Role for protease activity in visceral pain in irritable bowel syndrome
Nicolas Cenac, Christopher N. Andrews, Marinella Holzhausen, Kevin Chapman, Graeme Cottrell, Patricia Andrade-Gordon, Martin Steinhoff, Giovanni Barbara, Paul Beck, Nigel W. Bunnett, Keith A. Sharkey, Jose Geraldo P. Ferraz, Eldon Shaffer, Nathalie Vergnolle
Nicolas Cenac, Christopher N. Andrews, Marinella Holzhausen, Kevin Chapman, Graeme Cottrell, Patricia Andrade-Gordon, Martin Steinhoff, Giovanni Barbara, Paul Beck, Nigel W. Bunnett, Keith A. Sharkey, Jose Geraldo P. Ferraz, Eldon Shaffer, Nathalie Vergnolle
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Research Article Neuroscience

Role for protease activity in visceral pain in irritable bowel syndrome

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-κB. 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.

Authors

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

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Figure 6

Visceral sensitivity in response to human colonic biopsy supernatants.

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Visceral sensitivity in response to human colonic biopsy supernatants. R...
Recordings of mouse abdominal muscle contraction in response to colorectal distension before (control) or 6 hours after intracolonic administration of ascending colon biopsy supernatants from IBS patients (A and B) or control patients (filled triangles in C). (A) Representative traces of mouse abdominal muscle contractions in response to 60 mmHg colorectal distension, in PAR2+/+ or PAR2–/– mice before (control) or after intracolonic (i.c.) administration of IBS ascending colon biopsy supernatant alone or in combination with the protease inhibitor FUT or a PAR2 antagonist. (B) Abdominal contraction responses to different pressures of distension (15–60 mmHg) before (time 0) or after intracolonic administration of IBS patient ascending colon biopsy supernatants. Data are mean ± SEM; n = 8. *P < 0.05, **P < 0.01, ***P < 0.005 compared with basal (time 0) measurements. (C) Mouse abdominal contraction response to increasing pressures of distension in PAR2+/+ or PAR2–/– mice before (control distension) or 6 hours after intracolonic administration of IBS biopsy supernatants (filled squares) alone or in combination with the protease inhibitor FUT or a PAR2 antagonist or after the intracolonic administration of biopsy supernatants from control patients (filled triangles). Data are mean ± SEM; n = 12 for the biopsy supernatants from control patients; n = 18 for IBS biopsy supernatants. *P < 0.05, **P < 0.01, ***P < 0.005 compared with control distension. For all data in this figure, biopsies were collected from the ascending colon.