoya H., Robbins D., Miller S., Nutting E., Woods E., Crager M., Nissen C. Misoprostol heals gastroduodenal injury in patients with rheumatoid arthritis receiving aspirin. Arch Intern Med. 1989 Apr;149(4):775–779. [PubMed] [Google Scholar]
  21. Silverstein F. E., Graham D. Y., Senior J. R., Davies H. W., Struthers B. J., Bittman R. M., Geis G. S. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995 Aug 15;123(4):241–249. doi: 10.7326/0003-4819-123-4-199508150-00001. [DOI] [PubMed] [Google Scholar]
  22. Takahashi M., Ota S., Hata Y., Ogura K., Kurita M., Terano A., Nakamura T., Omata M. Constitutive expression of hepatocyte growth factor may maintain the sheet construction of gastric epithelial cells through facilitating actin-myosin contractile system. Biochem Biophys Res Commun. 1996 Feb 6;219(1):40–46. doi: 10.1006/bbrc.1996.0178. [DOI] [PubMed] [Google Scholar]
  23. Takahashi M., Ota S., Shimada T., Hamada E., Kawabe T., Okudaira T., Matsumura M., Kaneko N., Terano A., Nakamura T. Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture. J Clin Invest. 1995 May;95(5):1994–2003. doi: 10.1172/JCI117884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Takahashi M., Ota S., Terano A., Yoshiura K., Matsumura M., Niwa Y., Kawabe T., Nakamura T., Omata M. Hepatocyte growth factor induces mitogenic reaction to the rabbit gastric epithelial cells in primary culture. Biochem Biophys Res Commun. 1993 Mar 15;191(2):528–534. doi: 10.1006/bbrc.1993.1250. [DOI] [PubMed] [Google Scholar]
  25. Tashiro K., Hagiya M., Nishizawa T., Seki T., Shimonishi M., Shimizu S., Nakamura T. Deduced primary structure of rat hepatocyte growth factor and expression of the mRNA in rat tissues. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3200–3204. doi: 10.1073/pnas.87.8.3200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tsujii H., Okamoto Y., Kikuchi E., Matsumoto M., Nakano H. Prostaglandin E2 and rat liver regeneration. Gastroenterology. 1993 Aug;105(2):495–499. doi: 10.1016/0016-5085(93)90725-r. [DOI] [PubMed] [Google Scholar]
  27. Tsujii M., DuBois R. N. Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell. 1995 Nov 3;83(3):493–501. doi: 10.1016/0092-8674(95)90127-2. [DOI] [PubMed] [Google Scholar]
  28. Walt R. P. Misoprostol for the treatment of peptic ulcer and antiinflammatory-drug-induced gastroduodenal ulceration. N Engl J Med. 1992 Nov 26;327(22):1575–1580. doi: 10.1056/NEJM199211263272207. [DOI] [PubMed] [Google Scholar]
  29. Watanabe S., Hirose M., Wang X. E., Maehiro K., Murai T., Kobayashi O., Nagahara A., Sato N. Hepatocyte growth factor accelerates the wound repair of cultured gastric mucosal cells. Biochem Biophys Res Commun. 1994 Mar 30;199(3):1453–1460. doi: 10.1006/bbrc.1994.1394. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES