Skip to main content
SpringerLink
Log in

Changes in Sulfated Macromolecules Produced In Vivo During Normal and Indomethacin-Delayed Ulcer Healing in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The aim of this study was to examine thesynthesis of sulfated glycosaminoglycans during normalhealing of experimental acetic acid-induced gastriculcers in rats and to investigate the effect ofindomethacin, a drug known to delay ulcer healing, on thissynthesis using an in vivo labelling system. Analysisrevealed the presence of two major sulfated species incontrol tissue; a population of sulfated mucins and glycosaminoglycans, predominantlygalactosaminoglycans. The incorporation of[35S]sulfate label into glycosaminoglycanssynthesized in the granulation tissue of healing ulcersincreased significantly (P < 0.05) as compared to day 0 and controllevels at day 14. Treatment of animals with indomethacin(1 mg/kg daily) resulted in a further significant (P< 0.01) rise in sulfated glycosaminoglycan synthesis in indomethacin-treated ulcer tissue comparedto that found in healing ulcers at day 14. The increasedglycosaminoglycan synthesis was due to increased levelsof chondroitin sulfate and dermatan sulfate. Glycosaminoglycan synthesis is elevated at theulcer site during healing of experimental gastriculcers; however, indomethacin treatment, which delaysulcer healing, significantly increases the synthesis of glycosaminoglycans above that seen inhealing ulcers. Changes in the sulfatedglycosaminoglycan content of the ulcer may play a rolein the healing process and may give further insight intothe mechanisms by which indomethacin delays ulcerhealing.

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. Penney AG, Andrews FJ, O'Brien PE: Effects of misoprostol on delayed ulcer healing induced by aspirin. Dig Dis Sci 39:934–939, 1994

    Google Scholar 

  2. Ogihara Y, Fuse Y, Okabe S: Effects of indomethacin and prednisolone on connective tissue at the base on acetic acid-induced gastric ulcers in rats. In Mechanisms of Injury, Protection and Repair in the Upper Gastrointestinal Tract. A Garner, PE O'Brien (eds). Chichester, Wiley, 1991, pp 455–465

    Google Scholar 

  3. Tsuchida T, Tsukamoto Y, Segawa K, Goto H, Hase S: Effects of Cimetidine and Omeprazole on angiogenesis in granulation tissue of acetic acid-induced gastric ulcers in rats. Digestion 47:8–14, 1990

    Google Scholar 

  4. Tarnawski A, Hollander D, Stachura J, Krause WJ, Eltorai M, Dabros W, Gergely H: Vascular and microvascular changes—key factors in the development of acetic acid induced gastric ulcers in rats. J Clin Gastroenterol 12:S148–S157, 1990

    Google Scholar 

  5. Jackson RL, Busch SJ, Cardin AD: Glycosaminoglycans: Molecular properties, protein interactions, and role in physiological processes. Physiol Rev 71:481–539, 1991

    Google Scholar 

  6. Gallagher JT: The extended family of proteoglycans: Social residents of the pericellular zone. Curr Opin Cell Biol 1:1201–1218, 1989

    Google Scholar 

  7. Bently JP: Rate of chondroitin sulfate formation in wound healing. Ann Surg 186–191, 1967

  8. Rooney P, Kumar S: Inverse relationship between hyaluronan and collagens in development and angiogenesis. Differentiation 54:1–9, 1993

    Google Scholar 

  9. Scott JE: Proteoglycan: Collagen interactions and subfibrillar structure in collagen fibrils: Implications in the development and ageing of connective tissue. J Anat 169:23–35, 1990

    Google Scholar 

  10. West DC, Hampson IN, Arnold F, Kumar S: Angiogenesis induced by degradation products of hyaluronic acid. Science 228:1324–1326, 1985

    Google Scholar 

  11. Maquart F-X, Bellon G, Chaqour B, Wegrowski J, Patt LM, Trachy RE, Monboisse J-C, Chastang F, Birembaut P, Gillery P, Borel J-P: In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds. J Clin Invest 92:2368–2376, 1993

    Google Scholar 

  12. Pierce GF, Berg JV, Rudolph R, Tarpley J, Mustoe TA: Platelet-derived growth factor-BB and transforming growth factor beta 1 selectively modulate glycosaminoglycans, collagen and myofibroblasts in excisional wounds. Am J Pathol 138:629–649, 1991

    Google Scholar 

  13. Lyons KC, Andrews FJ, Comper WD, O'Brien PE: Sulphated macromolecules produced in vivo labelling in the rat gastric mucosa. J Gastroenterol Hepatol 10:1–8, 1995

    Google Scholar 

  14. Goso K, Ishihara K, Ohara S, Kakei M, Hotta K: Characterisation of sulphated glycoconjugates in human gastric mucosa. Digestion 31:205–212, 1985

    Google Scholar 

  15. Suzuki Y, Ito M, Sudo Y: Changes in connective tissue components in ulcer tissue during the healing process of acetic acid ulcer in rat. Jpn J Pharmacol 29:821–828, 1979

    Google Scholar 

  16. Wiebkin OW, Shearman DJC: Maintenance of gastric mucosal integrity: Active role for tissue-specific intercellular matrix. J Gastroenterol Hepatol 1:20–26, 1989

    Google Scholar 

  17. Wiebkin OW, Hillen D, Wiebkin SC, Shearman DJC: Intercellular matrix in the gut: Putative roles in gastric protection. In Mechanisms of injury, protection and repair of the upper gastrointestinal tract, A Garner, PE O'Brien (eds). Chichester, Wiley, 1991 pp 343–355

    Google Scholar 

  18. Somasundaram K, Ganguly AK: Gastric mucosal protection during restraint stress: Histologically identifiable gastric mucosal glycosaminoglycan content in albino rats. Physiol Bohemoslov 35:94–95, 1986

    Google Scholar 

  19. Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ: Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet 341:711–714, 1993

    Google Scholar 

  20. Vassiliou P, Tay M, Comper WD: Partial ischemia and proteinuria during isolated kidney perfusion is accompanied by the release of vascular [35S]heparan sulphate. Biochem Int 19:1241–1251, 1989

    Google Scholar 

  21. Shively JE, Conrad HE: Formation of anhydrosugars in the chemical depolymerisation of heparin. Biochem 1:3932–3942, 1976

    Google Scholar 

  22. Carney SL: Proteoglycans. In Carbohydrate Analysis: A Practical Approach. MF Chaplin, JF Kennedy (eds). Oxford, IRL Press, 1986, pp 97–141

    Google Scholar 

  23. Bitter T, Muir HM: A modified uronic acid carbazole reaction. Anal Biochem 4:330–334, 1962

    Google Scholar 

  24. Kato M, Oike Y, Suzuki S, Kimata K: Selective removal of heparan sulphate chains from proteoheparan sulphate with a commercial preparation of heparitinase. Anal Biochem 148:479–484, 1985

    Google Scholar 

  25. Tarnawski A, Douglass TG, Stachura J, Krause WJ: Quality of gastric ulcer healing: Histological and ultrastructural assessment. Aliment Pharmacol Ther 5:79–90, 1991

    Google Scholar 

  26. Clark RAF: Cutaneous wound repair. In Physiology, Biochemistry and Molecular Biology of the skin, 2nd ed. LA Goldsmith (ed). New York, Oxford University Press, 1993, pp 343–355

    Google Scholar 

  27. Postlethwaite AE, Kang AH: Fibroblasts and matrix proteins. In Inflammation: Basic Principles and Clinical Correlates, 2nd ed. JI Gallin, IM Goldstein, R Snyderman (eds). New York, Raven Press, 1992, pp 747–773

    Google Scholar 

  28. Tarnawski A, Hollander D, Krause WJ, Dabrous W, Stachura J, Gergely H: “Healed” experimental gastric ulcers remain histologically and ultrastructurally abnormal. J Clin Gastroenterol 12:S139–S147, 1990

    Google Scholar 

  29. Fisher LW: Decorin. In Guidebook to the Extracellular Matrix and Adhesion Proteins. T Kreis, R Vale (eds). Oxford, Oxford University Press, 1993, pp 48–49

    Google Scholar 

  30. Vogek KG, Paulson M, Heinegård D: Specific inhibition of type I and type II collagen fibrillogenesis by the small proteoglycan of tendon. J Biochem 223:587–597, 1984

    Google Scholar 

  31. Yamaguchi Y, Mann DM, Ruoslahti E: Negative regulation of transforming growth factor-β by the proteoglycan decorin. Nature 346:281–284, 1990

    Google Scholar 

  32. Gillessen A, Vob B, Rauterberg J, Domschke W: Distribution of collagen types I, III, and IV in peptic ulcer and normal gastric mucosa in man. Scand J Gastroenterol 28:688–689, 1993

    Google Scholar 

  33. Zimmerman DR: Versican. In Guidebook to the Extracellular Matrix and Adhesion Proteins. T Kreis, R Vale (eds). Oxford, Oxford University Press, 1993, pp 48–49

    Google Scholar 

  34. Yeo T-K, Brown L, Dvorak HF: Alterations in proteoglycan synthesis common to healing wounds and tumours. Am J Pathol 138:1437–1450, 1991

    Google Scholar 

  35. Collier S, Ghosh P: Comparison of the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures. Biochem Pharmacol 41:1375–1384, 1991

    Google Scholar 

  36. Mitrovic D, McCall E, Front Ph, Aprile F, Darmon N, Dray F: Anti-inflammatory drugs, prostanoid and proteoglycan production by cultured bovine articular chondrocytes. Prostaglandins 28:417–434, 1984

    Google Scholar 

  37. Bjelle A, Eronen I: The in vitro effect of six NSAIDs on the glycosaminoglycan metabolism of rabbit chondrocytes. Clin Exp Rheumatol 9:369–374, 1991

    Google Scholar 

  38. Tarnawski A, Stachura J, Douglass TG, Krause WJ, Gergely H, Sarfeh IJ: Indomethacin impairs quality of experimental gastric ulcer healing: A quantitative histological and ultrastructural analysis. In Mechanisms of Injury, Protection and Repair of the Upper Gastrointestinal Tract. A Garner, PE O'Brien (eds). Chichester, Wiley, 1991, pp 521–531

    Google Scholar 

  39. Ogihara Y, Okabe S: Mechanism by which indomethacin delays gastric ulcer healing in the rat: Inhibited contraction of the ulcer base. Jpn J Pharmacol 61:123–131, 1993

    Google Scholar 

  40. Grodzinsky AJ, Frank EH, Kim Y-J, Buschmann MD: The role of specific macromolecules in cell-matrix interactions and in matrix function: Physicochemical and mechanical mediators of chondrocyte biosynthesis. In Extracellular Matrix, Vol 2, Molecular Components and Interactions. WD Comper (ed). Amsterdam, Harwood Academic, 1996, pp 310–334

    Google Scholar 

  41. Tarnawski A, Stachura J, Krause WJ, Douglass TG, Gergely H: Quality of gastric ulcers healing: A new, emerging concept. J Clin Gastroenterol 13:S42–S47, 1991

    Google Scholar 

Download references

Authors
  1. K. C. Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. J. Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. D. Comper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. E. O'Brien
    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

Lyons, K.C., Andrews, F.J., Comper, W.D. et al. Changes in Sulfated Macromolecules Produced In Vivo During Normal and Indomethacin-Delayed Ulcer Healing in Rats. Dig Dis Sci 42, 1755–1764 (1997). https://doi.org/10.1023/A:1018830002964

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1018830002964

Search

Navigation