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Role for protease activity in visceral pain in irritable bowel syndrome

Cenac, N. ., Andrews, C. N., Holzhausen, M., Chapman, K., Cottrell, G. S., Andrade-Gordon, P., Steinhoff, M., Barbara, G., Beck, P., Bunnett, N. W., Sharkey, K. A., Ferraz, J. G., Shaffer, E. and Vergnolle, N. (2007) Role for protease activity in visceral pain in irritable bowel syndrome. The Journal of Clinical Investigation, 117 (3). pp. 636-647. ISSN 0021-9738

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To link to this item DOI: 10.1172/JCI29255

Abstract/Summary

Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30273
Uncontrolled Keywords:Abdominal Pain/*enzymology/etiology Adult Colon/enzymology/innervation/pathology Endopeptidases/analysis/drug effects/*physiology Female Humans Hyperalgesia/*enzymology/etiology Irritable Bowel Syndrome/*complications/enzymology/pathology Male Middle Aged NF-kappa B/metabolism Neurons, Afferent/drug effects/*metabolism Receptor, PAR-2/agonists Serine Proteinase Inhibitors/pharmacology Trypsin/analysis/drug effects/metabolism Tryptases/analysis/antagonists & inhibitors/metabolism alpha 1-Antitrypsin/analysis/metabolism
Additional Information:Cenac, Nicolas Andrews, Christopher N Holzhausen, Marinella Chapman, Kevin Cottrell, Graeme S Andrade-Gordon, Patricia Steinhoff, Martin Barbara, Giovanni Beck, Paul Bunnett, Nigel W Sharkey, Keith A Ferraz, Jose Geraldo P Shaffer, Eldon Vergnolle, Nathalie DK43207/DK/NIDDK NIH HHS/ DK57480/DK/NIDDK NIH HHS/ J Clin Invest. 2007 Mar;117(3):636-47. Epub 2007 Feb 15.
Publisher:American Society for Clinical Investigation

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