J Clin Invest. 2007 Feb 15; [Epub ahead of print]
Role for protease activity in visceral pain in irritable bowel syndrome.
Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, Steinhoff M, Barbara G, Beck P, Bunnett NW, Sharkey KA, Ferraz JG, Shaffer E, Vergnolle N.
Department of Pharmacology and Therapeutics and Department of Medicine, Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada. Departments of Surgery and Physiology, UCSF, San Francisco, California, USA. R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA. Department of Dermatology and Interdisciplinary Center for Clinical Research (IZKF) Munster, University of Munster, Munster, Germany. Departments of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy. Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
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 (PAR(2)). 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 PAR(2) antagonist and were absent in PAR(2)-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 PAR(2).
PMID: 17304351 [PubMed - as supplied by publisher]