Abstract
Objective
The aim of this study is to determine whether a changed expression ratio of PAR-1 and PAR-2 in the colon is associated with diarrhea-predominant IBS patients.
Methods
PAR-1, -2, thrombin, mast cell tryptase, tryptophan hydroxylase (TPH), and chromgranin A (ChrA) in colonic biopsy samples from 10 diarrhea-predominant IBS patients and 13 healthy control subjects were semiquantified with immunofluorescence and image analysis. Serotonin concentrations in biopsy samples were evaluated by capillary electrophoresis.
Results
Significantly lower expression of PAR-1 and higher expression of mast cell tryptase was detected in the colons of patients, with statistically unchanged expression of PAR-2. Thrombin-, TPH-, and ChrA-positive cells were markedly increased in IBS patients, but no significant difference in serotonin concentration existed in the colons between two groups. The ratio of PAR-1/PAR-2 expression was significantly decreased in patients (0.33 ± 0.19 versus 0.66 ± 0.22, P = 0.001) and negatively correlated to ChrA-positive cells.
Conclusions
Changed expression ratio of PAR-1 to PAR-2 in the colon is connected with diarrhea-predominant IBS patients. Methods to restore an appropriate balance of PAR-1 and PAR-2 activation in the colon may offer a promising future therapeutic strategy for IBS patients.
Similar content being viewed by others
References
Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome in general practice: prevalence, characteristics, and referral. Gut. 2000;46:78–82.
Foxx-Orenstein A. IBS—review and what’s new. Med Gen Med. 2006;8:20.
Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet. 2002;360:555–64.
Schwetz I, Bradesi S, Mayer EA. The pathophysiology of irritable bowel syndrome. Minerva Med. 2004;95:419–26.
Spiller RC. Irritable bowel syndrome. Br Med Bull. 2005;72:15–29.
Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001;280:G519–24.
Collins SM, Piche T, Rampal P. The putative role of inflammation in the irritable bowel syndrome. Gut. 2001;49:743–5.
Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA. 1999;96:11023–7.
Vergnolle N. Modulation of visceral pain and inflammation by protease-activated receptors. Br J Pharmacol. 2004;141:1264–74.
Noorbakhsh F, Vergnolle N, Hollenberg MD, Power C. Proteinase-activated receptors in the nervous system. Nat Rev Neurosci. 2003;4:981–90.
Coelho A, Bunnett NW. Intestinal activation of proteinase-activated receptor-1 (PAR1) reduces visceral nociception associated to rectal distension (RD) in rats. Gastroenterology 2003;124:A-1.
Asfaha S, Brussee V, Chapman K, Zochodne DW, Vergnolle N. Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli. Br J Pharmacol. 2002;135:1101–6.
Vergnolle N, Cellars L, Chapman K. Proteinase-activated receptor-1 agonists attenuate visceral pain. Gastroenterology 2003;124:A-252.
Hollenberg MD, Compton SJ. International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev. 2002;54:203–17.
Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, et al. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med. 2001;7:821–6.
Reed DE, Barajas-Lopez C, Cottrell G, Velazquez-Rocha S, Dery O, Grady EF, et al. Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons. J Physiol. 2003;547:531–42.
Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest. 2007;117:636–47.
Li Z, Zhang XJ, Xu HX, Sung JJY, Bian ZX. Intracolonical administration of protease-activated receptor-2 agonists produced visceral hyperalgesia by up-regulating serotonin in the colon of rats. Eur J Pharmacol. 2009;606(1–3):199–204.
Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology. 2007;132:397–414.
Grundy D. Serotonin and sensory signalling from the gastrointestinal lumen. J Physiol. 2006;575(Pt 1):1–2.
Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol. 2004;141:1285–93.
Spiller RC, Jenkins D, Thornley JP, Hebden JM, Wright T, Skinner M, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–11.
Crowell MD, Shetzline MA, Moses PL, Mawe GM, Talley NJ. Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function. Curr Opin Investig Drugs. 2004;5:55–60.
Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1067–76.
Miwa J, Echizen H, Matsueda K, Umeda N. Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits. Digestion. 2001;63:188–94.
Drossman DA, Corrazziari E, Delvaux M, Spiller RC, Talley NJ, Thompson WG, et al. Rome III: the functional gastrointestinal disorders diagnosis, pathophysiology, and treatment: a multinational consensus. Mclean, VA: Degnon Association; 2006.
Sjolund K, Sanden G, Hakanson R, Sundler F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology. 1983;85:1120–30.
Du M, Flanigan V, Ma Y. Simultaneous determination of polyamines and catecholamines in PC-12 tumor cell extracts by capillary electrophoresis with laser-induced fluorescence detection. Electrophoresis. 2004;25:1496–502.
Kawao N, Ikeda H, Kitano T, Kuroda R, Sekiquchi F, Kataoka K, et al. Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2. J Pharmacol Sci. 2004;94:277–85.
Coelho AM, Vergnolle N, Guiard B, Fioramonti J, Bueno L. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology. 2002;122:1035–47.
Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693–702.
Park JH, Rhee PL, Kim HS, Lee JH, Kim YH, Kim JJ, et al. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. J Gastroenterol Hepatol. 2006;21:71–8.
Kawabata A, Kawao N, Kuroda R, Tanaka A, Shimada C. The PAR-1-activating peptide attenuates carrageenan-induced hyperalgesia in rats. Peptides. 2002;23:1181–3.
Fang M, Kovacs KJ, Fisher LL, Larson AA. Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: possible mediation by endothelin. J Physiol. 2003;549:903–17.
Massi D, Naldini A, Ardinghi C, Carraro F, Franchi A, Paglierani M, et al. Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Hum Pathol. 2005;36:676–85.
MacNaughton WK. Epithelial effects of proteinase-activated receptors in the gastrointestinal tract. Mem Inst Oswaldo Cruz. 2005;100(Suppl 1):211–5.
Acknowledgments
This study was supported by grants from the Jockey Club Institute of Chinese Medicine, Hong Kong (JCICM-16-02), and Hong Kong Baptist University Faculty research Grant (FRG/06-07/II-72).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bian, Z.X., Li, Z., Huang, Z.X. et al. Unbalanced expression of protease-activated receptors-1 and -2 in the colon of diarrhea-predominant irritable bowel syndrome patients. J Gastroenterol 44, 666–674 (2009). https://doi.org/10.1007/s00535-009-0058-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-009-0058-2