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Homocysteine Promotes Intestinal Fibrosis in Rats with Trinitrobenzene Sulfonic Acid-Induced Colitis

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Abstract

Background and Aim

Previous studies have revealed significantly increased levels of plasma and mucosal homocysteine (Hcy) in patients with Crohn’s disease (CD); however, whether Hcy is involved in intestinal fibrosis of CD remains unclear. This study aimed to investigate the effects of Hcy on intestinal fibrosis in TNBS/ethanol-induced colitis and to elucidate its potential mechanisms.

Methods

Sprague–Dawley rats were divided into 4 groups: normal control, normal + Hcy injection, TNBS model and TNBS model + Hcy injection. Hyperhomocysteinemia was induced by subcutaneous injection of Hcy. DAI, CMDI and HI were calculated to evaluate the severity of colitis. Masson trichrome staining was performed to assess the severity of fibrosis. The plasma and mucosal levels of Hcy were measured by HPLC-FD. The levels of IL-1β, IL-6, TNF-α, TGF-β1, CTGF, MMP-2,9 and collagen I, III in the colon were determined by ELISA, and the mRNA expressions of TGF-β1, MMP-2,9 and TIMP-1 were detected by RT-PCR.

Results

Hcy was found to increase the scores of DAI, CMDI and HI; levels of IL-1β, Il-6, TNF-α, TGF-β1, CTGF, MMP-2,9 and collagen I, III; and mRNA expressions of TGF-β1, MMP-2,9 and TIMP-1 in colonic tissue of rats with TNBS/ethanol-induced colitis.

Conclusions

Hcy promotes intestinal fibrosis in rats with TNBS/ethanol-induced colitis, the underlying mechanisms of which may be attributed to its effects of increasing inflammatory damage, promoting the expression of profibrogenic cytokines and influencing MMPs/TIMPs balance.

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References

  1. Cohen RD, Larson LR, Roth JM, et al. The cost of hospitalization in Crohn’s disease. Am J Gastroenterol. 2000;95:524–530.

    Article  CAS  PubMed  Google Scholar 

  2. Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn’s disease: Markov model analysis of a population-based cohort. Gastroenterology. 1999;117:49–57.

    Article  CAS  PubMed  Google Scholar 

  3. Latella G, Sferra R, Speca S, et al. Can we prevent, reduce or reverse intestinal fibrosis in IBD? Eur Rev Med Pharmacol Sci. 2013;17:1283–1304.

    CAS  PubMed  Google Scholar 

  4. Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 2007;117:524–529.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Latella G, Rogler G, Bamias G, et al. Results of the 4th scientific workshop of the ECCO (I): pathophysiology of intestinal fibrosis in IBD. J Crohns Colitis. 2014. doi:10.1016/j.crohns.2014.03.008.

  6. San-Miguel B, Crespo I, Kretzmann NA, et al. Glutamine prevents fibrosis development in rats with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. J Nutr. 2010;140:1065–1071.

    Article  CAS  PubMed  Google Scholar 

  7. Joseph J, Joseph L, Devi S, Kennedy RH. Effect of anti-oxidant treatment on hyperhomocysteinemia-induced myocardial fibrosis and diastolic dysfunction. J Heart Lung Transpl. 2008;27:1237–1241.

    Article  Google Scholar 

  8. Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol. 2008;28:254–264.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Robert K, Nehme J, Bourdon E, et al. Cystathionine β-synthase deficiency promotes oxidative stress, fibrosis and steatosis in mice liver. Gastroenterology 2005;128:1405–14l5.

  10. Hamelet J, Maurin N, Fulchiron R, et al. Mice lacking cystathionine beta synthase have lung fibrosis and air space enlargement. Exp Mol Pathol. 2007;83:249–253.

    Article  CAS  PubMed  Google Scholar 

  11. Kallel L, Feki M, Sekri W, et al. Prevalence and risk factors of hyperhomocysteinemia in Tunisian patients with Crohn’s disease. J Crohns Colitis. 2011;5:110–114.

    Article  PubMed  Google Scholar 

  12. Peyrin-Biroulet L, Guéant-Rodriguez RM, Chen M, et al. Association of MTRR 66A>G polymorphism with superoxide dismutase and disease activity in patients with Crohn’s disease. Am J Gastroenterol. 2008;103:399–406.

    Article  CAS  PubMed  Google Scholar 

  13. Danese S, Sgambato A, Papa A, et al. Homocysteine triggers mucosal microvascular activationininflammatorybowel diease. Am J Gastroenterol. 2005;100:886–895.

    Article  CAS  PubMed  Google Scholar 

  14. Morris GP, Beck PL, Erridge MS, et al. Hapten induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795–803.

    CAS  PubMed  Google Scholar 

  15. Vowinkel T, Kalogeris TJ, Mori M, et al. Impact of dextran sulfate sodium load on the severity of inflammation in experimental colitis. Dig Dis Sci. 2004;49:556–564.

    Article  CAS  PubMed  Google Scholar 

  16. Scherer E, da Cunha AA, Kolling J, et al. Development of an animal model for chronic mild hyperhomocysteinemia and its response to oxidative damage. Int J Dev Neurosci. 2011;29:693–699.

  17. Horváth K, Varga C, Berkó A, et al. The involvement of heme oxygenase-1 activity in the therapeutic actions of 5-aminosalicylic acid in rat colitis. Eur J Pharmacol. 2008;581:315–323.

    Article  PubMed  Google Scholar 

  18. Videla S, Vilaseca J, Medina C, et al. Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis. J Pharmacol Exp Ther. 2006;316:940–945.

    Article  CAS  PubMed  Google Scholar 

  19. Chen M, Mei Q, Xu J, et al. Detection of melatonin and homocysteine simultaneously in ulcerative colitis. Clin Chim Acta. 2012;413:30–33.

    Article  CAS  PubMed  Google Scholar 

  20. Chen Y, Ge W, Xu L, et al. miR-200b is involved in intestinal fibrosis of Crohn’s disease. Int J Mol Med. 2012;29:601–606.

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol. 2012;18:3635–3661.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ito H. IL-6 and Crohn’s disease. Curr Drug Targets Inflamm Allergy. 2003;2:125–130.

    Article  CAS  PubMed  Google Scholar 

  23. Sands BE, Kaplan GG. The role of TNFalpha in ulcerative colitis. J Clin Pharmacol. 2007;47:930–941.

    Article  CAS  PubMed  Google Scholar 

  24. San Miguel B, Alvarez M, Culebras JM, et al. N-acetyl-cysteine protects liver from apoptotic death in an animal model of fulminant hepatic failure. Apoptosis 2006;11:1945–1957.

  25. Medina C, Santos-Martinez MJ, Santana A, et al. Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis. J Pathol. 2011;224:461–472.

    Article  CAS  PubMed  Google Scholar 

  26. Kalani A, Kamat PK, Givvimani S, et al. Nutri-epigenetics ameliorates blood-brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid. J Mol Neurosci. 2014;52:202–215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Bescond A, Augier T, Chareyre C, et al. Influence of homocysteine on matrix metalloproteinase-2: activation and activity. Biochem Biophys Res Commun. 1999;263:498–503.

    Article  CAS  PubMed  Google Scholar 

  28. Wengrower D, Zannineli G, Pappo O, et al. Prevention of fibrosis in experimental colitis by captopril: the role of TGF-β1. Inflamm Bowel Dis. 2004;10:536–545.

    Article  PubMed  Google Scholar 

  29. Beddy D, Mulsow J, Watson RW, et al. Expression and regulation of connective tissue growth factor by transforming growth factor beta and tumour necrosis factor alpha in fibroblasts isolated from strictures in patients with Crohn’s disease. Br J Surg. 2006;93:1290–1296.

    Article  CAS  PubMed  Google Scholar 

  30. Abreu JG, Ketpura NI, Reversade B, De Robertis EM. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol. 2002;4:599–604.

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work is supported by The Natural Science Foundation of Anhui Province (1308085MH146) and Fund of Yang Sen Science Research Council China (2012JRCC Digest 02).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Hao Ding, Hui-Zhong Gan, Li-Yu Cao, Jian-Ming Xu & Qiao Mei

  2. Tongling People’s Hospital, Tongling, 244000, China

    Hao Ding & Wen-Jie Fan

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  1. Hao Ding
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  2. Hui-Zhong Gan
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  3. Wen-Jie Fan
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  4. Li-Yu Cao
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  6. Qiao Mei
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Corresponding author

Correspondence to Qiao Mei.

Additional information

Hui-Zhong Gan contributed equally to this work and should be considered as co-first author.

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Ding, H., Gan, HZ., Fan, WJ. et al. Homocysteine Promotes Intestinal Fibrosis in Rats with Trinitrobenzene Sulfonic Acid-Induced Colitis. Dig Dis Sci 60, 375–381 (2015). https://doi.org/10.1007/s10620-014-3379-9

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  • DOI: https://doi.org/10.1007/s10620-014-3379-9

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