Digestive Diseases and Sciences

, Volume 39, Issue 12, pp 2671–2678 | Cite as

Systemic treatment with recombinant human epidermal growth factor accelerates healing of sclerotherapy-induced esophageal ulcers and prevents esophageal stricture formations in pigs

  • Claus Orloff Juhl
  • Lars Vinter-Jensen
  • Lone Susanne Jensen
  • Ebba Nexø
  • Jens Christian Djurhuus
  • Esam Zapher Dajani
Liver: Infections, Inflammatory, And Metabolic Disorders

Abstract

Human epidermal growth factor (EGF), a small polypeptide (6 kDa) with mitogenic properties, has been implicated in the protection of gastrointestinal mucosal integrity. The efficacy of EGF in the prevention and healing of sclerotherapy-induced esophageal lesions was investigated in 24 minipigs with surgically induced portal hypertension. In addition, the effect of EGF on intragastric acidity and pharmacokinetics was investigated as possible means to explain its protective mechanism of action. The animals underwent three weekly sessions of sclerotherapy with polidocanol 2% and were concomitantly and for an additional three weeks treated with either placebo or EGF administered paravenously in the esophagus and/or subcutaneously. The subcutaneous treatment with EGF significantly (P<0.05) reduced esophageal stricture and scar formations associated with sclerotherapy. Gastric pH values were significantly (P<0.01) elevated only in animals receiving subcutaneous injections of EGF. Furthermore, the subcutaneous administration of EGF was associated with unexpected prolonged plasma concentration of the peptide. These results suggest a possible clinical value of EGF as an adjunctive treatment with the sclerotherapy.

Key words

epidermal growth factor sclerotherapy esophageal ulcers 

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References

  1. 1.
    Singai AK, Sarin SK, Misra SP, Broor SL: Ulceration after esophageal and gastric variceal sclerotherapy-Influence of sucralfate and other factors on healing. Endoscopy 20:238–240, 1988PubMedGoogle Scholar
  2. 2.
    Soerensen TIA, Burcharth F, Pedersen ML, Findahl F: Oesophageal stricture and dysphagia after endoscopic sclerotherapy for bleeding. Gut 25:473–477, 1984PubMedGoogle Scholar
  3. 3.
    Pulanic R, Vrhovac B, Jokic N, Rosandic-Pilas M, Salamon V, Opacic M, Rustemovic N, Korac C, Vucelic B: Prophylactic administration of ranitidine after sclerotherapy of esophageal varices. Int J Clin Pharmacol Toxicol 29:347–351, 1991Google Scholar
  4. 4.
    Tabibian N, Smith JL, Graham DY: Sclerotherapy-associated esophageal ulcers: Lessons from a double-blind, randomized comparison of sucralfate suspension versus placebo. Gastrointestinal Endoscopy 35:312–315, 1989PubMedGoogle Scholar
  5. 5.
    Paquet KJ, Koussouris P, Keinath R, Rambach W, Kalk J-F: A comparison of sucralfate with placebo in the treatment of esophageal ulcers following therapeutic endoscopic sclerotherapy of esophageal varices—a prospective controlled randomized trial. Am J Med 91:S147-S150, 1991Google Scholar
  6. 6.
    Johlin FC, Labrecque DR, Neil GA: Omeprazole heals mucosal ulcers associated with endoscopic injection sclerotherapy. Dig Dis Sci 37:1373–1376, 1992PubMedGoogle Scholar
  7. 7.
    Gimson A, Polson R, Westaby D, Williams R: Omeprazole in the management of intractable esophageal ulceration following injection sclerotherapy. Gastroenterology 99:1829–1831, 1990PubMedGoogle Scholar
  8. 8.
    Bhargava DK, Garg P: Sclerotherapy associated esophageal ulcers: Omeprazole versus placebo—a double-blind randomized study. Abstract from Second Osaka International Symposium on Gastroenterology, Osaka, Japan. November 1993Google Scholar
  9. 9.
    Carpenter G, Cohen S: Epidermal growth factor. J Biol Chem 265:7709–7712, 1990PubMedGoogle Scholar
  10. 10.
    Nexø E, Olsen PS, Poulsen K: Exocrine and endocrine secretion of renin and epidermal growth factor from the mouse submandibular glands. Regul Pept 8:327–334, 1984PubMedGoogle Scholar
  11. 11.
    Sarosiek J, Feng T, McCallum RW: The interrelationship between salivary epidermal growth factor and the functional integrity of the esophageal mucosal barrier in the rat. Am J Med Sci 302:359–363, 1991PubMedGoogle Scholar
  12. 12.
    Elder JR, Ganguli PC, Gillispie IE, Gerring EL, Gregory H: Effect of urogastrone on gastric secretion and plasmagastrin levels in normal subjects. Gut 16:887–893, 1975PubMedGoogle Scholar
  13. 13.
    Goodlad RA, Wilson TJ, Lenton W, Gregory H, Mccullagh KG, Wright NA: Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats. Gut 28:573–582, 1987PubMedGoogle Scholar
  14. 14.
    Marti U, Burwen SJ, Jones AL: Biological effects of epidermal growth factor, with emphasis on the gastrointestinal tract and liver: An update. Hepatology 9:126–138, 1989PubMedGoogle Scholar
  15. 15.
    Jensen LS, Krarup N, Larsen JA, Juhl C, Nielsen TH, Dybdahl H: Effect of endoscopic sclerotherapy of esophageal varices on liver blood flow and liver function. Scand J Gastroenterol 22:619–626, 1987PubMedGoogle Scholar
  16. 16.
    Juhl CO, Jensen LS, Steiniche T, Moussa E: Recombinant human epidermal growth factor prevents sclerotherapy-induced esophageal ulcer and stricture formations in pigs. Dig Dis Sci 39:393–401, 1994PubMedGoogle Scholar
  17. 17.
    Jensen LS, Krarup N, Larsen JA, Juhl C, Nielsen TH: Effect of acute portal hypertension on hepatosplanchnic hemodynamics and liver function. Scand J Gastroenterol 22:463–470, 1986Google Scholar
  18. 18.
    Weibel ER: Stereological Methods. Practical Methods for Biological Morphometry. New York, Academic Press, 1980Google Scholar
  19. 19.
    Nexø E, Jørgensen PE, Hansen MR: Human epidermal growth factor—on molecular forms present in urine and blood. Regul Pept 42:75–84, 1992PubMedGoogle Scholar
  20. 20.
    Banks-Schlegel SP, Quintero J: Human esophageal carcinoma cells have fewer, but higher affinity epidermal growth factor receptors. J Biol Chem 261:4359–4362, 1986PubMedGoogle Scholar
  21. 21.
    Sarin SK, Nanda R, Anand BS: Oesophageal ulceration after sclerotherapy—a complication or an accompaniment? Endoscopy 18:44–45, 1986Google Scholar
  22. 22.
    Kochhar R, Goenka MK, Mehta SK: Esophageal strictures following endoscopic variceal sclerotherapy. Antecedents, clinical profile, and management. Dig Dis Sci 37:347–352, 1992PubMedGoogle Scholar
  23. 23.
    Gregory PB: Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. N Engl J Med 324:1779–1784, 1991PubMedGoogle Scholar
  24. 24.
    Tyson LM, Browne CA, Jenkin G, Thorburn GD: The fate and uptake of murine epidermal growth factor in the sheep. J Endocrinol 123:121–130, 1989PubMedGoogle Scholar
  25. 25.
    Jørgensen PE, Poulsen SS, Nexø E: Distribution of i.v. administered epidermal growth factor in the rat. Regul Pept 23:161–169, 1988PubMedGoogle Scholar
  26. 26.
    Olsen PS, Poulsen SS, Kirkegaard P, Nexø E: Role of submandibular saliva and epidermal growth factor in gastric cytoprotection. Gastroenterology 87:103–108, 1984Google Scholar
  27. 27.
    Olsen PS, Poulsen SS, Therkelsen K, Nexø E: Effect of sialoadenectomy and synthetic human urogastrone on healing of chronic gastric ulcers in rats. Gut 27:1443–1449, 1986PubMedGoogle Scholar
  28. 28.
    Brzozowski T, Majka J, Garlicki J, Drozdowicz D, Konturek SJ: Role of polyamines and prostaglandins in gastroprotective action of epidermal growth factor against ethanol injury. J Clin Gastroenterol 13:S98-S102, 1991PubMedGoogle Scholar
  29. 29.
    Olsen PS, Poulsen SS, Therkelsen K, Nexø E: Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats. Gastroenterology 90:911–917, 1986PubMedGoogle Scholar
  30. 30.
    Jaeger LA, Lamar CH, Cline TR, Cardona CJ: Immunolocalization of epidermal growth factor (EGF) and EGF receptors in the porcine upper gastrointestinal tract. Am J Vet Res 53:1685–1692, 1992PubMedGoogle Scholar
  31. 31.
    Jankowski J, Murphy S, Coghill G, Grant A, Wormsley KG, Sanders DSA, Kerr M, Hopwood D: Epidermal growth factor receptors in the oesophagus. Gut 33:439–443, 1992PubMedGoogle Scholar
  32. 32.
    Dutta SK, Orestes M, Vengulekur S, Kwo P: Ethanol and human saliva: effect of chronic alcoholism on flow rate, composition, and epidermal growth factor. Am J Gastroenterol 87:350–354, 1992PubMedGoogle Scholar
  33. 33.
    Harris RC, Hoover RL, Jacobson HR, Badr KF: Evidence for glomerular actions of epidermal growth factor in the rat. J Clin Invest 82:1028–1039, 1988PubMedGoogle Scholar
  34. 34.
    Gan BS, MacCannell KL, Hollenberg MD: Epidermal growth factor-urogastrone causes vasodilatation in the anesthetized dog. J Clin Invest 80:199–206, 1987PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Claus Orloff Juhl
    • 3
    • 1
    • 2
  • Lars Vinter-Jensen
    • 3
    • 1
    • 2
  • Lone Susanne Jensen
    • 3
    • 1
    • 2
  • Ebba Nexø
    • 3
    • 1
    • 2
  • Jens Christian Djurhuus
    • 3
    • 1
    • 2
  • Esam Zapher Dajani
    • 3
    • 1
    • 2
  1. 1.Department of Clinical BiochemistryUniversity Hospital of Aarhus, Section KHDenmark
  2. 2.International Drug Development Consultants, a Division of Mid GulfU.S.A., Inc.Chicago
  3. 3.Institute of Experimental Clinical ResearchUniversity Hospital of Aarhus, Section SkejbyAarhus CDenmark

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