Digestion

Original Paper: Gastric Disorders

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

Brzozowski T.a · Konturek P.C.b · Konturek S.J.a · Schuppan D.b · Drozdowicz D.a · Kwiecień S.a · Majka J.a · Nakamura T.c · Hahn E.G.b

Author affiliations

aDepartment of Physiology, Jagiellonian University School of Medicine, Cracow, Poland; bDepartment of Medicine I, University of Medicine Erlangen-Nuremberg , Erlangen, Germany; cBiomedical Research Center, Osaka University Medical School, Osaka, Japan

Keywords: Ulcer healingEpidermal growth factorHepatocyte growth factorBasic fibroblast growth factorGastric blood flowCyclooxygenase-1Cyclooxygenase-2

Related Articles for ""
Digestion 2001;64:15–29
https://doi.org/10.1159/000048835

Log in to MyKarger to check if you already have access to this content.




Forgot your password
Sign up to MyKarger

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more
CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!


If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates

Select
* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Original Paper: Gastric Disorders

Published online: September 10, 2001
Issue release date: 2001

Number of Print Pages: 15
Number of Figures: 12
Number of Tables: 2

ISSN: 0012-2823 (Print)
eISSN: 1421-9867 (Online)

For additional information: https://www.karger.com/DIG

Abstract

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 accelerate ulcer healing due to enhancement in the microcirculation around the ulcer and these effects are specific because they can be abolished by neutralization with antibodies; (2) COX-2-derived prostaglandins and suppression of gastric secretion may play an important role in the acceleration of ulcer healing by various growth factors, and (3) the local effects of EGF, HGF and bFGF on ulcer healing can be reproduced by their systemic application indicating the high efficacy of growth factors to accelerate this healing.

© 2001 S. Karger AG, Basel



Related Articles:

References

  1. Konturek SJ: Role of growth factors in gastroduodenal protection and healing of peptic ulcers. Gastroenterology 1990;1:40–65.
  2. Lee H, Hansson HA, Norstrom E, Helander HF: Immunoreactivities for epidermal growth factor (EGF) and for receptors in rats with gastric ulcers. Cell Tissue Res 1991;265:211–218.
    External Resources
  3. Wright NA, Pike C, Elia G: Induction of a novel epidermal growth factor – Secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 1990;343:82–85.
    External Resources
  4. Tarnawski A, Stachura J, Durbin T, Sarfeh IJ, Gergely H: Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats. Gastroenterology 1992;102:695–698.
    External Resources
  5. Konturek PCh, Brzozowski T, Konturek SJ, Ernst H, Drozdowicz D, Pajdo R: Expression of epidermal growth factor and transforming growth factor alpha during ulcer healing. Scand J Gastroenterol 1997;32:6–15.
    External Resources
  6. Szabo S, Folkman J, Vattay P, Morales RE, Pinkus GS, Kato K: Accelerated healing of duodenal ulcers by oral administration of a mutein of basic fibroblast growth factor in rats. Gastroenterology 1994;106:1106–1111.
    External Resources
  7. Konturek SJ, Brzozowski T, Majka J, Pawlik W, Stachura J: Omentum and basic fibroblast growth factor in healing of chronic gastric ulcerations in rats. Dig Dis Sci 1994;39:1064–1071.
    External Resources
  8. Kinoshita Y, Nakata H, Hassan S, Ashara M, Kawanami CH, Matsushima Y, Inamoto Y, Ping CY, Min D, Nakamwa A, Chiba T: Gene expression of keratinocyte and hepatocyte growth factors during the healing of rat gastric mucosal lesions. Gastroenterology 1995;109:1068–1077.
    External Resources
  9. Schmassmann A, Stettler Ch, Poulson R, Tarasova N, Hirschi C, Flogerzi B, Matsumo K, Nakamwa T, Halter F: Roles of hepatocyte growth factor and its receptor during gastric ulcer healing in rats. Gastroenterology 1997;113:1858–1872.
    External Resources
  10. Eberhart CE, Dubois RN: Eicosanoids and the gastrointestinal tract. Gastroenterology 1995;109:258–301.
  11. Masferrer IL, Zweifel BS, Maming PT, Hauser SD, Eaky KM, Smith WG, Isakson PC, Siebert K: Selective inhibition of inducible cyclooxygenase-2 in vivo is anti-inflammatory and ulcerogenic. Proc Natl Acad Sci USA 1994;9:3228–3232.
  12. Vane JR, Botting RM: New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995;44:1–10.
    External Resources
  13. Mizuno H, Sakamoto Ch, Matsuda K, Wada K, Kchida T, Noguchi H, Akamatsu T, Kasuga M: Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997;12:387–397.
  14. Ernst H, Konturek P, Hahn EG, Brzozowski T, Konturek SJ: Acceleration of wound healing in gastric ulcers by local injection of neutralizing antibody to transforming growth factor β1. Gut 1996;39:172–175.
    External Resources
  15. Furst DE: Pharmacology and efficacy of cyclooxygenase (COX) inhibitors. Am J Med 1999;107:185–228.
    External Resources
  16. Konturek SJ, Brzozowski T, Garlicki J, Majka J, Stachura J, Nauert CM: Intragastric pH in the gastroprotective and ulcer healing activity of aluminium-containing antacids. Digestion 1991;49:140–141.
    External Resources
  17. Okabe S, Pfeiffer CJ, Roth ILA: A method for experimental penetrating gastric and duodenal ulcers in rats. Digestion 1987;38:103–113.
    External Resources
  18. Konturek SJ, Stachura J, Radecki T, Drozdowicz D, Brzozowski T: Cytoprotective and ulcer healing properties of prostaglandin E2, colloidal bismuth and sucralfate in rats. Digestion 1987;38:102–113.
  19. Konturek PC, Brzozowski T, Konturek SJ, Ernst H, Drozdowicz D, Pajdo R, Hahn EG: Expression of epidermal growth factor and transforming growth factor alpha during ulcer healing. Time sequence study. Scand J Gastroenterol 1997;32:6–15.
    External Resources
  20. Futaki N, Yoshikawa K, Hamasaka Y, Arai I, Higuchi S, Izuka H, Otomo S: NS-398 a novel non-steroidal anti-inflammatory drug with potent analgesic and antipyretic effects which causes minimal stomach lesions. Gen Pharmacol 1993;24:105–110.
    External Resources
  21. Xie W, Chipman JG, Robertson DL, Erikson DL, Simmons DL: Expression of a mitogen responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proc Natl Acad Sci USA 1991;88:2692–2696.
    External Resources
  22. Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Riendeau D, Yuan W, Porras A, Wittereich J, Seibold JR, De Schepper P, Mehlisch DR, Gertz BJ: Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999;65:336–347.
    External Resources
  23. Brzozowski T, Konturek PCh, Konturek SJ, Sliwowski Z, Drozdowicz D, et al: Role of prostaglandins generated by cyclooxygenase-1 and cyclooxygenase-2 in healing of ischemia-reperfusion-induced gastric lesions. Eur J Pharmacol 1999;385:47–61.
    External Resources
  24. Konturek SJ, Brzozowski T, Majka J, Pytko-Polonczyk J, Stachura J: Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers. Eur J Pharmacol 1993;239:215–217.
    External Resources
  25. Brzozowski T, Konturek PCh, Konturek SJ, Pajdo R, Drozdowicz D, Kwiecien S, et al: Acceleration of ulcer healing by cholecystokinin (CCK): Role of CCK-A receptors, somatostatin, nitric oxide and sensory nerves. Reg Pept 1999;82:19–33.
    External Resources
  26. Konturek SJ, Brzozowski T, Bielanski W, Schally AV: Role of endogenous gastrin in gastroprotection. Eur J Pharmacol 1995;278:203–212.
    External Resources
  27. Brzozowski T, Drozdowicz D, Szlachcic A, Pytko-Polonczyk J, Majka J, et al: Role of nitric oxide and prostaglandins in gastroprotection induced by capsaicin and papaverine. Digestion 1993;54:24–34.
    External Resources
  28. Chomczynski P, Sacchi N: A single-step method of RNA isolation by acid guanidinum thiocyanate. Anal Biochem 1987;162:156–159.
    External Resources
  29. Kennedy BP, Chan CC, Culp SA, Cronlish WA: Cloning and expression of rat prostaglandin endoperoxide synthase (cyclooxygenase)-2 cDNA. Biochem Biophys Res Commun 1993;197:494–500.
    External Resources
  30. O’Banion MK, Winn VD, Young DA: Cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA 1992;89:4888–4892.
    External Resources
  31. Konturek PCh, Brzozowski T, Konturek SJ, Taut A, Kwiecien S, Pajdo R, Sliwowski Z, Hahn EG: Bacterial lipopolysaccharide protects gastric mucosa against acute injury in rats by activation of genes for cyclooxygenase and endogenous prostaglandins. Digestion 1998;59:284–297.
    External Resources
  32. Konturek PC, Brzozowski T, Sulekova Z, Meixner H, Hahn EG, Konturek SJ: Enhanced expression of leptin following acute gastric injury in rat. J Physiol Pharmacol 1999;50:587–596.
    External Resources
  33. Li H, Helander H: Hypergastrinemia increases proliferation of gastroduodenal epithelium during gastric ulcer healing in rats. Dig Dis Sci 1996;41:40–48.
    External Resources
  34. Kargman S, Charleson S, Cartwright M, Frank J, Rindean D, Mancini J, Evans J, O’Neill G: Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology 1996;111:445–454.
    External Resources
  35. Wang JY, Yamasaki S, Takeuchi K, Okabe S: Delayed healing of acetic acid-induced gastric ulcers in rats by indomethacin. Gastroenterology 1989;96:393–402.
    External Resources
  36. Konturek SJ, Brzozowski T, Majka J, Dembinski A, Slomiany A, Slomiany BL: Transforming growth factor and epidermal growth factor in protection and healing of gastric mucosal injury. Scand J Gastroenterol 1992;27:649–655.
    External Resources
  37. Hirose H, Takeuchi K, Okabe S: Effect of indomethacin on gastric mucosal blood flow around acetic acid-induced gastric ulcers in rats. Gastroenterology 1991;100:1259–1265.
    External Resources
  38. Feng L, Sun W, Xia Y, Tang WW, Chanmugan P, Soyoda E, et al: Cloning two isoforms of rat cyclooxygenase; differential regulation of their expression. Arch Biochem Biophys 1992;307:361–368.
    External Resources
  39. Nakano O, Sakamoto Ch, Matsuda K, Konda Y, Matozaki T, Nishisaki H, Wada K, Suzuki T, Uchida T, Nagao M, Kasyga M: Induction of cyclooxygenase protein and stimulation of prostaglandin E2 release by epidermal growth factor in cultured guinea pig gastric mucous cells. Dig Dis Sci 1995;40:1679–1686.
    External Resources
  40. Horie-Sakata K, Shimada T, Hiraishi H, Terano A: Role of cyclooxygenase-2 in hepatocyte growth factor-mediated gastric epithelial restitution. J Clin Gastroenterol 1998;27(suppl 1): S40–S46.
  41. Sasaki E, Pai R, Halter F, Komurasaki T, Arakawa T, Kobayashi K, Kuroki T, Tarnawski AS: Induction of cyclooxygenase-2 in a rat gastric epithelial cell line by epiregulin and basic fibroblast growth factor. J Clin Gastroenterol 1998;27(suppl 1):S21–S27.
  42. Jones MK, Sasaki E, Halter F, Pai R, Nakamura T, Arakawa T, Kuroki T, Tarnawski AS: HGF triggers activation of the COX-2 gene in rat gastric epithelial cells: Action mediated through the ERK2 signaling pathway. FASEB J 1999;13:2186–2194.
    External Resources
  43. Takeuchi K, Suzuki K, Yammamoto H, Araki H, Mizoguchi H, Ukawa H: Cyclooxygenase-2 selective and nitric oxide-releasing nonsteroidal anti-inflammatory drugs and gastric mucosal responses. J Physiol Pharmacol 1998;49:501–505.
    External Resources
  44. Schmassmann A, Peskar BM, Stettler C, Netzer P, Stroff T, Flogerzi B, Halter F: Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastrointestinal ulcer models in rats. Br J Pharmacol 1997;123:795–804.
    External Resources
  45. Takahashi S, Shigeta J, Inoue H, Tanabe T, Okabe S: Localization of cyclooxygenase-2 and regulation of its mRNA expression in gastric ulcers in rats. Am J Physiol 1998;275:1137–1145.
  46. Lesch CA, Gilbertsen RB, Song Y, Dyer RD, Sehrier D, Kraus ER, Sanchez B, Guglietta A: Effect of novel anti-inflammatory compounds on healing of acetic acid-induced gastric ulcer in rats. J Pharmacol Exp Ther 1998;287:301–306.
    External Resources
  47. Palmer RH: COX-2 selectivity and lack of gastrointestinal toxicity: True, true and unrelated? Gastroenterology 2000;118:640.
    External Resources
  48. Brzozowski T, Konturek PCh, Konturek SJ, Pajdo R, Schuppan D, Drozdowicz D, Ptak A, Pawlik M, Nakamura T, Hahn EG: Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and hepatocyte growth factor. J Physiol Pharmacol 2000;51:751–773.
    External Resources
  49. Marchant IL, Demediuk B, Brand SJ: A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol 1991;11:2686–2696.
    External Resources

Article / Publication Details

First-Page Preview
Abstract of Original Paper: Gastric Disorders

Published online: September 10, 2001
Issue release date: 2001

Number of Print Pages: 15
Number of Figures: 12
Number of Tables: 2

ISSN: 0012-2823 (Print)
eISSN: 1421-9867 (Online)

For additional information: https://www.karger.com/DIG

Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Article Tools
Article Details

2001, Vol.64, No. 1

2001

Article

Recommend This
TOP