Increased mucosal thrombin is associated with Crohn's disease and causes inflammatory damage through Protease-Activated Receptors activation
| Autor: | Motta, Jean-Paul, Palese, Simone, Giorgio, Carmine, Chapman, Kevin, Denadai-Souza, Alexandre, Rousset, Perrine, Sagnat, David, Guiraud, Laura, Edir, Anissa, Seguy, Carine, Alric, Laurent, Bonnet, Delphine, Bournet, Barbara, Buscail, Louis, Gilletta, Cyrielle, Buret, Andre, Wallace, John, Hollenberg, Morley, Oswald, Eric, Barocelli, Elisabetta, Le Grand, Sylvie, Le Grand, Bruno, Deraison, Céline, Vergnolle, Nathalie |
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| Přispěvatelé: | Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CVasThera, University of Parma, University of Calgary, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées, Occitanie region grant ('contrat innovation' reference: DEI-SYNAPSE), MICILIP project (NCT01990716), cellular imaging facility TRI-CPTP, COLIC collection (DC-2015-2443), Alberta-Innovate Health Services (AIHS), FEDER funding (EU and Occitanie region: Nanorgan project), Antibe Therapeutics, UMS 006 (animal care facility, histopathology core facility), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), European Project: 310973,EC:FP7:ERC,ERC-2012-StG_20111109,PIPE(2013), European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), University of Parma = Università degli studi di Parma [Parme, Italie], SEGUIN, Nathalie, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Physiology of the Intestine: Proteases from the Epithelium - PIPE - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 310973 - VALID, AgreenSkills+ - AGREENSKILLSPLUS - - EC:FP7:PEOPLE2014-05-05 - 2019-05-04 - 609398 - VALID, Università degli studi di Parma = University of Parma (UNIPR), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
EXPRESSION [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Pyridines colitis Receptors Proteinase-Activated INHIBITION [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Lactones Mice Crohn Disease MARKERS [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] Animals Humans Rats Wistar AcademicSubjects/MED00260 Mice Inbred BALB C [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology Science & Technology Gastroenterology & Hepatology Thrombin protease-activated receptors [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Original Articles thrombin Rats Up-Regulation inflammation Case-Control Studies barrier Female ALPHA-THROMBIN epithelium BOWEL DISEASES Life Sciences & Biomedicine ELASTASE SYSTEM [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Journal of Crohn's and Colitis Journal of Crohn's and Colitis, Elsevier-Oxford University Press, 2020, ⟨10.1093/ecco-jcc/jjaa229⟩ Journal of Crohn's and Colitis, Elsevier-Oxford University Press, 2021, 15 (5), pp.787-799. ⟨10.1093/ecco-jcc/jjaa229⟩ Journal of Crohn's & Colitis Journal of Crohn's and Colitis, 2021, 15 (5), pp.787-799. ⟨10.1093/ecco-jcc/jjaa229⟩ |
| ISSN: | 1873-9946 1876-4479 |
| Popis: | BACKGROUND AND AIMS: Thrombin levels in the colon of Crohn's disease patients have recently been found to be elevated 100-fold compared with healthy controls. Our aim was to determine whether and how dysregulated thrombin activity could contribute to local tissue malfunctions associated with Crohn's disease. METHODS: Thrombin activity was studied in tissues from Crohn's disease patients and healthy controls. Intracolonic administration of thrombin to wild-type or protease-activated receptor-deficient mice was used to assess the effects and mechanisms of local thrombin upregulation. Colitis was induced in rats and mice by the intracolonic administration of trinitrobenzene sulphonic acid. RESULTS: Active forms of thrombin were increased in Crohn's disease patient tissues. Elevated thrombin expression and activity were associated with intestinal epithelial cells. Increased thrombin activity and expression were also a feature of experimental colitis in rats. Colonic exposure to doses of active thrombin comparable to what is found in inflammatory bowel disease tissues caused mucosal damage and tissue dysfunctions in mice, through a mechanism involving both protease-activated receptors -1 and -4. Intracolonic administration of the thrombin inhibitor dabigatran, as well as inhibition of protease-activated receptor-1, prevented trinitrobenzene sulphonic acid-induced colitis in rodent models. CONCLUSIONS: Our data demonstrated that increased local thrombin activity, as it occurs in the colon of patients with inflammatory bowel disease, causes mucosal damage and inflammation. Colonic thrombin and protease-activated receptor-1 appear as possible mechanisms involved in mucosal damage and loss of function and therefore represent potential therapeutic targets for treating inflammatory bowel disease. ispartof: JOURNAL OF CROHNS & COLITIS vol:15 issue:5 pages:787-799 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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