Skip to main content
SpringerLink
Log in

Thromboxane-prostanoid receptor expression and antagonism in dextran-sodium sulfate-induced colitis

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

In the current study of murine colitis, the potential roles of thromboxane and the thromboxane-prostanoid (TP) receptor were investigated, in as much as thromboxane signaling has been implicated in human inflammatory bowel disease.

Methods

Colitis was induced in C57BL/6 mice via ingestion of dextran sodium sulfate (DSS), with or without co-administration of the thromboxane synthase inhibitor ozagrel (25 mg/kg/day) or the TP receptor antagonist vapiprost (2.5 mg/kg/day).

Results

Immunohistochemistry of colonic tissue demonstrated a DSS-induced increase in TP receptor expression, but not of thromboxane synthase. Moreover, tissue levels of the metabolite thromboxane B2 were unchanged by DSS. Vapiprost, but not ozagrel, partially attenuated histologic signs of inflammation induced by DSS, with vapiprost allowing a smaller increase in colon weight per unit length than ozagrel. Vapiprost also tended to attenuate DSS-induced alterations in intestinal transit.

Conclusions

In summary, TP receptor antagonism was more effective than thromboxane synthase inhibition in alleviating DSS-induced colitis in mice.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Carty E, Nickols C, Feakins RM, Rampton DS. Thromboxane synthase immunohistochemistry in inflammatory bowel disease. J Clin Pathol. 2002;55:367–70.

    Article  CAS  PubMed  Google Scholar 

  2. Ligumsky M, Karmeli F, Sharon P, Zor U, Cohen F, Rachmilewitz D. Enhanced thromboxane A2 and prostacyclin production by cultured rectal mucosa in ulcerative colitis and its inhibition by steroids and sulfasalazine. Gastroenterology. 1981;81:444–9.

    CAS  PubMed  Google Scholar 

  3. Hawkey CJ, Karmeli F, Rachmilewitz D. Imbalance of prostacyclin and thromboxane synthesis in Crohn’s disease. Gut. 1983;24:881–5.

    Article  CAS  PubMed  Google Scholar 

  4. Lauritsen K, Laursen LS, Bukhave K, Rask-Madsen J. In vivo profiles of eicosanoids in ulcerative colitis, Crohn’s colitis, and Clostridium difficile colitis. Gastroenterology. 1988;95:11–7.

    CAS  PubMed  Google Scholar 

  5. Tytgat GN, Van Nueten L, Van De Velde I, Joslyn A, Hanauer SB. Efficacy and safety of oral ridogrel in the treatment of ulcerative colitis: two multicentre, randomized, double-blind studies. Aliment Pharmacol Ther. 2002;16:87–99.

    Article  CAS  PubMed  Google Scholar 

  6. Carty E, Rampton DS, Schneider H, Rutgeerts P, Wright JP. Lack of efficacy of ridogrel, a thromboxane synthase inhibitor, in a placebo-controlled, double-blind, multi-centre clinical trial in active Crohn’s disease. Aliment Pharmacol Ther. 2001;15:1323–9.

    Article  CAS  PubMed  Google Scholar 

  7. Dogne JM, de Leval X, Hanson J, Frederich M, Lambermont B, Ghuysen A, et al. New developments on thromboxane and prostacyclin modulators part I: thromboxane modulators. Curr Med Chem. 2004;11:1223–41.

    CAS  PubMed  Google Scholar 

  8. Feletou M, Huang Y, Vanhoutte PM. Vasoconstrictor prostanoids. Pflugers Arch. 2010;459(6):941–50.

    Article  CAS  PubMed  Google Scholar 

  9. Gomi T, Ikeda T, Sasaki Y, Kosugi T, Shibuya Y, Sakurai J. Protective effect of thromboxane synthetase inhibitor on hypertensive renal damage in Dahl salt-sensitive rats. Clin Exp Pharmacol Physiol Suppl. 1995;22:S371–3.

    Article  CAS  PubMed  Google Scholar 

  10. Gomi T, Ikeda T, Ishimitsu T, Uehara Y. Effects of OKY-046, a selective thromboxane synthetase inhibitor, on blood pressure and thromboxane synthesis in spontaneously hypertensive rats. Prostaglandins Leukot Essent Fatty Acids. 1989;37:139–44.

    Article  CAS  PubMed  Google Scholar 

  11. Tanaka T, Fukuta Y, Higashino R, Sato R, Nomura Y, Fukuda Y, et al. Antiplatelet effect of Z-335, a new orally active and long-lasting thromboxane receptor antagonist. Eur J Pharmacol. 1998;357:53–60.

    Article  CAS  PubMed  Google Scholar 

  12. Dieleman LA, Palmen MJ, Akol H, Bloemena E, Pena AS, Meuwissen SG, et al. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. 1998;114:385–91.

    Article  CAS  PubMed  Google Scholar 

  13. Holma R, Salmenpera P, Virtanen I, Vapaatalo H, Korpela R. Prophylactic potential of montelukast against mild colitis induced by dextran sulphate sodium in rats. J Physiol Pharmacol. 2007;58:455–67.

    CAS  PubMed  Google Scholar 

  14. Vowinkel T, Mori M, Krieglstein CF, Russell J, Saijo F, Bharwani S, et al. Apolipoprotein A-IV inhibits experimental colitis. J Clin Invest. 2004;114:260–9.

    CAS  PubMed  Google Scholar 

  15. Sato K, Ohkura S, Kitahara Y, Ohama T, Hori M, Sato M, et al. Involvement of CPI-17 downregulation in the dysmotility of the colon from dextran sodium sulphate-induced experimental colitis in a mouse model. Neurogastroenterol Motil. 2007;19:504–14.

    Article  CAS  PubMed  Google Scholar 

  16. Zipser RD, Patterson JB, Kao HW, Hauser CJ, Locke R. Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis. Am J Physiol. 1985;249:G457–63.

    CAS  PubMed  Google Scholar 

  17. Appleyard CB, Alvarez A, Percy WH. Temporal changes in colonic vascular architecture and inflammatory mediator levels in animal models of colitis. Dig Dis Sci. 2002;47:2007–14.

    Article  CAS  PubMed  Google Scholar 

  18. Vilaseca J, Salas A, Guarner F, Rodriguez R, Malagelada JR. Participation of thromboxane and other eicosanoid synthesis in the course of experimental inflammatory colitis. Gastroenterology. 1990;98:269–77.

    CAS  PubMed  Google Scholar 

  19. Taniguchi T, Tsukada H, Nakamura H, Kodama M, Fukuda K, Tominaga M, et al. Effects of a thromboxane A2 receptor antagonist in an animal model of inflammatory bowel disease. Digestion. 1997;58:476–8.

    Article  CAS  PubMed  Google Scholar 

  20. Harris NR, Whatley JR, Carter PR, Specian RD. Venular constriction of submucosal arterioles induced by dextran sodium sulfate. Inflamm Bowel Dis. 2005;11:806–13.

    Article  PubMed  Google Scholar 

  21. Mori M, Stokes KY, Vowinkel T, Watanabe N, Elrod JW, Harris NR, et al. Colonic blood flow responses in experimental colitis: time course and underlying mechanisms. Am J Physiol Gastrointest Liver Physiol. 2005;289:G1024–9.

    Article  CAS  PubMed  Google Scholar 

  22. Schultheiss G, Diener M. Inhibition of spontaneous smooth muscle contractions in rat and rabbit intestine by blockers of the thromboxane A2 pathway. Zentralbl Veterinarmed A. 1999;46:123–31.

    CAS  PubMed  Google Scholar 

  23. Diener M, Gabato D. Thromboxane-like actions of prostaglandin D2 on the contractility of the rat colon in vitro. Acta Physiol Scand. 1994;150:95–101.

    Article  CAS  PubMed  Google Scholar 

  24. Okada Y, Hara A, Ma H, Xiao CY, Takahata O, Kohgo Y, et al. Characterization of prostanoid receptors mediating contraction of the gastric fundus and ileum: studies using mice deficient in prostanoid receptors. Br J Pharmacol. 2000;131:745–55.

    Article  CAS  PubMed  Google Scholar 

  25. Borjesson L, Delbro DS. Neurogenic and non-neurogenic mechanisms in response of rat distal colon muscle to dextran sulphate sodium treatment. Auton Neurosci. 2003;107:74–80.

    Article  CAS  PubMed  Google Scholar 

  26. Gonzalez A, Sarna SK. Different types of contractions in rat colon and their modulation by oxidative stress. Am J Physiol Gastrointest Liver Physiol. 2001;280:G546–54.

    CAS  PubMed  Google Scholar 

  27. Murakami I, Hamada Y, Yamane S, Fujino H, Horie S, Murayama T. Nicotine-induced neurogenic relaxation in the mouse colon: changes with dextran sodium sulfate-induced colitis. J Pharmacol Sci. 2009;109:128–38.

    Article  CAS  PubMed  Google Scholar 

  28. Howes LG, James MJ, Florin T, Walker C. Nv-52: a novel thromboxane synthase inhibitor for the treatment of inflammatory bowel disease. Expert Opin Investig Drugs. 2007;16:1255–66.

    Article  CAS  PubMed  Google Scholar 

  29. Hirota Y, Suzuki M, Katsube N. Thromboxane A2 up-regulates neutrophil elastase release in Syrian hamsters with trinitrobenzene sulfonic acid-induced colitis. J Pharmacol Sci. 2005;98:430–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was performed with funding from the National Institute of Diabetes and Digestive and Kidney Diseases (P01DK043785-18; Project 2 plus Cores B and C).

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA

    Patsy R. Carter, Robert M. McElhatten, William S. Wright & Norman R. Harris

  2. Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    Songlin Zhang

Authors
  1. Patsy R. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert M. McElhatten
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Songlin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William S. Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norman R. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norman R. Harris.

Additional information

Responsible Editor: Ian Ahnfelt-Rønne.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carter, P.R., McElhatten, R.M., Zhang, S. et al. Thromboxane-prostanoid receptor expression and antagonism in dextran-sodium sulfate-induced colitis. Inflamm. Res. 60, 87–92 (2011). https://doi.org/10.1007/s00011-010-0240-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-010-0240-2

Keywords

Search

Navigation