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The Role of Zinc and Metallothionein in the Dextran Sulfate Sodium-Induced Colitis Mouse Model

Abstract

Zinc (Zn) and its binding protein metallothionien (MT) have been proposed to suppress the disease activity in ulcerative colitis. To determine the role of Zn and MT in the dextran sulfate sodium (DSS)-induced model of colitis in mice, a DSS dose-response study was conducted in male C57BL/6 wild-type (MT+/+) and MT-null (MT−/−) mice by supplementing 2%, 3%, and 4% DSS in the drinking water for 6 days. In the intervention study, colitis was induced with 2% DSS, Zn (24 mg/ml as ZnO) was gavaged (0.1 ml) daily, concurrent with DSS administration, and the disease activity index (DAI) was scored daily. Histology, MT levels, and myeloperoxidase (MPO) activity were determined. DAI was increased (P<0.05) by 16% and 21% with 3% and 4% concentrations of DSS, respectively, compared to 2%, evident after 5 days of DSS administration. MPO activity was increased in MT+/+ compared to MT−/− mice and those receiving DSS. Zn administration had a 50% (P<0.05) lower DAI compared to DSS alone. Zn partially prevented the distal colon of MT+/+ by 47% from DSS-induced damage compared to MT−/− mice. MT did not prevent DSS-induced colitis and Zn was partially effective in amelioration of DSS-induced colitis.

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References

  1. 1.

    Rutgeerts P (2002) A critical assessment of new therapies in inflammatory bowel disease. J Gastroenterol Hepatol 17:S176–S185

    PubMed  Article  Google Scholar 

  2. 2.

    Knigge KL (2002) Inflammatory bowel disease. Clin Cornerstone 4(4):49–60

    PubMed  Article  Google Scholar 

  3. 3.

    Danese S, Sans M, Fiocchi C (2004) Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 3(5):394–400

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Hugot JP (2004) Inflammatory bowel disease: a complex group of genetic disorders. Best Pract Res Clin Gastroenterol 18(3):451–462

    PubMed  Article  Google Scholar 

  5. 5.

    Hanauer SB (2006) Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis 12(Suppl 1):S3–S9

    PubMed  Article  Google Scholar 

  6. 6.

    Kruidenier L, Kuiper I, van Duijn W, Marklund SL, van Hogezand RA, Lamers CB, Verspaget HW (2003) Differential mucosal expression of three superoxide dismutase isoforms in inflammatory bowel disease. J Pathol 201:7–16

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Segui J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Pique JM, Panes J (2004) Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine. J Leukoc Biol 76:537–544

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Kruidenier L, van Meeteren ME, Kuiper I, Jaarsma D, Lamers CB, Zijlstra FJ, Verspaget HW (2003) Attenuated mild colonic inflammation and improved survival from severe DSS-colitis of transgenic Cu/Zn-SOD mice. Free Radic Biol Med 34:753–765

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Simmonds NJ, Allen RE, Stevens TR, Van Someren RN, Blake DR, Rampton DS (1992) Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterology 103(1):186–196

    PubMed  CAS  Google Scholar 

  10. 10.

    Luk HH, Ko JK, Fung HS, Cho CH (2002) Delineation of the protective role of zinc sulfate on ulcerative colitis in rats. Eur J Pharmacol 443:197–204

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Chen BW, Wang HH, Liu JX, Liu XG (1999) Zinc sulfate solution enema decreases inflammation in experimental colitis in rats. J Gastroenterol Hepatol 14:1088–1092

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Yoshikawa T, Yamaguchi T, Yoshida N, Yamamoto H, Kitazumi S, Takahashi S, Naito Y, Kondo M (1997) Effect of Z—103 on TNB-induced colitis in rats. Digestion 58(5):464–468

    PubMed  CAS  Article  Google Scholar 

  13. 13.

    Ohkawara T, Takeda H, Kato K, Miyashita K, Kato M, Iwanaga T, Asaka M (2005) Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice. Scand J Gastroenterol 40(11):1321–1327

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Sturniolo GC, Fries W, Mazzon E, Di Leo V, Barollo M, D’inca R (2002) Effect of zinc supplementation on intestinal permeability in experimental colitis. J Lab Clin Med 139:311–315

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Di Leo V, D’Inca R, Barollo M, Tropea A, Fries W, Mazzon E, Irato P, Cecchetto A, Sturniolo GC (2001) Effect of zinc supplementation on trace elements and intestinal metallothionein concentrations in experimental colitis in the rat. Dig Liver Dis 33:135–139

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Tran CD, Butler RN, Howarth GS, Philcox JC, Rofe AM, Coyle P (1999) Regional distribution and localization of zinc and metallothionein in the intestine of rats fed diets differing in zinc content. Scand J Gastroenterol 7:689–695

    Article  Google Scholar 

  17. 17.

    Sato M, Kondoh M (2002) Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku J Exp Med 196(1):9–22

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Michalska AE, Choo KH (1993) Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse. Proc Natl Acad Sci USA 90:8088–8092

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Korenaga D, Takesue F, Kido K, Yasuda M, Inutsuka S, Honda M, Nagahama S (2002) Impaired antioxidant defence system of colonic tissue and cancer development in dextran sodium sulfate sodium-induced colitis in mice. J Surg Res 102:144–149

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Vowinkel T, Kalogeris TJ, Mori M, Krieglstein CF, Granger DN (2004) Impact of dextran sulfate sodium load on the severity of inflammation in experimental colitis. Dig Dis Sci 49:556–564

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Melgar S, Karlsson A, Michaelsson E (2005) Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. Am J Physiol Gastrointest Liver Physiol 288(6):G1328–G1338

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Geier MS, Tenikoff D, Yazbeck R, McCaughan GW, Abbott CA, Howarth GS (2005) Development and resolution of experimental colitis in mice with targeted deletion of Dipeptidyl Peptidase IV. J Cell Physiol 204:687–692

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Howarth GS, Xian CJ, Read LC (2000) Pre-disposition to colonic dysplasia is unaffected by continuous administration of insulin-like growth factor-I for twenty weeks in a rat model of chronic inflammatory bowel disease. Growth Factors 18:119–133

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Howarth GS, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorates intestinal damage by methotrexate when administered orally to rats. J Nutr 126:2519–2530

    PubMed  CAS  Google Scholar 

  25. 25.

    Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78:206–209

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Oz HS, Chen T, de Villiers WJ, McClain CJ (2005) Metallothionein overexpression does not protect against inflammatory bowel disease in a murine colitis model. Med Sci Monit 11:BR69–BR73

    PubMed  CAS  Google Scholar 

  27. 27.

    Tran CD, Butler RN, Philcox JC, Rofe AM, Howarth GS, Coyle P (1998) Regional distribution of metallothionein and zinc in the mouse gut: comparison with metallothionien–null mice. Biol Trace Elem Res 63(3):239–251

    PubMed  CAS  Google Scholar 

  28. 28.

    Mulder TP, Verspaget HW, Janssens AR, de Bruin PA, Pena AS, Lamers CB (1991) Decrease in two intestinal copper/zinc containing proteins with antioxidant function in inflammatory bowel disease. Gut 32(10):1146–1150

    PubMed  CAS  Google Scholar 

  29. 29.

    Sturniolo GC, Mestriner C, Lecis PE, D’Odorico A, Venturi C, Irato P, Cecchetto A, Tropea A, Longo G, D’Inca R (1998) Altered plasma and mucosal concentrations of trace elements and antioxidants in active ulcerative colitis. Scand J Gastroenterol 33(6):644–649

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Lih-Brody L, Powell SR, Collier KP, Reddy GM, Cerchia R, Kahn E, Weissman GS, Katz S, Floyd RA, McKinley MJ, Fisher SE, Mullin GE (1996) Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig Dis Sci 41(10):2078–2086

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Bruwer M, Schmid KW, Metz KA, Krieglstein CF, Senninger N, Schurmann G (2001) Increased expression of metallothionein in inflammatory bowel disease. Inflam Res 50:289–293

    Article  CAS  Google Scholar 

  32. 32.

    Simmonds NJ, Rampton DS (1993) Inflammatory bowel disease: a radical view. Gut 34(7):865–868

    PubMed  CAS  Google Scholar 

  33. 33.

    Dieleman LA, Palmen MJ, Akol H, Bloemena E, Pena AS, Meuwissen SG, Van Rees EP (1998) Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol 114:385–391

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Vetuschi A, Latella G, Sferra R, Caprilli R, Gaudio E (2002) Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci 47:1447–1457

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors would also like to thank Ms. Kerry Lymn and Mr. Chad Mauger for technical assistance throughout the project and Mr. Mark Geier for assistance with histological analysis. This work was supported by the National Health and Medical Research Council Industry Fellowship to Dr. Tran.

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Correspondence to C. D. Tran.

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Tran, C.D., Ball, J.M., Sundar, S. et al. The Role of Zinc and Metallothionein in the Dextran Sulfate Sodium-Induced Colitis Mouse Model. Dig Dis Sci 52, 2113–2121 (2007). https://doi.org/10.1007/s10620-007-9765-9

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Keywords

  • Inflammatory bowel disease
  • DSS-induced colitis
  • Zinc
  • Metallothionein (MT)
  • MT knockout