Role for protease activity in visceral pain in irritable bowel syndrome
Nicolas Cenac, … , Eldon Shaffer, Nathalie Vergnolle
Nicolas Cenac, … , Eldon Shaffer, Nathalie Vergnolle
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):636-647. https://doi.org/10.1172/JCI29255.
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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 3

Tryptase immunoreactivity in rectal biopsies from control (A, D, and E) and IBS patients (B, C, and F).

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Tryptase immunoreactivity in rectal biopsies from control (A, D, and E) ...
Tryptase was mostly localized to cells found throughout the lamina propria (A–C) and around the base of rectal mucosal crypts (C). Some cells (e.g., C), had obvious processes at either the apical and/or basal poles, and often these cells displayed intense immunoreactivity compared with neighboring cells (images in B and C were taken under identical exposure conditions and reflect differences in intensity). Occasional tryptase-immunoreactive cells were found in the epithelium of both control (D) and IBS patients; these had the appearance of enteroendocrine cells, based on the obvious basolateral process. No differences were observed in the cell populations of IBS and control patients with respect to either the density of cells in rectal biopsies (G) or the intensity of immunoreactivity. Alcian blue–labeled mast cells in a control (E) and IBS patient (F). Note that the majority of tryptase-immunoreactive cells (e.g., B) have the size, shape, and cellular location of mast cells. Scale bars: 50 μm.