Role for protease activity in visceral pain in irritable bowel syndrome

Nicolas Cenac, Christopher Andrews, Marinella Holzhausen, Kevin Chapman, Graeme Cottrell, Patricia Andrade-Gordon, Martin Steinhoff, Giovanni Barbara, Paul Beck, Nigel Bunnett, Keith Sharkey, Jose Ferraz, Eldon Shaffer, Nathalie Vergnolle

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452 Citations (Scopus)

Abstract

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-I?B. 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 receptora??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.
Original languageEnglish
Pages (from-to)636 - 647
Number of pages12
JournalJournal of Clinical Investigation
Volume117
Issue number3
DOIs
Publication statusPublished - 2007

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