Skip to main content
SpringerLink
Log in

Comparison of the antisecretory and antiulcer activity of epidermal growth factor, urogastrone and transforming growth factor alpha and its derivative in rodents in vivo

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

This study investigates the effects of epidermal growth factor (EGF), urogastrone (UG) and transforming growth factor-alpha (TGFα) and its derivative on dimaprit- and pentagastrin-induced gastric acid secretion and on acidified ethanol (AE)-evoked ulcer formation in anaesthetized rats. EGF, TGFα and UG administered subcutaneously (s.c.) 30 min before dimaprit inhibited gastric acid secretion. Against pentagastrin-stimulated secretion, TGFα inhibited, while EGF and UG potentiated, acid secretion dose-dependently. Intraduodenal (i.d.) administration of TGFα and UG had no effect, while EGF potentiated, both secretagogue-induced acid secretion in the same dosage schedule. Administration of either EGF, UG or TGFα i.v. bolus, in response to continuous infusion of dimaprit resulted in a significant (p < 0.05–p < 0.001) inhibition of acid secretion which was transient and returned to normal within 30–45 min for UG while it slowly returned to normal for EGF and TGFα. The truncated form of TGFα (amino acids 34–43) did not show any antisecretory effect when administered parenterally. Acidified ethanol produced gastric haemorrhagic lesions in the rat 1 h after oral administration. The gastric mucosal protective effects of TGFα, EGF and UG administered either orally or s.c. 30 min before the administration of AE were dose-dependent against this model of ulcer induction. Indomethacin (Indo), administered 15 min before AE to inhibit prostanoids biosynthesis, significantly (p < 0.001) reduced the cytoprotective effects of TGFα, EGF and UG and aggravated the ulcer index when administered s.c. The results show that PGs may be involved in mediating the protective effects of the three growth factors. Administration of NG-nitro-L argininemethylester (L-NAME) 15 min prior to TGFα, EGF and UG s.c. or orally, significantly (p < 0.001) decreased the degree of ulcer indices and was able to reduce the protective effects of TGFα, EGF and UG, thus including the role of NO in mediating the protective effects of these growth factors. In conclusion, these results have demonstrated that EGF, UG and TGFα have a short and reversible inhibitory effect on dimaprit-stimulated gastric acid secretion and each is effective parenterally but not orally. UG and EGF potentiated, while, TGFα inhibited pentagastrin-stimulated acid secretion. In addition, TGFα seems to lose its activity when it is truncated from the C terminus. The present study also suggests that EGF, UG and TGFα are equally effective against AE-induced gastric ulcer and bring about their cytoprotective action through their reduction of acid secretion and through PG and NO pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Cohen S: Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening of newborn animals. J Biol Chem 237: 1155–1159, 1962

    PubMed  Google Scholar 

  2. Gregory H, Tracey HJ: The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 54: 105–114, 1964

    Google Scholar 

  3. Anzano MA, Roberts AB, Smith MJ, Sporn MB, De Larco JE: Sarcoma growth factor from conditioned medium of virally transformed cells is composed of both type a and b transforming growth factors. Proc Natl Acad Sci USA 80: 6264–6268, 1983

    PubMed  Google Scholar 

  4. Marquardt H, Hunkapiller MW, Hood LE, Todaro GJ: Transforming growth factors produced by retrovirus transformed rodent fibroblasts and human melanoma cells: Amino acid sequence homology with epidermal growth factor. Proc Natl Acad Sci USA 80: 4684–4688, 1983

    PubMed  Google Scholar 

  5. Marquardt H, Hunkapiller MW, Hood LE, Todaro GJ: Rat transforming growth factor type I: Structure and relationship to epidermal growth factor. Science 223: 1079–1082, 1984

    PubMed  Google Scholar 

  6. Lee DC, Rose TM, Webb NR, Todaro GJ: Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha. Nature (Lond) 313: 489–491, 1985

    Google Scholar 

  7. Defeo-Jones D, Tai JY, Wegrzyn RJ, Vuocolo GA, Baker AE, Payne LS, Garsky VM, Oliff A, Riemen MW: Structure function analysis of synthetic and recombinant derivatives of transforming growth factor alpha. Mol Cell Biol 8: 2999–3007, 1988

    PubMed  Google Scholar 

  8. Lazar E, Vicenzi E, Van Obberghen-Schilling E, Wolfe B, Dalton S, Watanabe S, Sporn MB: Transforming growth factor α: An aromatic side chain at position 38 is essential for biological activity. Mol Cell Biol 9: 860–864, 1989

    PubMed  Google Scholar 

  9. Bielanski WJ, Keogh JP, Wang SL, Lui SL, Konturek SJ, Slomiany S, Slomiany BL: Transforming growth factor alpha binds to the epidermal growth factor receptor in gastric mucosa. Biochem Int 25: 419–427, 1991

    PubMed  Google Scholar 

  10. Winkler ME, O'Connor L, Winget M, Fendly B: Epidermal growth factor and transforming growth factor alpha bind differently to the epidermal growth factor receptor. Biochemistry 28: 6373–6378, 1989

    PubMed  Google Scholar 

  11. Derynck R: Transforming growth factor α. Cell 54: 593–595, 1988

    PubMed  Google Scholar 

  12. Wang L, Lucey MR, Fras AM, Wilson EJ, Del Valle J: Epidermal growth factor and transforming growth factor-alpha directly inhibit parietal cell function through a similar mechanism. J Pharmacol Exp Ther 265: 308–313, 1993

    PubMed  Google Scholar 

  13. Beauchamp RD, Barnard JA, McCutchen CH, Chemer JA, Coffey RJ: Localization of transforming growth factor and its receptor in gastric mucosa cells. Implications for regulatory role in acid secretion and mucosal renewal. J Clin Invest 84: 1017–1023, 1989

    PubMed  Google Scholar 

  14. Cartlidge AA, Elder JB: Transforming growth factor alpha and epidermal growth factor levels in normal human gastrointestinal mucosa. Br J Cancer 60: 657–660, 1989

    PubMed  Google Scholar 

  15. Gregory H, Thomas CE, Young JA, Willshire IR, Garner A: The contribution of the C-terminal undecapeptide sequence of urogastroneepidermal growth factor to its biological action. Reg Pep 22: 217–226, 1988

    Google Scholar 

  16. Finke U, Barbera L, Zumtobel V: Effect of epidermal growth factor (EGF) and indomethacin on stimulated gastric acid secretion in vitro. Gastroenterology 96: A151, 1989

    Google Scholar 

  17. Rao RK, Chang HH, Levenson S, Porreca F, Brannon PM, Davis TP, Koldovsky O: Ontogenic differences in the inhibition of gastric acid secretion by epidermal growth factor. J Pharmacol Exp Ther 266: 647–654, 1993

    PubMed  Google Scholar 

  18. Konturek SJ, Brzozowski T, Piastucki I, Dembinstki A, Radecki T, Dembinska-Kiec A, Zmuda A, Gregory H: Role of mucosal prostaglandins and DNA synthesis in gastric cytoprotection by luminal epidermal growth factor. Gut 22: 927–932, 1981

    PubMed  Google Scholar 

  19. Brzozowski T, Majka J, Konturek SJ, Bielanski W, Slomiany BL, Garner A: Gastroprotective activity and receptor expression of transforming growth factor alpha, epidermal growth factor and basic fibroblast growth factor in the rat stomach. Eur J Gastroenterol Hepatol 6: 337–343, 1994

    Google Scholar 

  20. Rutten MJ, Dempsey PJ, Solomon TE, Coffey RJ: TGFα is a potent mitogen for primary cultures of guinea pig gastric mucous epithelial cells. Am J Physiol 265: G361–G369, 1993

    PubMed  Google Scholar 

  21. Rackoff PJ, Zdon MJ, Tyshkov M, Modlin IM: Epidermal growth factor (EGF) inhibits intrinsic factor and acid secretion in histamine-stimulated isolated gastric glands. Regul Pept 21: 279–287, 1988

    PubMed  Google Scholar 

  22. Schroeder JA, Thompson MC, Gardner MM, Gendler SJ. Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland. J Biol Chem 276: 13057–13064, 2001

    PubMed  Google Scholar 

  23. Cowing BE, Saker KE: Polyunsaturated fatty acids and epidermal growth factor receptor/mitogen-activated protein kinase signaling in mammary cancer. J Nutr 131: 1125–1128, 2001

    PubMed  Google Scholar 

  24. Tarnawski A, Stachura J, Durbin T, Sarfeh IJ, Gergely H: Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats. Gastroenterology 102: 695–698, 1992

    PubMed  Google Scholar 

  25. Konturek JW, Hengst K, Konturek SJ, Domschke W: Epidermal growth factor in gastric ulcer healing by nocloprost, a stable prostaglandin E2 derivative. Scand J Gastroenterol 32: 980–984, 1997

    PubMed  Google Scholar 

  26. Rhodes JA, Tam J.P, Finke U, Saunders M, Bernanke J, Silen W, Murphy RA: Transforming growth factor α inhibits secretion of gastric acid. Proc Natl Acad Sci USA 83: 3844–3846, 1986

    PubMed  Google Scholar 

  27. Lewis JJ, Goldenring JR, Modlin IM, Coffey RJ: Inhibition of parietal cell H+ secretion by transforming growth factor alpha: A possible autocrine regulatory mechanism. Surgery 108: 220–227, 1990

    PubMed  Google Scholar 

  28. Grupcev G, Wallin C, Emas S, Theodorsson E, Hellstrom PM: Transforming growth factor-alpha and epidermal growth factor inhibit gastric acid secretion and stimulate release of somatostatin and neurotensin in the conscious rat. Reg Pep 52: 111–118, 1994

    Google Scholar 

  29. Guglietta A, Lesch CA, Romano M, McClure RW, Coffey RJ: Effect of transforming growth factor (TGFα) on gastric acid secretion in rats and monkeys. Dig Dis Sci 39: 177–182, 1994

    PubMed  Google Scholar 

  30. Joshi V, Ray GS, Goldenring JR: Inhibition of parietal cell acid secretion is mediated by the classical epidermal growth factor receptor. Dig Dis Sci 42: 1199–1209, 1997

    PubMed  Google Scholar 

  31. Bower JM, Gamble R, Gregory H, Gerring EL, Willshire IR: The inhibition of gastric acid secretion by epidermal growth factor. Experientia 31: 825–826, 1975

    PubMed  Google Scholar 

  32. Elder JB, Ganguly PC, Gillespie IE, Gerring EL, Gregory H: Effect of urogastrone on gastric secretion and plasma gastrin levels in normal subjects. Gut 16: 887–893, 1975

    PubMed  Google Scholar 

  33. Miettinen PJ: Transforming growth factor-alpha and epidermal growth factor expression in human fetal gastrointestinal tract. Paediatr Res 33: 481–486, 1993

    Google Scholar 

  34. Yamaura T, Umehara N, Takenaga K, Numoto T, Tosaka K: Inhibitory action of urogastrone from pregnant horse's urine on gastric acid secretion. Nippon Yakurigaku Zasshi-Folia Pharmacologica Japonica 78: 305–318, 1981

    Google Scholar 

  35. Saxena SK, Thomson JS, Crouse DA, Sharp JG: Epithelial cell proliferation and uptake of radiolabelled urogastrone in the intestinal tissues following abdominal irradiation in the mouse. Radiat Res 128: 37–42, 1991

    PubMed  Google Scholar 

  36. Saxena SK, Thomson JS, Crouse DA, Sharp JG: Epithelial cell proliferation and biodistribution of radiolabelled urogastrone in the gastrointestinal mucosa of young and old mice. Life Sci 56: 199–204, 1995

    PubMed  Google Scholar 

  37. Mercer DW, Cross JM, Barreto JC, Strobel NHP, Russell DH, Miller TA: Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat. Dig Dis Sci 40: 651–660, 1995

    PubMed  Google Scholar 

  38. Nishida A, Takinami Y, Yuki H, Kobayashi A, Akuzawa S, Kamato T, Ito H, Yamano M, Nagakura Y, Miyata K: YM022 ((R)-1–[2,3–dihydro-1–(2′-methylphenacyl)-2–oxo-5–phenyl-1H-1, 4–benzodiazepin-3–yl]-3–(methylphenyl) urea), a potent and selective gastrin/cholecystokinin-B receptor antagonist, prevents gastric and duodenal lesions in rats. J Pharmacol Exp Ther 270: 1256–1261, 1994

    PubMed  Google Scholar 

  39. Sandvik AK, Waldum HL: CCK-B (gastrin) receptor regulates gastric histamine release and acid secretion. Am J Physiol 260: G925–G928, 1991

    PubMed  Google Scholar 

  40. Praissman M, Brand DL, Praissman LA, Walden M, Fay ME, Lane BP, Manoukian A, Lu YM: Autoradiographic identification of a gastrin receptor on the human parietal cell. Reg Pep 73: 183–190, 1998

    Google Scholar 

  41. Akagi K, Nagao T, Urushidani T: Calcium oscillations in single cultured Chinese hamster ovary cells stably transfected with a cloned human cholecystokinin (CCK B) receptor. Jpn J Pharmacol 75: 33–42, 1997

    PubMed  Google Scholar 

  42. Francis SH, Corbin JD: Structure and function of cyclic nucleotidedependent protein kinases. Annu Rev Physiol 56: 237–272, 1994

    PubMed  Google Scholar 

  43. Neer EJ, Clapham DE: Roles of G protein subunits in transmembrane signaling. Nature 333: 129–134, 1988

    Article  PubMed  Google Scholar 

  44. Chew CS: Inhibitory action of somatostatin on isolated gastric glands and parietal cells. Am J Physiol 245: G221–G229, 1983

    PubMed  Google Scholar 

  45. Schubert ML: Regulation of gastric acid secretion. Curr Opin Gastroenterol 14: 425–432, 1988

    Google Scholar 

  46. Garcia JV, Gehm BD, Rosner MR: An evolutionarily conserved enzyme degrades transforming growth factor-alpha as well as insulin. J Cell Biol 109: 1301–1307, 1989

    PubMed  Google Scholar 

  47. Mori S, Morishita Y, Sakai K, Kurimoto S, Okamoto M, Kawamoto T, Kuroki T: Electron microscopic evidence for epidermal growth factor receptor (EGF-R)-like immunoreactivity associated with the basolateral surface of gastric parietal cells. Acta Pathol Jpn 12: 1909–1912, 1987

    Google Scholar 

  48. Playford RJ, Marchbank T, Calnan DP, Calam J, Royston P, Batten JJ, Hansen HF: Epidermal growth factor digested to smaller, less active forms in acidic gastric juice. Gastroenterology 108: 92–101, 1995

    PubMed  Google Scholar 

  49. Lewis JJ, Goldenring JR, Asher VA, Modlin IM: Pancreastatin: A novel peptide inhibitor of parietal cell signal transduction. Biochem Biophys Res Commun 163: 667–673, 1989

    PubMed  Google Scholar 

  50. Scheiman JM, Meise KS, Greenson JK, Coffey RJ: Transforming growth factor-alpha (TGFα) levels in human proximal gastrointestinal epithelium. Effect of mucosal injury and acid inhibition. Dig Dis Sci 42: 333–341, 1997

    PubMed  Google Scholar 

  51. Chen MC, Olson C, Tarner M, Soll AH: Apical TGFα/EGF receptors mediate enhanced resistance of gastric mucosal cell monolayers to apical acidification. Gastroenterology 100: A42, 1991

    Google Scholar 

  52. Chew CS, Nakamura K, Petropoulos AC: Multiple actions of epidermal growth factor and TGFα on gastric parietal cell function. Am J Physiol 267 (Gastrointest Liver Physiol 30): G818–G826, 1994

    PubMed  Google Scholar 

  53. Darlak K, Franklin G, Woost P, Sonnenfeld E, Twardzik D, Spatola A, Schultz G: Assessment of biological activity of synthetic fragments of transforming growth factor-alpha. J Cell Biochem 36: 341–352, 1988

    PubMed  Google Scholar 

  54. Defeo-Jones D, Tai JY, Vuocolo GA, Wegrzyn RJ, Schofield TL, Riemen MW, Oliff A: Substitution of lysine for arginine at position 42 of human transforming growth factor-α eliminates biological activity without changing internal disulfide bonds. Mol Cell Biol 9: 4083–4086, 1989

    PubMed  Google Scholar 

  55. Goldenring JR, Tsunoda Y, Stoch SA, Coffey RJ, Modlin IM: Transforming growth factor-alpha (TGFα) inhibition of parietal cell secretion: Structural requirements of reactivity. Reg Pep 43: 37–47, 1993

    Google Scholar 

  56. Lacy ER, Ito S: Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology 83: 619–625, 1982

    PubMed  Google Scholar 

  57. Szabo S, Trier J, Brown A, Schnoor J: Early vascular injury and increased vascular permeability in gastric mucosal injury caused by ethanol in the rat. Gastroenterology 88: 228–236, 1985

    PubMed  Google Scholar 

  58. Schoen R, Vender R: Mechanism of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med 86: 449–458, 1989

    PubMed  Google Scholar 

  59. Jacobson ED, Chaudhury TK, Thompson WL: Mechanism of gastric mucosal cytoprotection by prostaglandins. Gastroenterology 70: 897–902, 1976

    Google Scholar 

  60. Chaudhury TK, Jacobson ED: Prostaglandin cytoprotection of gastric mucosa. Gastroenterology 74: 58–63, 1978

    PubMed  Google Scholar 

  61. Whittle BJR: Potentiation of taurocholate-induced rat gastric erosions following parenteral administration of cyclooxygenase inhibitors. Br J Pharmacol 80: 545–551, 1983

    PubMed  Google Scholar 

  62. Takeuchi K, Furukawa O, Tanaka H, Okabe S: A new model of duodenal ulcers induced in rats by indomethacin plus histamine. Gastroenterology 90: 636–645, 1986

    PubMed  Google Scholar 

  63. Takeuchi K, Furukawa O, Nishiwaki H, Okabe S: 16, 16–Dimethyl prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats: Possible role of the increased mucosal vascular permeability. Gastroenterology 93: 1276–1288, 1987

    PubMed  Google Scholar 

  64. Burget DW, Stephen G, Chiverton SG, Hunt RH: Is there an optimal degree of acid suppression for healing of duodenal ulcer? A model of the relationship between ulcer healing and acid suppression. Gastroenterology 99: 345–351, 1990

    PubMed  Google Scholar 

  65. Whittle BJR, Lopez BJ, Moncada S: Regulation of gastric mucosal integrity by endogenous nitric oxide: Interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol 99: 607–611, 1990

    PubMed  Google Scholar 

  66. Takeuchi K, Okabe S: Mechanism of gastric alkaline response in the stomach after damage. Roles of nitric oxide and prostaglandins. Dig Dis Sci 40: 865–871, 1995

    PubMed  Google Scholar 

  67. Takeuchi K, Kato S, Yasuhiro T, Yagi K: Mechanism of acid secretory changes in rat stomach after damage by taurocholate: Role of nitric oxide, histamine and sensory neurons. Dig Dis Sci 42: 645–653, 1997

    PubMed  Google Scholar 

  68. Brown JF, Keates AC, Hanson PJ, Whittle BJR: Nitric oxide generators and cGMP stimulate mucus secretion by rat gastric mucosal cells. Am J Physiol 265: G418–G422, 1993

    PubMed  Google Scholar 

  69. Pique JM, Whittle BJR, Esplugues JV: The vasodilator role of endogenous nitric oxide in the rat gastric microcirculation. Eur J Pharmacol 174: 293–296, 1989

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE

    S.M.A. Bastaki & S.I. Chandranath

  2. Department of Biological Sciences, University of Central Lancashire, Preston, UK

    J. Singh

Authors
  1. S.M.A. Bastaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S.I. Chandranath
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bastaki, S., Chandranath, S. & Singh, J. Comparison of the antisecretory and antiulcer activity of epidermal growth factor, urogastrone and transforming growth factor alpha and its derivative in rodents in vivo . Mol Cell Biochem 236, 83–94 (2002). https://doi.org/10.1023/A:1016144016908

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016144016908

Search

Navigation