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Role for protease activity in visceral pain in irritable bowel syndrome
Open accessAbstract
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.
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“However, some studies failed to demonstrate increased activated mast cells in IBS patients (35, 36, 57, 58, 168) and there are no consistent differences in the tissue concentrations of activated mast cells in patients with different IBS subtypes (36, 189).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [35]
In the citing paper
“Other studies have reported elevated levels of histamine and tryptase release in patients with IBS compared with controls (11, 13, 35, 73).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [35]
In the citing paper
“For example, Trypsin-like activity and tryptase release are increased in colonic biopsies from IBS patients.7,58”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [58]
In the citing paper
“Similar to IBD, studies in mice and humans have provided evidence that host- and bacterial-derived proteases may contribute to pathogenesis and symptom generation.7,13,57,58”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [58]
In the citing paper
“Biopsy supernatants from IBS patients have also been shown to excite spinal afferent neurons via PAR-2 activation.7,58,155”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [58]
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Tryptase and Protease-Activated Receptor 2 Expression Levels in Irritable Bowel Syndrome
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Self-citationQuarter-Century Explorations of Bioactive Polyphenols: Diverse Health Benefits
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“FUT175 (6-amidino-2-naphthyl 4-guanidino-benzoate) consistent with PAR-deficiency eases IBD/IBS [142].”
The gut–brain axis and pain signalling mechanisms in the gastrointestinal tract
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Traditional Thoughts on the Pathophysiology of Irritable Bowel Syndrome
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Role of transient receptor potential vanilloid 4 in rat joint inflammation
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Self-citationWhat does irritable bowel syndrome share with non-alcoholic fatty liver disease?
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“Moreover, IBS supernatants activate visceral sensory neurons in rodent dorsal root ganglia (DRG; Barbara et al. 2007; Cenac et al. 2007; Cremon et al. 2011) and induced somatic and visceral hypersensitivity in mice (Cenac et al. 2007).”
BackgroundInfluentialTryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome
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“There is accumulating evidence that inflammatory cells, such as mast cells, can influence nociceptive signaling via tryptase, a PAR2 agonist [5,6,15].”
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“Mast cells have been widely studied in IBS and results showed that their number was enhanced and that they were effectively activated, leading to the generation of visceral hypersensitivity and acute abdominal pain (22-24).”
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“research group postulated a role for proteases in mediating visceral hypersensitivity.(45) Subsequent studies have supported this theory.”
BackgroundExisting and Emerging Therapies for Managing Constipation and Diarrhea
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“In animal models of visceral hypersensitivity, PAR-2 antagonists and a PAR-4 agonist reversed colonic visceral hypersensitivity induced by supernatants from colonic biopsies from IBS patients.[39,40] Perhaps proteases such as trypsin 3 released from the epithelium of IBS patients activated sensory nerve endings.”
BackgroundAssessment of the association between Blastocystis infection and irritable bowel syndrome.
Surangsrirat, S., Thamrongwittawatpong, L., Piyaniran, W., Naaglor, T., Khoprasert, C., Taamasri, P., Mungthin, M., & Leelayoova, S. (2010) · PubMed · Cited by 46
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“PAR activation is known to modulate inflammatory processes and there are some data concerning its significance in pain processing (Vergnolle et al., 2001a; Cenac et al., 2007), but the role of PARs in arthritis and related pain has not been clearly and thoroughly elucidated.”
BackgroundActivity of Protease-Activated Receptors in the Human Submucous Plexus
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“…studies have indicated a pro-inflammatory role for PAR2 activation in the development of arthritis (Ferrell et al., 2003; Busso et al., 2007), colitis (Cenac et al., 2007; Hyun et al., 2008), and other chronic diseases (Schmidlin et al., 2002; Noorbakhsh et al., 2006; Sokolova and Reiser, 2007).”
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“exogenous proteases of any organ system, and recent work has demonstrated a protease/anti-protease balance in the pathology of inflammatory bowel diseases, intestinal allergies, or pancreatitis (93, 94), notably mediated by PAR signaling (26, 69).”
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“Considerable evidence documents that sensitizing proinflammatory mediators, mast cells and their products, tryptases, are increased in tissues of patients with colorectal hypersensitivity (Cenac et al., 2007; Balestra et al., 2012; Buhner et al., 2012).”
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“Proteolytic activity via activation of PAR2 is suggested to be responsible for visceral hypersensitivity in both IBD (Vergnolle, 2005) and IBS (Cenac et al., 2007).”
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“and their functional relevance is underscored in bioassay experiments.”
BackgroundSelf-citationCalcium Imaging of Nerve-Mast Cell Signaling in the Human Intestine
Bühner, S., Barki, N., Greiter, W., Giesbertz, P., Demir, İ. E., Ceyhan, G. O., Zeller, F., Daniel, H., & Schemann, M. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00971 · Cited by 37
“Having said that, a MC to nerve signaling may be more prominent in disease states like IBS or IBD where the number and/or the reactivity of MCs in close proximity to nerves is increased (Raithel et al., 2001; Barbara et al., 2004, 2007; Cenac et al., 2007; Guilarte et al., 2007).”
BackgroundProfiling of how nociceptor neurons detect danger – new and old foes
Crosson, T., Roversi, K., Balood, M., Othman, R., Ahmadi, M., Wang, J.-C., Pereira, P. J. S., Tabatabaei, M., Couture, R., Eichwald, T., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12957 · Cited by 37
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“Proteases can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2 (Cenac et al., 2007), and stimulation of PAR2 produces visceral hyperalgesia that is mediated by TRPV4 (Cenac et al., 2008).”
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“Future studies could investigate the detailed expression of PAR2 with this fluorescent probe at different time points after its intraluminal administration and correlate these observations with the appearance of pathophysiological features, such as altered smooth muscle contractility, enteric nervous system activation…”
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“This innovative approach has arisen as a powerful paradigm for investigating the mechanisms of peripheral nociception in both mice and human patients (Barbara et al., 2004; Cenac et al., 2007; Akbar et al., 2008).”
Hansen, K. K., Οικονομοπούλου, Κ., Yang, L., & Hollenberg, M. D. (2007) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-007-0194-2 · Cited by 35
“Others have also identified serine proteinases in the settings of IBD and IBS (Cenac et al. 2007).”
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“These mediators act on intestinal epithelial cells, and influence the expression and localization of TJ proteins, resulting in increased intestinal permeability and intestinal barrier dysfunction (Ferrier et al., 2003; Cenac et al., 2007; Coëffier et al., 2010).”
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They Must Hold Tight: Junction Proteins, Microbiota And Immunity In Intestinal Mucosa
Castoldi, Â., de Aguiar, C. F., Moraes‐Vieira, P. M., & Câmara, N. O. S. (2015) · Current Protein and Peptide Science · doi:10.2174/1389203716666150630133141 · Cited by 33
Ochoa‐Cortés, F., Alba, R. G., Valdez-Moráles, E. E., Spreadbury, I., Barajas‐López, C., Castro, M., Bertrand‐Michel, J., Cénac, N., Vergnolle, N., & Vanner, S. J. (2013) · Neurogastroenterology & Motility · doi:10.1111/nmo.12268 · Cited by 34
Self-citationSerine Protease Inhibition Reduces Post-Ischemic Granulocyte Recruitment in Mouse Intestine
Gobbetti, T., Cénac, N., Motta, J., Rolland, C., Martin, L., Andrade‐Gordon, P., Steinhoff, M. S., Barocelli, E., & Vergnolle, N. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.09.031 · Cited by 34
Self-citationPAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells
Nasri, I., Bonnet, D., Zwarycz, B., d'Aldebert, E., Khou, S., Jarraya, R. M., Quaranta, M., Rolland, C., Bonnart, C., Mas, E., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00328.2015 · Cited by 34
“Also, IBD- and CRC-derived tissues exhibit increased proteolytic activities of proteases such as thrombin and matrix metalloprotease 1 that activate PAR1 and trypsin-like serine proteases, tissue factor, and matriptase, which activate PAR2 (9, 47).”
Self-citationEditorial: Abnormal Immune Regulation and Low-Grade Inflammation in IBS: Does One Size Fit All?
Schmulson, M. J., & Chey, W. D. (2012) · The American Journal of Gastroenterology · doi:10.1038/ajg.2011.427 · Cited by 34
Takahashi, K., Khwaja, I., Schreyer, J. R., Bulmer, D. C., Peiris, M., Terai, S., & Aziz, Q. (2021) · Crohn s & Colitis 360 · doi:10.1093/crocol/otab073 · Cited by 33
O’Malley, D., Dinan, T. G., & Cryan, J. F. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.04.003 · Cited by 33
“As previously described (Cenac et al., 2007), 3 cm segments of full thickness distal colon from male SD and WKY rats were bubbled in 2 ml of Hanks Buffered Saline Solution (HBSS, 1 h, 37 °C).”
Mechanisms Underlying Food-Triggered Symptoms in Disorders of Gut-Brain Interactions
den Houte, K. V., Berčík, P., Simrén, M., Tack, J. F., & Vanner, S. J. (2022) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000001812 · Cited by 40
Aluminum Ingestion Promotes Colorectal Hypersensitivity in Rodents
Esquerre, N., Basso, L., Dubuquoy, C., Djouina, M., Chappard, D., Blanpied, C., Desreumaux, P., Vergnolle, N., Vignal, C., & Body–Malapel, M. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.09.012 · Cited by 35
“Ten-second distensions were performed at pressures of 15, 30, 45, and 60 mm Hg acquired by inflating the balloon in a stepwise fashion with water (20, 40, 60 and 80 mL respectively) with 5-min rest intervals.(51) Electromyographic activity of the abdominal muscles was recorded and visceromotor responses were calculate…”
MethodSelf-citationProtease activated receptor 4 status of mast cells in post infectious irritable bowel syndrome
Han, W., Zhimin, W. A. N. G., Lu, X. F., & Guo, C. (2011) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2011.01841.x · Cited by 32
Protease-Activated Receptors as Therapeutic Targets in Visceral Pain
Cénac, N. (2013) · Current Neuropharmacology · doi:10.2174/1570159x113119990039 · Cited by 32
“Neurons from PAR2-deficient mice failed to respond to those supernatants, and PAR2-deficient mice did not develop hypersensitivity symptoms when administered with supernatants from IBS patient biopsies [38].”
BackgroundMethodInfluentialZhang, R., Zou, N., Li, J., Lv, H., Wei, J., Fang, X., & Qian, J. (2011) · International Journal of Colorectal Disease · doi:10.1007/s00384-011-1153-4 · Cited by 32
“Soluble factors released from colonic mucosal specimens of IBS patients activate visceral afferent neurons and induce visceral hypersensitivity in rats [7] and mice [8].”
BackgroundSerine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Cζ
Swystun, V. A., RENAUX, B. S., Moreau, F., Wen, S., Peplowski, M. A., Hollenberg, M. D., & MacNaughton, W. K. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00096.2009 · Cited by 32
“Indeed, a strong case has been made implicating the increased release of trypsin and tryptase (with no change in an endogenous serine protease inhibitor) from colonic biopsies of patients with irritable bowel syndrome in the visceral pain associated with the disease (9).”
BackgroundTargeting G protein-coupled receptors for the treatment of chronic pain in the digestive system
Gottesman-Katz, L., Latorre, R., Vanner, S. J., Schmidt, B. L., & Bunnett, N. W. (2020) · Gut · doi:10.1136/gutjnl-2020-321193 · Cited by 31
Self-citationG-protein–coupled receptors are dynamic regulators of digestion and targets for digestive diseases
Canals, M., Poole, D. P., Veldhuis, N. A., Schmidt, B. L., & Bunnett, N. W. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.01.266 · Cited by 35
Self-citationFagundes, J. A. G., Monoo, L. D., Alves, V. T. E., Pannuti, C. M., Cortelli, S. C., Cortelli, J. R., & Holzhausen, M. (2011) · Journal of Periodontology · doi:10.1902/jop.2011.110073 · Cited by 31
Self-citationLee, M. J., Jung, H., Lee, K. E., Mun, Y., & Park, S. (2019) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm18176 · Cited by 31
Proteinase-activated receptors (PARs) in infection and inflammation in the gut
Vergnolle, N. (2008) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2008.01.016 · Cited by 31
Self-citationEpithelial–Neuronal Communication in the Colon: Implications for Visceral Pain
Najjar, S. A., Davis, B. M., & Albers, K. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2019.12.007 · Cited by 32
“These supernatants also induce visceral hypersensitivity in mice, but not in the presence of a protease-activated receptor-2 (PAR2) antagonist or in PAR2-deficient mice [93].”
BackgroundProteinases as hormones: targets and mechanisms for proteolytic signaling
Hansen, K. K., Οικονομοπούλου, Κ., Baruch, A., Ramachandran, R., Beck, P. L., Diamandis, E. P., & Hollenberg, M. D. (2008) · Biological Chemistry · doi:10.1515/bc.2008.120 · Cited by 31
“, 1997) and with inflammatory bowel syndrome (Cenac et al., 2007).”
BackgroundSelf-citationIBS and the role of otilonium bromide
Boeckxstaens, G. E., Corazziari, E. S., Mearin, F., & Tack, J. F. (2012) · International Journal of Colorectal Disease · doi:10.1007/s00384-012-1598-0 · Cited by 30
“For example, the supernatants of mucosal biopsies of IBS patients activated rat mesenteric afferent nerves in vitro [36] and activated sensory neurons and induced visceral hypersensitivity in mice when applied intracolonically [39].”
BackgroundJalili, M., Vahedi, H., Poustchi, H., & Hekmatdoost, A. (2019) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2019.09.003 · Cited by 30
Cattaruzza, F., Amadesi, S., Carlsson, J., Murphy, J. E., Lyo, V., Kirkwood, K. S., Cottrell, G. S., Bogyo, M. S., Knecht, W., & Bunnett, N. W. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12738 · Cited by 30
“…algesic actions of diverse stimulants Serine and cysteine proteases can cause neurogenic inflammation and pain by activating PAR2 on nociceptive neurons (Steinhoff et al., 2000; Vergnolle et al., 2001; Cenac et al., 2002; 2007; Ferrell et al., 2003; Lam and Schmidt, 2010; Cattaruzza et al., 2011).”
BackgroundInfluentialSelf-citationPeripheral relays in stress-induced activation of visceral afferents in the gut
van den Wijngaard, R. M., Klooker, T. K., de Jonge, W. J., & Boeckxstaens, G. E. (2009) · Autonomic Neuroscience · doi:10.1016/j.autneu.2009.07.004 · Cited by 30
Zhao, J., Dong, L., Shi, H., Wang, Z.-Y., Shi, H., & Ding, H. (2011) · Digestive Diseases and Sciences · doi:10.1007/s10620-011-1827-3 · Cited by 29
“In IBS patients, proteases are released in the colon and which can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2 [9].”
Pathophysiological roles of proteases in gastrointestinal disease
Edgington‐Mitchell, L. E. (2015) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00393.2015 · Cited by 29
Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota
Guarino, M. P. L., Cicala, M., Putignani, L., & Severi, C. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i45.9871 · Cited by 29
Guilarte, M., Vicario, M., Martínez, C., de Torres, I., Lobo, B., Pigrau, M., González-Castro, A., Rodiño-Janeiro, B., Salvo-Romero, E., Fortea, M., et al. (2020) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000789 · Cited by 28
Maeda, S., Ohno, K., Uchida, K., Igarashi, H., Goto‐Koshino, Y., Fujino, Y., & Tsujimoto, H. (2014) · Journal of Veterinary Medical Science · doi:10.1292/jvms.14-0060 · Cited by 29
“Furthermore, the PAR-2 activators trypsin and tryptase are present at elevated levels in the colons of human patients with IBD [2, 3, 9, 35].”
BackgroundThe Role of Visceral Afferents in Disease
Christianson, J. A., & Davis, B. M. (2009) · Frontiers in neuroscience · doi:10.1201/9781439812105-c3 · Cited by 28
The enteric nervous system: “A little brain in the gut”
Annaházi, A., & Schemann, M. (2020) · e-Neuroforum · doi:10.1515/nf-2019-0027 · Cited by 30
“In line with these findings, biopsy samples from the colon or rectum of IBS patients released proteases with 2 to 3 fold higher activity than biopsies from controls, and these biopsy supernatants with elevated protease activity caused hyperalgesia and allodynia in response to colorectal distension after intracolonic i…”
BackgroundResultProtease Activated Receptors and Arthritis
Lucena, F., & McDougall, J. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179352 · Cited by 28
Coagulation factor Xa signaling: the link between coagulation and inflammatory bowel disease?
Borensztajn, K., Peppelenbosch, M. P., & Spek, C. A. (2008) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2008.10.007 · Cited by 28
Bian, Z. X., Li, Z., Huang, Z. X., Zhang, M., Chen, H. L., Xu, H., & Sung, J. J. �. (2009) · Journal of Gastroenterology · doi:10.1007/s00535-009-0058-2 · Cited by 28
“In IBS patients, proteases could be released that stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR-2 [17].”
BackgroundLower gastrointestinal functions
Bharucha, A. E. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2008.01111.x · Cited by 28
Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome
Remoortel, S. V., Hussein, H., & Boeckxstaens, G. E. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101780 · Cited by 27
“30,36 Similarly, IBS supernatant induces increased activation of human submucosal neurons compared to healthy supernatant, an effect mediated by histamine, serotonin, and proteases, further indicating that increased presence of these mediators in the IBS microenvironment plays a direct role in…”
BackgroundInfluentialRocha, H. L. D. A., Dantas, B. P. V., Wanderley, T. L. R., Costa, B. A., & de Medeiros, A. C. (2014) · PubMed Central · Cited by 27
Uhlig, F., Grundy, L., Garcia‐Caraballo, S., Brierley, S. M., Foster, S. J., & Grundy, D. (2020) · iScience · doi:10.1016/j.isci.2020.101695 · Cited by 26
Metadata
- Authors
- Cenac, N., Andrews, C. N., Holzhausen, M., Chapman, K., Cottrell, G., Andrade-Gordon, P., Steinhoff, M., Barbara, G., Beck, P., Bunnett, N. W., Sharkey, K. A., Ferraz, J. G. P., Shaffer, E., & Vergnolle, N.
- Affiliations
- University of Calgary (CA)
- University of California, San Francisco (US)
- University of Münster (DE)
- University of Bologna (IT)
- Corresponding author
- Vergnolle, Nathalie
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-03-01
- Volume
- 117
- Issue
- 3
- Pages
- 636-647
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1794118
- OpenAlex
- W2140528350
- Cited by
- 591
- References
- 66
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 22 · 2023: 19 · 2022: 21 · 2021: 24 · 2020: 26 · 2019: 27 · 2018: 25 · 2017: 32 · 2016: 37 · 2015: 28 · 2014: 36 · 2013: 38 · 2012: 41
- FWCI
- 39.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Crohn's and Colitis Foundation
- Crohn's and Colitis Foundation of Canada
- Canadian Association of Gastroenterology
- Fondation pour la Recherche Médicale
- Alberta Heritage Foundation for Medical Research
- National Institutes of Health (DK43207, DK57480)
- Canadian Institutes of Health Research (DK43207)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 43207, R01DK043207, DK-57480, R56DK043207)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, visceral pain, proteolytic activity, NF-κB, trypsin, tryptase, protease-activated receptor 2, sensory neuron sensitization, visceral hypersensitivity, allodynia, serine protease inhibitors, colonic biopsy
- MeSH terms
- Adult, alpha 1-Antitrypsin, Colon, Female, Humans, Hyperalgesia, Male, Middle Aged, Neurons, Afferent, Endopeptidases, Trypsin, Abdominal Pain, Serine Proteinase Inhibitors, NF-kappa B, Irritable Bowel Syndrome, Receptor, PAR-2, Tryptases
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