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1
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Vergnolle N. Thrombin stories in the gut. Biochimie 2024; 226:107-112. [PMID: 38521125 DOI: 10.1016/j.biochi.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/11/2024] [Accepted: 03/14/2024] [Indexed: 03/25/2024]
Abstract
Many studies have demonstrated the involvement of proteases in gut physiology and pathophysiology over the recent years. Among them, thrombin has appeared for a long time as an old player only involved in blood clotting upon tissue injury. The fact that thrombin receptors (Protease-Activated Receptors-1 and -4) are expressed and functional in almost all cell types of the gut, contributing to barrier, immune or motility functions, suggested that thrombin could actually be at the crossroad of intestinal physiology. Recent work has unraveled the constitutive release of active thrombin by intestinal epithelial cells, opening new research avenues on the role of thrombin in the gut. These roles are considered in the present review, as well as the regulation of thrombin in the gut. The potential of thrombin as a target for treatments of intestinal pathologies is also discussed here.
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Affiliation(s)
- Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS), CS60039, Toulouse, Cedex 03, 31024, France; Department of Physiology & Pharmacology, University of Calgary Cumming School of Medicine, 3330 Hospital Drive NW, Calgary, Ab T2N 4N1, Canada.
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2
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Jannati S, Patnaik R, Banerjee Y. Beyond Anticoagulation: A Comprehensive Review of Non-Vitamin K Oral Anticoagulants (NOACs) in Inflammation and Protease-Activated Receptor Signaling. Int J Mol Sci 2024; 25:8727. [PMID: 39201414 PMCID: PMC11355043 DOI: 10.3390/ijms25168727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/20/2024] [Accepted: 07/22/2024] [Indexed: 09/02/2024] Open
Abstract
Non-vitamin K oral anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs-apixaban, rivaroxaban, edoxaban, and dabigatran-not only as anticoagulants, but also as modulators of inflammation via protease-activated receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as factor Xa (FXa) and thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles, but also paves the way for future research and clinical applications in inflammation and cardiovascular health.
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Affiliation(s)
- Shirin Jannati
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
| | - Rajashree Patnaik
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
| | - Yajnavalka Banerjee
- Yajnavalkaa Banerrji Research Group, College of Medicine and Health Sciences, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Health, Dubai P.O. Box 505055, United Arab Emirates; (S.J.); (R.P.)
- Centre for Medical Education, University of Dundee, Dundee DD1 4HN, UK
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3
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Deraison C, Bonnart C, Langella P, Roget K, Vergnolle N. Elafin and its precursor trappin-2: What is their therapeutic potential for intestinal diseases? Br J Pharmacol 2023; 180:144-160. [PMID: 36355635 PMCID: PMC10098471 DOI: 10.1111/bph.15985] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/22/2022] [Accepted: 05/07/2022] [Indexed: 11/12/2022] Open
Abstract
Elafin and its precursor trappin-2 are known for their contribution to the physiological mucosal shield against luminal microbes. Such a contribution seems to be particularly relevant in the gut, where the exposure of host tissues to heavy loads of microbes is constant and contributes to mucosa-associated pathologies. The expression of trappin-2/elafin has been shown to be differentially regulated in diseases associated with gut inflammation. Accumulating evidence has demonstrated the protective effects of trappin-2/elafin in gut intestinal disorders associated with acute or chronic inflammation, or with gluten sensitization disorders. The protective effects of trappin-2/elafin in the gut are discussed in terms of their pleiotropic modes of action: acting as protease inhibitors, transglutaminase substrates, antimicrobial peptides or as a regulator of pro-inflammatory transcription factors. Further, the question of the therapeutic potential of trappin-2/elafin delivery at the intestinal mucosa surface is raised. Whether trappin-2/elafin mucosal delivery should be considered to ensure intestinal tissue repair is also discussed.
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Affiliation(s)
- Céline Deraison
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS), Toulouse, France
| | - Chrystelle Bonnart
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS), Toulouse, France
| | - Philippe Langella
- Université Paris-Saclay, AgroParisTech, Micalis Institute, INRAE, Jouy-en-Josas, France
| | | | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRAE, ENVT, Univ Toulouse III - Paul Sabatier (UPS), Toulouse, France.,Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
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4
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Zhuo X, Wu Y, Fu X, Liang X, Xiang Y, Li J, Mao C, Jiang Y. The Yin‐Yang roles of protease‐activated receptors in inflammatory signalling and diseases. FEBS J 2022; 289:4000-4020. [DOI: 10.1111/febs.16406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/26/2022] [Accepted: 02/15/2022] [Indexed: 12/15/2022]
Affiliation(s)
- Xin Zhuo
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Yue Wu
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Xiujuan Fu
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Xiaoyu Liang
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Yuxin Xiang
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Jianbin Li
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Canquan Mao
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
| | - Yuhong Jiang
- School of Life Science and Engineering Southwest Jiaotong University Chengdu China
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5
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Jacenik D, Fichna J, Małecka-Wojciesko E, Mokrowiecka A. Protease-Activated Receptors - Key Regulators of Inflammatory Bowel Diseases Progression. J Inflamm Res 2022; 14:7487-7497. [PMID: 35002281 PMCID: PMC8721023 DOI: 10.2147/jir.s335502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis and course of inflammatory bowel diseases are related to both immune system disorders and dysfunction of colon permeability. Moreover, co-existing diseases in patients with Crohn's disease and ulcerative colitis are identified. Currently, there are some therapeutic strategies that affect the function of cytokine/s causing inflammation in the intestinal wall. However, additional approaches which target other components of inflammatory bowel diseases pathogenesis are still needed. Accumulating evidence suggests that proteases and protease-activated receptors seem to be responsible for colitis progression. Experimental and observational studies showed alteration of protease-activated receptors expression in the colon of patients with Crohn's disease and ulcerative colitis. Furthermore, it was suggested that the expression of protease-activated receptors correlated with inflammatory bowel diseases activity. Moreover, regulation of protease-activated receptors seems to be responsible for the modulation of colitis and clinical manifestation of inflammatory bowel diseases. In this review, we present the current state of knowledge about the contribution of protease-activated receptors to Crohn's disease and ulcerative colitis and its implications for diagnosis and treatment.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Anna Mokrowiecka
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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6
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Role of proteinase-activated receptors 1 and 2 in nonsteroidal anti-inflammatory drug enteropathy. Pharmacol Rep 2020; 72:1347-1357. [DOI: 10.1007/s43440-020-00119-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022]
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7
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Kriaa A, Jablaoui A, Mkaouar H, Akermi N, Maguin E, Rhimi M. Serine proteases at the cutting edge of IBD: Focus on gastrointestinal inflammation. FASEB J 2020; 34:7270-7282. [PMID: 32307770 DOI: 10.1096/fj.202000031rr] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/27/2020] [Accepted: 03/28/2020] [Indexed: 12/15/2022]
Abstract
Serine proteases have been long recognized to coordinate many physiological processes and play key roles in regulating the inflammatory response. Accordingly, their dysregulation has been regularly associated with several inflammatory disorders and suggested as a central mechanism in the pathophysiology of digestive inflammation. So far, studies addressing the proteolytic homeostasis in the gut have mainly focused on host serine proteases as candidates of interest, while largely ignoring the potential contribution of their bacterial counterparts. The human gut microbiota comprises a complex ecosystem that contributes to host health and disease. Yet, our understanding of microbially produced serine proteases and investigation of whether they are causally linked to IBD is still in its infancy. In this review, we highlight recent advances in the emerging roles of host and bacterial serine proteases in digestive inflammation. We also discuss the application of available tools in the gut to monitor disease-related serine proteases. An exhaustive representation and understanding of such functional potential would help in closing existing gaps in mechanistic knowledge.
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Affiliation(s)
- Aicha Kriaa
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
| | - Amin Jablaoui
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
| | - Héla Mkaouar
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
| | - Nizar Akermi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
| | - Emmanuelle Maguin
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
| | - Moez Rhimi
- Microbiota Interaction with Human and Animal Team (MIHA), Micalis Institute, AgroParisTech, Université Paris-Saclay, INRAE, Jouy-en-Josas, France
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8
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Boucher AA, Rosenfeldt L, Mureb D, Shafer J, Sharma BK, Lane A, Crowther RR, McKell MC, Whitt J, Alenghat T, Qualls J, Antoniak S, Mackman N, Flick MJ, Steinbrecher KA, Palumbo JS. Cell type-specific mechanisms coupling protease-activated receptor-1 to infectious colitis pathogenesis. J Thromb Haemost 2020; 18:91-103. [PMID: 31539206 PMCID: PMC7026906 DOI: 10.1111/jth.14641] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 08/29/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Protease-activated receptor-1 (PAR-1) plays a major role in multiple disease processes, including colitis. Understanding the mechanisms coupling PAR-1 to disease pathogenesis is complicated by the fact that PAR-1 is broadly expressed across multiple cell types. OBJECTIVE Determine the specific contributions of PAR-1 expressed by macrophages and colonic enterocytes to infectious colitis. METHODS Mice carrying a conditional PAR-1 allele were generated and bred to mice expressing Cre recombinase in a myeloid- (PAR-1ΔM ) or enterocyte-specific (PAR-1ΔEPI ) fashion. Citrobacter rodentium colitis pathogenesis was analyzed in mice with global PAR-1 deletion (PAR-1-/- ) and cell type-specific deletions. RESULTS Constitutive deletion of PAR-1 had no significant impact on weight loss, crypt hypertrophy, crypt abscess formation, or leukocyte infiltration in Citrobacter colitis. However, colonic shortening was significantly blunted in infected PAR-1-/- mice, and these animals exhibited decreased local levels of IL-1β, IL-22, IL-6, and IL-17A. In contrast, infected PAR-1ΔM mice lost less weight and had fewer crypt abscesses relative to controls. PAR-1ΔM mice had diminished CD3+ T cell infiltration into colonic tissue, but macrophage and CD4+ T cell infiltration were similar to controls. Also contrasting results in global knockouts, PAR-1ΔM mice exhibited lower levels of IL-1β, but not Th17-related cytokines (ie, IL-22, IL-6, IL-17A). Infected PAR-1ΔEPI mice exhibited increased crypt hypertrophy and crypt abscess formation, but local cytokine elaboration was similar to controls. CONCLUSIONS These studies reveal complex, cell type-specific roles for PAR-1 in modulating the immune response to Citrobacter colitis that are not readily apparent in analyses limited to mice with global PAR-1 deficiency.
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Affiliation(s)
- Alexander A. Boucher
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Leah Rosenfeldt
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Duaa Mureb
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jessica Shafer
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Bal Krishan Sharma
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Adam Lane
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rebecca R. Crowther
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Melanie C. McKell
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
- Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jordan Whitt
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Joseph Qualls
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Silvio Antoniak
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Nigel Mackman
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Matthew J. Flick
- Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kris A. Steinbrecher
- Division of Gastroenterology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Joseph S. Palumbo
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
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9
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Pontarollo G, Mann A, Brandão I, Malinarich F, Schöpf M, Reinhardt C. Protease-activated receptor signaling in intestinal permeability regulation. FEBS J 2019; 287:645-658. [PMID: 31495063 DOI: 10.1111/febs.15055] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 08/01/2019] [Accepted: 09/03/2019] [Indexed: 12/11/2022]
Abstract
Protease-activated receptors (PARs) are a unique class of G-protein-coupled transmembrane receptors, which revolutionized the perception of proteases from degradative enzymes to context-specific signaling factors. Although PARs are traditionally known to affect several vascular responses, recent investigations have started to pinpoint the functional role of PAR signaling in the gastrointestinal (GI) tract. This organ is exposed to the highest number of proteases, either from the gut lumen or from the mucosa. Luminal proteases include the host's digestive enzymes and the proteases released by the commensal microbiota, while mucosal proteases entail extravascular clotting factors and the enzymes released from resident and infiltrating immune cells. Active proteases and, in case of a disrupted gut barrier, even entire microorganisms are capable to translocate the intestinal epithelium, particularly under inflammatory conditions. Especially PAR-1 and PAR-2, expressed throughout the GI tract, impact gut permeability regulation, a major factor affecting intestinal physiology and metabolic inflammation. In addition, PARs are critically involved in the onset of inflammatory bowel diseases, irritable bowel syndrome, and tumor progression. Due to the number of proteases involved and the multiple cell types affected, selective regulation of intestinal PARs represents an interesting therapeutic strategy. The analysis of tissue/cell-specific knockout animal models will be of crucial importance to unravel the intrinsic complexity of this signaling network. Here, we provide an overview on the implication of PARs in intestinal permeability regulation under physiologic and disease conditions.
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Affiliation(s)
- Giulia Pontarollo
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany
| | - Amrit Mann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany
| | - Inês Brandão
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany.,Centro de Apoio Tecnológico Agro Alimentar (CATAA), Zona Industrial de Castelo Branco, Portugal
| | - Frano Malinarich
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany
| | - Marie Schöpf
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg University of Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site RheinMain, Mainz, Germany
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10
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Kuboi Y, Nishimura M, Ikeda W, Nakatani T, Seki Y, Yamaura Y, Ogawa K, Hamaguchi A, Muramoto K, Mizuno K, Ogasawara H, Yamauchi T, Yasuda N, Onodera H, Imai T. Blockade of the fractalkine–CX3CR1 axis ameliorates experimental colitis by dislodging venous crawling monocytes. Int Immunol 2019; 31:287-302. [DOI: 10.1093/intimm/dxz006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 01/17/2019] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yoshikazu Kuboi
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan
| | | | - Wataru Ikeda
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
| | | | - Yukie Seki
- Research Institute, EA Pharma Co., Ltd., Kawasaki-ku, Kawasaki-shi, Kanagawa, Japan
| | - Yui Yamaura
- Research Institute, EA Pharma Co., Ltd., Kawasaki-ku, Kawasaki-shi, Kanagawa, Japan
| | - Kana Ogawa
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
| | | | - Kenzo Muramoto
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan
- Medical Communication Section, Medical Division, Eisai Co., Ltd., Bunkyo-ku, Tokyo, Japan
| | - Keiko Mizuno
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
| | | | - Toshihiko Yamauchi
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Nobuyuki Yasuda
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan
| | - Hiroshi Onodera
- Photon Science Center of the University of Tokyo, Department of Electrical Engineering and Information System, Graduate School of Engineering, Bunkyo-ku, Tokyo, Japan
| | - Toshio Imai
- KAN Research Institute Inc., Chuo-ku, Kobe, Hyogo, Japan
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11
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Sébert M, Sola-Tapias N, Mas E, Barreau F, Ferrand A. Protease-Activated Receptors in the Intestine: Focus on Inflammation and Cancer. Front Endocrinol (Lausanne) 2019; 10:717. [PMID: 31708870 PMCID: PMC6821688 DOI: 10.3389/fendo.2019.00717] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022] Open
Abstract
Protease-activated receptors (PARs) belong to the G protein-coupled receptor (GPCR) family. Compared to other GPCRs, the specificity of the four PARs is the lack of physiologically soluble ligands able to induce their activation. Indeed, PARs are physiologically activated after proteolytic cleavage of their N-terminal domain by proteases. The resulting N-terminal end becomes a tethered activation ligand that interact with the extracellular loop 2 domain and thus induce PAR signal. PARs expression is ubiquitous and these receptors have been largely described in chronic inflammatory diseases and cancer. In this review, after describing their discovery, structure, mechanisms of activation, we then focus on the roles of PARs in the intestine and the two main diseases affecting the organ, namely inflammatory bowel diseases and cancer.
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12
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Sébert M, Denadai-Souza A, Quaranta M, Racaud-Sultan C, Chabot S, Lluel P, Monjotin N, Alric L, Portier G, Kirzin S, Bonnet D, Ferrand A, Vergnolle N. Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism. Br J Pharmacol 2018; 175:3656-3668. [PMID: 29959891 PMCID: PMC6109216 DOI: 10.1111/bph.14430] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/24/2018] [Accepted: 06/08/2018] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Thrombin is massively released upon tissue damage associated with bleeding or chronic inflammation. The effects of this thrombin on tissue regrowth and repair has been scarcely addressed and only in cancer cell lines. Hence, the purpose of the present study was to determine thrombin's pharmacological effects on human intestinal epithelium growth, proliferation and apoptosis, using three-dimensional cultures of human colon organoids. EXPERIMENTAL APPROACH Crypts were isolated from human colonic resections and cultured for 6 days, forming human colon organoids. Cultured organoids were exposed to 10 and 50 mU·mL-1 of thrombin, in the presence or not of protease-activated receptor (PAR) antagonists. Organoid morphology, metabolism, proliferation and apoptosis were followed. KEY RESULTS Thrombin favoured organoid maturation leading to a decreased number of immature cystic structures and a concomitant increased number of larger structures releasing cell debris and apoptotic cells. The size of budding structures, metabolic activity and proliferation were significantly reduced in organoid cultures exposed to thrombin, while apoptosis was dramatically increased. Both PAR1 and PAR4 antagonists inhibited apoptosis regardless of thrombin doses. Thrombin-induced inhibition of proliferation and metabolic activity were reversed by PAR4 antagonist for thrombin's lowest dose and by PAR1 antagonist for thrombin's highest dose. CONCLUSIONS AND IMPLICATIONS Overall, our data suggest that the presence of thrombin in the vicinity of human colon epithelial cells favours their maturation at the expense of their regenerative capacities. Our data point to thrombin and its two receptors PAR1 and PAR4 as potential molecular targets for epithelial repair therapies.
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Affiliation(s)
- Morgane Sébert
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | | | - Muriel Quaranta
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | | | | | | | | | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, Toulouse, France
| | - Guillaume Portier
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Sylvain Kirzin
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Delphine Bonnet
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Audrey Ferrand
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Nathalie Vergnolle
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.,Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
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13
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Basso L, Garnier L, Bessac A, Boué J, Blanpied C, Cenac N, Laffont S, Dietrich G. T-lymphocyte-derived enkephalins reduce T h1/T h17 colitis and associated pain in mice. J Gastroenterol 2018; 53:215-226. [PMID: 28424989 DOI: 10.1007/s00535-017-1341-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 04/04/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal Th1/Th17-associated inflammation, enkephalins released by colitogenic CD4+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in Th1/Th17-associated colitis. METHODS The anti-inflammatory effects of endogenous opioids were investigated in both Th1/Th17-associated (transfer of CD4+CD45RBhigh T lymphocytes) and Th2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4+CD45RBhigh T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred. RESULTS Peripheral opioid receptor blockade increases the severity of Th1/Th17-induced colitis and attenuates Th2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a Th2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4+CD45RBhigh T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury. CONCLUSIONS Endogenous opioids, including T-cell-derived enkephalins, promote a Th2-type immune response, which, depending on the context, may either attenuate (Th1/Th17-associated) or aggravate (Th2-associated) intestinal inflammation.
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Affiliation(s)
- Lilian Basso
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France
| | - Laure Garnier
- Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Sabatier (UPS), Toulouse, France
| | - Arnaud Bessac
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France
| | - Jérôme Boué
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France
| | - Catherine Blanpied
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France
| | - Nicolas Cenac
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France
| | - Sophie Laffont
- Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paul Sabatier (UPS), Toulouse, France
| | - Gilles Dietrich
- Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Paul Sabatier (UPS), Toulouse, France.
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Saeed MA, Ng GZ, Däbritz J, Wagner J, Judd L, Han JX, Dhar P, Kirkwood CD, Sutton P. Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity. Inflamm Bowel Dis 2017; 23:593-602. [PMID: 28296821 DOI: 10.1097/mib.0000000000001045] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Proteolytic cleavage of protease-activated receptor 1 (PAR1) can result in potent downstream regulatory effects on inflammation. Although PAR1 is expressed throughout the gastrointestinal tract and activating proteases are increased in inflammatory bowel disease, the effect of PAR1 activation on colitis remains poorly understood, and has not previously been studied in pediatric disease. METHODS Expression of PAR1 and inflammatory cytokines in colonic biopsies from pediatric patients with Crohn's disease exhibiting active moderate to severe colitis was measured by quantitative PCR. The functional relevance of these clinical data was further studied in a mouse model of Citrobacter rodentium-induced colitis. RESULTS PAR1 expression was significantly upregulated in the inflamed colons of pediatric patients with Crohn's disease, with expression levels directly correlating to disease severity. In patients with severe colitis, PAR1 expression uniquely correlated with Th17-related (IL17A, IL22, and IL23A) cytokines. Infection of PAR1-deficient (PAR1) and wildtype mice with colitogenic C. rodentium revealed that disease severity and colonic pathology were strongly attenuated in mice lacking PAR1. Furthermore, Th17-type immune response was completely abolished in the colons of infected PAR1 but not wildtype mice. Finally, PAR1 was shown to be essential for secretion of the Th17-driving cytokine IL-23 by C. rodentium-stimulated macrophages. CONCLUSIONS This study demonstrates a strong link between PAR1 expression, Th17-type immunity, and disease severity in both pediatric patients with Crohn's disease and C. rodentium-induced colitis in mice. The data presented suggest PAR1 exerts a proinflammatory role in colitis in both humans and mice by promoting a Th17-type immune response, potentially by supporting the production of IL-23.
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Affiliation(s)
- Muhammad A Saeed
- *Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia; †Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia; ‡Department of Paediatrics, University Medicine Rostock, Rostock, Mecklenburg-Vorpommern, Germany; and §Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
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Mihara K, Ramachandran R, Saifeddine M, Hansen KK, Renaux B, Polley D, Gibson S, Vanderboor C, Hollenberg MD. Thrombin-Mediated Direct Activation of Proteinase-Activated Receptor-2: Another Target for Thrombin Signaling. Mol Pharmacol 2016; 89:606-14. [PMID: 26957205 DOI: 10.1124/mol.115.102723] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 03/03/2016] [Indexed: 01/30/2023] Open
Abstract
Thrombin is known to signal to cells by cleaving/activating a G-protein-coupled family of proteinase-activated receptors (PARs). The signaling mechanism involves the proteolytic unmasking of an N-terminal receptor sequence that acts as a tethered receptor-activating ligand. To date, the recognized targets of thrombin cleavage and activation for signaling are PAR1 and PAR4, in which thrombin cleaves at a conserved target arginine to reveal a tethered ligand. PAR2, which like PAR1 is also cleaved at an N-terminal arginine to unmask its tethered ligand, is generally regarded as a target for trypsin but not for thrombin signaling. We now show that thrombin, at concentrations that can be achieved at sites of acute injury or in a tumor microenvironment, can directly activate PAR2 vasorelaxation and signaling, stimulating calcium and mitogen-activated protein kinase responses along with triggeringβ-arrestin recruitment. Thus, PAR2 can be added alongside PAR1 and PAR4 to the targets, whereby thrombin can affect tissue function.
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Affiliation(s)
- Koichiro Mihara
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Rithwik Ramachandran
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Mahmoud Saifeddine
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Kristina K Hansen
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Bernard Renaux
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Danny Polley
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Stacy Gibson
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Christina Vanderboor
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
| | - Morley D Hollenberg
- Inflammation Research Network-Snyder Institute for Chronic Disease, Department of Physiology and Pharmacology (K.M., R.R., M.S., K.K.H., B.R., D.P., S.G., M.D.H.), and Department of Medicine (M.D.H.), University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; and Department of Physiology and Pharmacology, Western University, London, Ontario, Canada (C.V., R.R.)
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Yi Q, Dong F, Lin L, Liu Q, Chen S, Gao F, He Q. PRSS1 mutations and the proteinase/antiproteinase imbalance in the pathogenesis of pancreatic cancer. Tumour Biol 2015; 37:5805-10. [PMID: 26546433 DOI: 10.1007/s13277-015-3982-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 08/24/2015] [Indexed: 02/07/2023] Open
Abstract
This study aimed to investigate the mutations in the serine protease 1 gene (PRSS1) and the imbalance between trypsin and α1-antitrypsin in patients with pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the sequences of PRSS1 from 65 patients with pancreatic cancer and 260 healthy controls, direct sequencing was performed, and the clinical features were analyzed. In addition, enzyme-linked immunosorbent assay (ELISA) was employed to detect serum trypsin and α1-antitrypsin in pancreatic cancer patients and healthy controls in the same period. Mutations were found at the promoter and exon 3 of the PRSS1 in patients with pancreatic cancer. That is, five patients had c.410 C > T mutation causing p.Thr 137 Met, and three patients had c. -338 T > G mutation at the promoter of the PRSS1. In patients with PRSS1 mutations, serum trypsin was 34.5 ± 18.3 ng/mL, which was significantly higher than that in normal controls (10.65 ± 6.03 ng/mL) and other pancreatic cancer (28.61 ± 8.96 ng/mL). What is more, in pancreatic cancer patients, serum α1-antitrypsin was 1.69 ± 0.86 g/L, which was comparable to that in normal controls (1.55 ± 0.53 g/L), while the ratio of serum trypsin to α1-antitrypsin was 1.46-fold to normal controls. The results presented here have provided a greater insight into the PRSS1 mutations and proteinase-inhibitor interactions occurring in pancreatic cancer.
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Affiliation(s)
- Qiang Yi
- Department of Laboratory Medicine, the 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Feng Dong
- Department of Radiation Oncology, the 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Liqing Lin
- Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, China
| | - Qicai Liu
- Department of Laboratory Medicine, the 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Shu Chen
- Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, China
| | - Feng Gao
- Department of Pathology, the 1st Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
| | - Qingliang He
- Department of Surgery, the first Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, Fujian Province, China.
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Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2. Infect Immun 2015; 83:2762-70. [PMID: 25916983 DOI: 10.1128/iai.00425-15] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 04/17/2015] [Indexed: 12/11/2022] Open
Abstract
Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2(-/-)) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2(-/-) mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2(-/-) mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2(-/-) mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2.
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Christensen J, Alfredson H, Andersson G. Protease-activated receptors in the Achilles tendon-a potential explanation for the excessive pain signalling in tendinopathy. Mol Pain 2015; 11:13. [PMID: 25880199 PMCID: PMC4369088 DOI: 10.1186/s12990-015-0007-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 02/20/2015] [Indexed: 01/07/2023] Open
Abstract
Background/Aim Tendinopathies are pathological conditions of tissue remodelling occurring in the major tendons of the body, accompanied by excessive nociceptive signalling. Tendinopathies have been shown to exhibit an increase in the number of mast cells, which are capable of releasing histamine, tryptase and other substances upon activation, which may play a role in the development of tendinopathies. This study set out to describe the distribution patterns of a family of receptors called protease-activated receptors (PARs) within the Achilles tendon. These four receptors (PAR1, PAR2, PAR3, PAR4) are activated by proteases, including tryptase released from mast cells, and are involved in fibrosis, hyperalgesia and neovascularisation, which are changes seen in tendinopathies. Method In order to study which structures involved in tendinopathy that these proteases can affect, biopsies from patients suffering of mid-portion Achilles tendinosis and healthy controls were collected and examined using immunohistochemistry. Tendon cells were cultured to study in vitro expression patterns. Results The findings showed a distribution of PARs inside the tendon tissue proper, and in the paratendinous tissue, with all four being expressed on nerves and vascular structures. Double staining showed co-localisation of PARs with nociceptive fibres expressing substance P. Concerning tenocytes, PAR2, PAR3, and PAR4, were found in both biopsies of tendon tissue and cultured tendon cells. Conclusions This study describes the expression patterns of PARs in the mid-portion of the Achilles tendon, which can help explain the tissue changes and increased pain signalling seen in tendinopathies. These findings also show that in-vitro studies of the effects of these receptors are plausible and that PARs are a possible therapeutic target in the future treatment strategies of tendinopathy.
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Affiliation(s)
- Jens Christensen
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, SE-90187, Sweden.
| | - Håkan Alfredson
- Department of Community Medicine and Rehabilitation, Sports Medicine, Umeå University, Umeå, SE-90187, Sweden. .,ISEH, UCLH, London, UK. .,Pure Sports Clinic, London, UK.
| | - Gustav Andersson
- Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, SE-90187, Sweden. .,Department of Surgical and Perioperative Science, Section for Hand and Plastic Surgery, Umeå University, Umeå, SE-90187, Sweden.
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Jackson MT, Moradi B, Zaki S, Smith MM, McCracken S, Smith SM, Jackson CJ, Little CB. Depletion of protease-activated receptor 2 but not protease-activated receptor 1 may confer protection against osteoarthritis in mice through extracartilaginous mechanisms. Arthritis Rheumatol 2015; 66:3337-48. [PMID: 25200274 DOI: 10.1002/art.38876] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 09/04/2014] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To explore the involvement of protease-activated receptor 1 (PAR-1) and PAR-2 in the pathologic processes of osteoarthritis (OA) and to identify the cells/tissues primarily affected by ablation of PAR-1 or PAR-2 in mice. METHODS OA was induced in the joints of wild-type (WT), PAR-1(+/+) , PAR-1(-/-) , and PAR-2(-/-) mice by destabilization of the medial meniscus (DMM), and scores of histologic features (cartilage aggrecan loss and erosion, subchondral bone sclerosis, osteophytes, and synovitis) were compared at 1, 4, and 8 weeks post-DMM. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/activity were studied in cultures of mouse femoral head tissue with or without interleukin-1α (IL-1α). At 1 week post-DMM, synovial expression of cytokines and metalloproteinase genes was measured by reverse transcription-polymerase chain reaction, and populations of inflammatory cells were quantified by flow cytometry. RESULTS Deletion of PAR-2, but not that of PAR-1, in mice significantly delayed the progression of cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1α-induced cartilage degradation or chondrocyte metalloproteinase expression/activation. A low but significant level of synovitis persisted in mice subjected to DMM compared to that in control mice subjected to sham surgery, but no differences between the genotypes were seen 4 or 8 weeks post-DMM. One week after DMM, increased synovial expression of proinflammatory cytokines and metalloproteinase genes, along with increased levels of CD4+ T cells, inflammatory monocytes, and activated macrophages, were seen in all genotypes. However, there was a significant reduction in the percentage of activated macrophages in PAR-2(-/-) mice compared to PAR-1(-/-) and WT mice. CONCLUSION Deletion of PAR-2, but not that of PAR-1, results in a significant decrease in DMM-induced cartilage damage. The chondroprotection in PAR-2(-/-) mice appears to occur indirectly through modulation of extracartilaginous events such as subchondral bone remodeling and synovial macrophage activation, rather than through alteration of chondrocyte catabolic responses.
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Affiliation(s)
- Miriam T Jackson
- Kolling Institute of Medical Research and the University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales, Australia
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Protease-activated receptor 1 suppresses Helicobacter pylori gastritis via the inhibition of macrophage cytokine secretion and interferon regulatory factor 5. Mucosal Immunol 2015; 8:68-79. [PMID: 24866378 DOI: 10.1038/mi.2014.43] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 04/28/2014] [Indexed: 02/08/2023]
Abstract
Chronic gastritis from Helicobacter pylori infection is a major factor in the development of gastric adenocarcinoma. Factors that regulate gastritis severity are important in determining which individuals are susceptible to H. pylori-associated disease. Although protease-activated receptor 1 (PAR1) has been identified as one such host factor, its mechanism of action is unknown. Using chimeric mice, we demonstrated that PAR1-mediated protection against H. pylori gastritis requires bone marrow-derived cells. Analyses of the gastric mucosa revealed that PAR1 suppresses cellular infiltration and both T helper type 1 (Th1) and T helper type 17 (Th17) responses to infection. Moreover, PAR1 expression was associated with reduced vaccine-mediated protection against H. pylori. Analyses of H. pylori-stimulated macrophages revealed that PAR1 activation suppressed secretion of interleukin (IL)-12 and IL-23, key drivers of Th1 and Th17 immunity, respectively. Furthermore, PAR1 suppressed interferon regulatory factor 5 (IRF5), an important transcription factor for IL-12 and IL-23, both in the infected mucosa and following bacterial stimulation. PAR1 suppression of IRF5 and IL-12/23 secretion by macrophages provides a novel mechanism by which the host suppresses the mucosal Th1 and Th17 response to H. pylori infection. Dysregulation of this process is likely an important factor in the susceptibility of some individuals to H. pylori-associated disease.
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Schmid W, Vogelsang H, Papay P, Primas C, Eser A, Gratzer C, Handler M, Novacek G, Panzer S. Increased responsiveness to thrombin through protease-activated receptors (PAR)-1 and -4 in active Crohn's disease. J Crohns Colitis 2014; 8:495-503. [PMID: 24291018 DOI: 10.1016/j.crohns.2013.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Revised: 10/03/2013] [Accepted: 11/02/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Platelets are essential in hemostasis and inflammation, thereby linking coagulation with inflammation. Abundant thrombin generation in association with inflammation is considered a major reason for the increased risk for thromboembolic events. We therefore investigated platelet responsiveness to thrombin. METHODS In this case-control study 85 patients with Crohn's disease (active CD 42, remission 43) and 30 sex- and age-matched controls were enrolled. Clinical disease activity (Harvey-Bradshaw-Index) was assessed and CD-related data were determined by chart review. Platelets' response to protease activated receptor-1 and -4 (PAR-1, -4) was assessed by whole blood platelet aggregometry (MEA), levels of platelets adhering to monocytes (PMA), and platelet surface P-selectin. RESULTS Platelets' aggregation after activation with the specific PAR-1 agonist (SFLLRN) and PAR-4 agonist (AYPGKF) was higher in patients with active CD compared to patients in remission and controls (p=0.0068 and p=0.0023 for SFLLRN, p=0.0019 and 0.0003 for AYPGKF). Likewise, levels of PMA after activation with PAR-1 and PAR-4 receptor agonists were higher in patients with active CD compared to patients in remission and controls (p=0.0001 and p<0.0001 for SFLLRN, p=0.0329 and p=0.0125 for AYPGKF). However, P-selectin expression on human platelets showed heterogeneous results. Only PAR-1 activation of platelets resulted in significant differences between CD patients and controls (p=0.0001 and p=0.0022 for active and inactive CD versus controls, respectively). CONCLUSIONS Our data suggest a new mechanism of platelet activation which has the potential to increase risk for thromboembolism in patients with active CD which might be due to platelets poised for thrombin-inducible activation.
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Affiliation(s)
- Werner Schmid
- Department of Anesthesiology, General Intensive Care and Pain Medicine, Division of Cardiothoracic and Vascular Anesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Harald Vogelsang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Pavol Papay
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christian Primas
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Eser
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Cornelia Gratzer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Handler
- Department of Anesthesiology, General Intensive Care and Pain Medicine, Division of Cardiothoracic and Vascular Anesthesia and Intensive Care, Medical University of Vienna, Vienna, Austria
| | - Gottfried Novacek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Simon Panzer
- Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria
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Vergnolle N. TRPV4: new therapeutic target for inflammatory bowel diseases. Biochem Pharmacol 2014; 89:157-61. [PMID: 24440740 DOI: 10.1016/j.bcp.2014.01.005] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 01/07/2014] [Accepted: 01/07/2014] [Indexed: 01/06/2023]
Abstract
The transient receptor potential vanilloid-4 (TRPV4) belongs to a family of ion channels and can be activated by warm temperature, hypotonicity, cell swelling or lipid mediators of the arachidonic cascade. The metabolites or events responsible for TRPV4 activation are associated with inflammation, arguing in favor of a role for this receptor in inflammatory diseases. The first studies have focused their attention on the role of TRPV4 in neurons and endothelial cells but TRPV4 cellular distribution is widespread, particularly in the gastrointestinal tract. Herein, we review a number of studies demonstrating the expression of TRPV4 in the gut, the regulation of its expression and functions by inflammatory mediators in that organ and the consequences of TRPV4 activation or inhibition in the intestine. We further discuss the relevance of considering this receptor as a potential target for therapeutic development in inflammatory bowel diseases.
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Affiliation(s)
- Nathalie Vergnolle
- Université de Toulouse, Université Paul Sabatier,Centre de Physiopathologie de Toulouse Purpan(CPTP), Toulouse, France; INSERM, U1043, Toulouse, France; CNRS, U5282, Toulouse, France.
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Aerts L, Hamelin MÈ, Rhéaume C, Lavigne S, Couture C, Kim W, Susan-Resiga D, Prat A, Seidah NG, Vergnolle N, Riteau B, Boivin G. Modulation of protease activated receptor 1 influences human metapneumovirus disease severity in a mouse model. PLoS One 2013; 8:e72529. [PMID: 24015257 PMCID: PMC3755973 DOI: 10.1371/journal.pone.0072529] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Accepted: 07/10/2013] [Indexed: 11/19/2022] Open
Abstract
Human metapneumovirus (hMPV) infection causes acute respiratory tract infections (RTI) which can result in hospitalization of both children and adults. To date, no antiviral or vaccine is available for this common viral infection. Immunomodulators could represent an interesting strategy for the treatment of severe viral infection. Recently, the role of protease-activated receptors (PAR) in inflammation, coagulation and infection processes has been of growing interest. Herein, the effects of a PAR1 agonist and a PAR1 antagonist on hMPV infection were investigated in BALB/c mice. Intranasal administration of the PAR1 agonist resulted in increased weight loss and mortality of infected mice. Conversely, the PAR1 antagonist was beneficial to hMPV infection by decreasing weight loss and clinical signs and by significantly reducing pulmonary inflammation, pro-inflammatory cytokine levels (including IL-6, KC and MCP-1) and recruitment of immune cells to the lungs. In addition, a significant reduction in pulmonary viral titers was also observed in the lungs of PAR1 antagonist-treated mice. Despite no apparent direct effect on virus replication during in vitro experiments, an important role for PAR1 in the regulation of furin expression in the lungs was shown for the first time. Further experiments indicated that the hMPV fusion protein can be cleaved by furin thus suggesting that PAR1 could have an effect on viral infectivity in addition to its immunomodulatory properties. Thus, inhibition of PAR1 by selected antagonists could represent an interesting strategy for decreasing the severity of paramyxovirus infections.
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Affiliation(s)
- Laetitia Aerts
- Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada
| | - Marie-Ève Hamelin
- Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada
| | - Chantal Rhéaume
- Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada
| | - Sophie Lavigne
- Department of Anatomo-pathology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada
| | - Christian Couture
- Department of Anatomo-pathology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec, Canada
| | - WooJin Kim
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Canada
| | - Delia Susan-Resiga
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Canada
| | - Annik Prat
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Canada
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Canada
| | - Nathalie Vergnolle
- Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
- Department of Physiology and Pharmacology, University of Calgary, Alberta, Canada
| | - Beatrice Riteau
- Virologie et Pathologie Humaine, Université Lyon, Faculté de Médecine RTH Laennec, Lyon, France
- Centre de Tours-Nouzilly Institut National de la Recherche Agronomique, Nouzilly, France
| | - Guy Boivin
- Centre de Recherche en Infectiologie du Centre Hospitalier Universitaire de Québec and Université Laval, Quebec, Canada
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Zhao Y, Liu M, Wang X, Liu X, Yang Y, Zou H, Sun S, Yu L, Rosenthal B, Shi H, Boireau P, Wu X. Modulation of inflammatory bowel disease in a mouse model following infection with Trichinella spiralis. Vet Parasitol 2013; 194:211-6. [DOI: 10.1016/j.vetpar.2013.01.058] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Motta JP, Bermudez-Humaran LG, Deraison C, Martin L, Rolland C, Rousset P, Boue J, Dietrich G, Chapman K, Kharrat P, Vinel JP, Alric L, Mas E, Sallenave JM, Langella P, Vergnolle N. Food-Grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis. Sci Transl Med 2012; 4:158ra144. [DOI: 10.1126/scitranslmed.3004212] [Citation(s) in RCA: 166] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Wang J, Kulkarni A, Chintala M, Fink LM, Hauer-Jensen M. Inhibition of protease-activated receptor 1 ameliorates intestinal radiation mucositis in a preclinical rat model. Int J Radiat Oncol Biol Phys 2012; 85:208-14. [PMID: 22580123 DOI: 10.1016/j.ijrobp.2012.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Revised: 02/02/2012] [Accepted: 02/03/2012] [Indexed: 11/16/2022]
Abstract
PURPOSE To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects. METHODS AND MATERIALS Rats underwent fractionated X-irradiation (5 Gy×9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 mg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 mg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation. RESULTS Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups. CONCLUSION Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.
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Affiliation(s)
- Junru Wang
- Division of Radiation Health, University of Arkansas for Medical Sciences, Surgery Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205, USA
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Targeting proteinase-activated receptors: therapeutic potential and challenges. Nat Rev Drug Discov 2012; 11:69-86. [PMID: 22212680 DOI: 10.1038/nrd3615] [Citation(s) in RCA: 248] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Proteinase-activated receptors (PARs), a family of four seven-transmembrane G protein-coupled receptors, act as targets for signalling by various proteolytic enzymes. PARs are characterized by a unique activation mechanism involving the proteolytic unmasking of a tethered ligand that stimulates the receptor. Given the emerging roles of these receptors in cancer as well as in disorders of the cardiovascular, musculoskeletal, gastrointestinal, respiratory and central nervous system, PARs have become attractive targets for the development of novel therapeutics. In this Review we summarize the mechanisms by which PARs modulate cell function and the roles they can have in physiology and diseases. Furthermore, we provide an overview of possible strategies for developing PAR antagonists.
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Gobbetti T, Cenac N, Motta JP, Rolland C, Martin L, Andrade-Gordon P, Steinhoff M, Barocelli E, Vergnolle N. Serine protease inhibition reduces post-ischemic granulocyte recruitment in mouse intestine. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 180:141-52. [PMID: 22067907 DOI: 10.1016/j.ajpath.2011.09.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 08/26/2011] [Accepted: 09/20/2011] [Indexed: 01/17/2023]
Abstract
Proteases and proteinase-activated receptor (PAR) activation are involved in several intestinal inflammatory conditions. We hypothesized that serine proteases and PAR activation could also modulate the intestinal injury induced by ischemia-reperfusion (I-R). C57Bl/6 mice were subjected to 90 minutes of intestinal ischemia followed or not by reperfusion. Sham-operated animals served as controls. After ischemia, plasma and tissue serine protease activity levels were increased compared to the activity measured in plasma and tissues from sham-operated mice. This increase was maintained or further enhanced after 2 and 5 hours of reperfusion, respectively. Trypsin (25 kDa) was detected in tissues both after ischemia and 2 hours of reperfusion. Treatment with FUT-175 (10 mg/kg), a potent serine protease inhibitor, increased survival after I-R, inhibited tissue protease activity, and significantly decreased intestinal myeloperoxidase (MPO) activity and chemokine and adhesion molecule expression. We investigated whether serine proteases modulate granulocyte recruitment by a PAR-dependent mechanism. MPO levels and adhesion molecule expression were significantly reduced in I-R groups pre-treated with the PAR(1) antagonist SCH-79797 (5 mg/kg) and in Par(2)(-/-)mice, compared, respectively, to vehicle-treated group and wild-type littermates. Thus, increased proteolytic activity and PAR activation play a pathogenic role in intestinal I-R injury. Inhibition of PAR-activating serine proteases could be beneficial to reduce post-ischemic intestinal inflammation.
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Affiliation(s)
- Thomas Gobbetti
- INSERM, U1043, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
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Motta JP, Magne L, Descamps D, Rolland C, Squarzoni-Dale C, Rousset P, Martin L, Cenac N, Balloy V, Huerre M, Fröhlich LF, Jenne D, Wartelle J, Belaaouaj A, Mas E, Vinel JP, Alric L, Chignard M, Vergnolle N, Sallenave JM. Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis. Gastroenterology 2011; 140:1272-82. [PMID: 21199654 DOI: 10.1053/j.gastro.2010.12.050] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Revised: 12/02/2010] [Accepted: 12/20/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Colonic tissues of patients with inflammatory bowel disease have been reported to have increased proteolytic activity, but no studies have clearly addressed the role of the balance between proteases and antiproteases in the pathogenesis of colitis. We investigated the role of Elafin, a serine protease inhibitor expressed by skin and mucosal surfaces in human inflammatory conditions, and the proteases neutrophil elastase (NE) and proteinase-3 (PR-3) in mice with colitis. METHODS We studied mice with heterozygous disruptions in NE and PR-3, mice that express human elafin (an inhibitor of NE and PR-3), and naïve mice that received intracolonic adenoviral vectors that express elafin. Trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulphate (DSS) was used to induce colitis. Protease, cytokine levels, and NF-κB activity were measured in colons of mice. Caco-2 and HT29 cells were studied in assays for cytokine expression, permeability, and NF-κB activity. RESULTS Elafin expression or delivery re-equilibrated the proteolytic balance in inflamed colons of mice. In mice given TNBS or DSS, transgenic expression of elafin or disruption of NE and PR-3 protected against the development of colitis. Similarly, adenoviral delivery of Elafin significantly inhibited inflammatory parameters. Elafin modulated a variety of inflammatory mediators in vitro and in vivo and strengthened intestinal epithelial barrier functions. CONCLUSIONS The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease.
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Affiliation(s)
- Jean-Paul Motta
- Inserm, U1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France
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Scaldaferri F, Lancellotti S, Pizzoferrato M, Cristofaro RD. Haemostatic system in inflammatory bowel diseases: New players in gut inflammation. World J Gastroenterol 2011; 17:594-608. [PMID: 21350708 PMCID: PMC3040331 DOI: 10.3748/wjg.v17.i5.594] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Revised: 03/25/2010] [Accepted: 04/01/2010] [Indexed: 02/06/2023] Open
Abstract
Inflammation and coagulation constantly influence each other and are constantly in balance. Emerging evidence supports this statement in acute inflammatory diseases, such as sepsis, but it also seems to be very important in chronic inflammatory settings, such as inflammatory bowel disease (IBD). Patients with Crohn’s disease and ulcerative colitis have an increased risk of thromboembolic events, and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels, where most severe inflammatory abnormalities occur. The aims of this review are to update and classify the type of coagulation system abnormalities in IBD, and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level. Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.
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Adams MN, Ramachandran R, Yau MK, Suen JY, Fairlie DP, Hollenberg MD, Hooper JD. Structure, function and pathophysiology of protease activated receptors. Pharmacol Ther 2011; 130:248-82. [PMID: 21277892 DOI: 10.1016/j.pharmthera.2011.01.003] [Citation(s) in RCA: 280] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Accepted: 01/03/2011] [Indexed: 12/18/2022]
Abstract
Discovered in the 1990s, protease activated receptors(1) (PARs) are membrane-spanning cell surface proteins that belong to the G protein coupled receptor (GPCR) family. A defining feature of these receptors is their irreversible activation by proteases; mainly serine. Proteolytic agonists remove the PAR extracellular amino terminal pro-domain to expose a new amino terminus, or tethered ligand, that binds intramolecularly to induce intracellular signal transduction via a number of molecular pathways that regulate a variety of cellular responses. By these mechanisms PARs function as cell surface sensors of extracellular and cell surface associated proteases, contributing extensively to regulation of homeostasis, as well as to dysfunctional responses required for progression of a number of diseases. This review examines common and distinguishing structural features of PARs, mechanisms of receptor activation, trafficking and signal termination, and discusses the physiological and pathological roles of these receptors and emerging approaches for modulating PAR-mediated signaling in disease.
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Affiliation(s)
- Mark N Adams
- Mater Medical Research Institute, Aubigny Place, Raymond Terrace, South Brisbane Qld 4101, Australia
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32
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Zhao D, Bakirtzi K, Zhan Y, Zeng H, Koon HW, Pothoulakis C. Insulin-like growth factor-1 receptor transactivation modulates the inflammatory and proliferative responses of neurotensin in human colonic epithelial cells. J Biol Chem 2011; 286:6092-9. [PMID: 21212273 DOI: 10.1074/jbc.m110.192534] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Neurotensin (NT) is a gastrointestinal neuropeptide that modulates intestinal inflammation and healing by binding to its high-affinity receptor NTR1. The dual role of NT in inflammation and healing is demonstrated in models of colitis induced by Clostridium difficile toxin A and dextran sulfate sodium, respectively, and involves NF-κB-dependent IL-8 expression and EGF receptor-mediated MAPK activation in human colonocytes. However, the detailed signaling pathways involved in these responses remain to be elucidated. We report here that NT/NTR1 coupling in human colonic epithelial NCM460 cells activates tyrosine phosphorylation of the insulin-like growth factor-1 receptor (IGF-1R) in a time- and dose-dependent manner. NT also rapidly induces Src tyrosine phosphorylation, whereas pretreatment of cells with the Src inhibitor PP2 before NT exposure decreases NT-induced IGF-1R phosphorylation. In addition, inhibition of IGF-1R activation by either its specific antagonist AG1024 or siRNA against IGF-1 significantly reduces NT-induced IL-8 expression and NF-κB-dependent reporter gene expression. Pretreatment with AG1024 also inhibits Akt activation and apoptosis induced by NT. Silencing of Akt expression by siRNA also substantially attenuates NT-induced IL-8 promoter activity and NF-κB-dependent reporter gene expression. This is the first report to indicate that NT transactivates IGF-1R and that this response is linked to Akt phosphorylation and NF-κB activation, contributing to both pro-inflammatory and tissue repair signaling pathways in response to NT in colonic epithelial cells. We propose that IGF-1R activation represents a previously unrecognized key pathway involved in the mechanisms by which NT and NTR1 modulate colonic inflammation and inflammatory bowel disease.
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Affiliation(s)
- Dezheng Zhao
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 022115, USA.
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Cirino G, Severino B. Thrombin receptors and their antagonists: an update on the patent literature. Expert Opin Ther Pat 2010; 20:875-84. [PMID: 20450349 DOI: 10.1517/13543776.2010.487864] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
IMPORTANCE OF THE FIELD Thrombin plays a central role in cardiovascular inflammation. Most of the cellular responses to thrombin are mediated by cell surface protease-activated receptors (PARs). Several preclinical studies indicate that PARs are potential targets for treating cardiovascular diseases such as thrombosis, atherosclerosis and restenosis. Among PARs, PAR-1 has emerged as an important therapeutic target. AREAS COVERED IN THIS REVIEW This review covers recent advances in the development of thrombin receptors antagonists. It is focused on the search for PAR-1 antagonists as this is at the moment the most promising and attractive target. However, some early promising studies on PAR-3 and -4 antagonists are also reported. WHAT THE READER WILL GAIN The review has been written in order to give to the reader hints and references that cover, in our opinion, the most interesting and/or promising approaches in this research field. TAKE HOME MESSAGE Research on PAR-1 antagonists has finally led to good clinical candidates such as SCH-530348 (Schering-Plough) and E-5555 (Eisai Co.). Clinical trials clearly demonstrate that development of PAR1 antagonists is not only possible but most likely will lead to development of antiplatelet drugs as well as of drugs useful for the treatment of inflammatory, proliferative and neurodegenerative diseases.
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Affiliation(s)
- Giuseppe Cirino
- University of Naples Federico II, Department of Experimental Pharmacology, Via Domenico Montesano 49, Napoli 80131, Italy.
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Hyun E, Andrade-Gordon P, Steinhoff M, Beck PL, Vergnolle N. Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis. Inflamm Res 2010; 59:699-709. [PMID: 20339899 PMCID: PMC2917702 DOI: 10.1007/s00011-010-0181-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2009] [Revised: 01/18/2010] [Accepted: 02/15/2010] [Indexed: 12/30/2022] Open
Abstract
Objective Our aim was to determine the contribution of proteinase-activated receptor-2 (PAR2)-expressing bone marrow-derived cells on the development of colonic inflammation. Materials Chimeric mice were generated by injecting bone marrow cells from wildtype (PAR2+/+) or PAR2 knockout mice (PAR2−/−) into irradiated PAR2+/+ or PAR2−/− mice. Treatments: Colitis was induced by giving 2.5% dextran sodium sulfate (DSS) solution for 7 days or by a single intracolonic administration of trinitrobenzene sulphonic acid (TNBS, 2 mg dissolved in 40% ethanol). Methods Seven days after the induction of colitis, bowel thickness, inflammatory parameters [myeloperoxidase (MPO) activity, macroscopic/microscopic damage scores], and leukocyte trafficking (visualized via intravital microscopy) were assessed. Results Total deficiency of PAR2 resulted in a marked reduction in severity of both TNBS and DSS induced colitis as assessed by MPO activity, macroscopic damage, bowel thickness, and leukocyte adherence. Colitis was attenuated in all chimeric lines in which there was loss of PAR2 in the host, non-bone marrow-derived tissue, independent of the status of PAR expression by bone marrow-derived cells. Interestingly, TNBS colitis was attenuated in PAR2+/+ chimeric mice with PAR2−/− derived bone marrow but these animals were not protected from DSS colitis. Conclusions Expression of PAR2 by host-derived tissues plays a dominant role in regulating colonic inflammation. PAR2 expression by bone marrow-derived cells appears to play a role in TNBS colitis but not in DSS induced injury. Electronic supplementary material The online version of this article (doi:10.1007/s00011-010-0181-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Eric Hyun
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1 Canada
| | - Patricia Andrade-Gordon
- Johnson & Johnson Pharmaceutical Research & Development, Welsh Rd and Mckean Rd, Spring House, PA 19477 USA
| | - Martin Steinhoff
- Department of Dermatology, Interdisciplinary Center for Clinical Research, University of Munster, Von-Esmarch-Strasse 58, 48149 Münster, Germany
| | - Paul L. Beck
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1 Canada
| | - Nathalie Vergnolle
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1 Canada
- Centre de Physiopathologie de Toulouse Purpan, CHU Purpan, INSERM U563, 31000 Toulouse, France
- Université Toulouse III Paul Sabatier, route de Narbonne, 31000 Toulouse, France
- CHU Purpan, INSERM U563, BP 3028, 31024 Toulouse Cedex, France
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Augé C, Balz-Hara D, Steinhoff M, Vergnolle N, Cenac N. Protease-activated receptor-4 (PAR 4): a role as inhibitor of visceral pain and hypersensitivity. Neurogastroenterol Motil 2009; 21:1189-e107. [PMID: 19413681 DOI: 10.1111/j.1365-2982.2009.01310.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Protease-activated receptor-4 (PAR(4)) belongs to the family of receptors activated by the proteolytic cleavage of their extracellular N-terminal domain and the subsequent binding of the newly released N-terminus. While largely expressed in the colon, the role of PAR(4) in gut functions has not been defined. We have investigated the effects of PAR(4) agonist on colonic sensations and sensory neuron signalling, and its role in visceral pain. We observed that a single administration of the PAR(4) agonist peptide (AYPGKF-NH(2)), but not the control peptide (YAPGKF-NH(2)) into the colon lumen of mice significantly reduced the visceromotor response to colorectal distension at different pressures of distension. Further, intracolonic administration of the PAR(4) agonist, but not the control peptide, was able to significantly inhibit PAR(2) agonist- and transcient receptor potential vanilloid-4 (TRPV4) agonist-induced allodynia and hyperalgesia in response to colorectal distension. Protease-activated receptor-4 was detected in sensory neurons projecting from the colon, and isolated from the dorsal root ganglia, where it co-expressed with PAR(2) and TRPV4. In total sensory neurons, PAR(4) agonist exposure inhibited free intracellular calcium mobilization induced by the pro-nociceptive agonists of PAR(2) and TRPV4. Finally, PAR(4)-deficient mice experienced increased pain behaviour in response to intracolonic administration of mustard oil, compared with wild-type littermates. These results show that PAR(4) agonists modulate colonic nociceptive response, inhibit colonic hypersensitivity and primary afferent responses to pro-nociceptive mediators. Endogenous activation of PAR(4) also plays a major role in controlling visceral pain. These results identify PAR(4) as a previously unknown modulator of visceral nociception.
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Affiliation(s)
- C Augé
- INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
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Protease-activated receptors as drug targets in inflammation and pain. Pharmacol Ther 2009; 123:292-309. [PMID: 19481569 DOI: 10.1016/j.pharmthera.2009.05.004] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Accepted: 05/05/2009] [Indexed: 12/12/2022]
Abstract
Proteases have been shown to signal to cells through the activation of a novel class of receptors coupled to G proteins: the protease-activated receptors (PARs). Those receptors are expressed in a wide range of cells, which ultimately are all involved in mechanisms of inflammation and pain. Numerous studies have considered the role of PARs in cells, organ systems or in vivo, highlighting the fact that PAR activation results in signs of inflammation. A growing body of evidences discussed here suggests that these receptors, and the proteases that activate them, interfere with inflammation and pain processes. Whether a role for PARs has been clearly defined in inflammatory and pain pathologies is discussed in this review. Further, the pros and cons for considering PARs as targets for the development of therapeutic options for the treatment of inflammation and pain are discussed.
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Coagulation factor Xa signaling: the link between coagulation and inflammatory bowel disease? Trends Pharmacol Sci 2009; 30:8-16. [DOI: 10.1016/j.tips.2008.10.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2008] [Revised: 10/22/2008] [Accepted: 10/23/2008] [Indexed: 02/06/2023]
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Martín MC, Oliver J, Luis Mendoza J, Fernández-Arquero M, Martín J, Urcelay E. Influencia de las mutaciones de los receptores activados por proteinasa F2R/PAR1 y F2RL1/PAR2 en la enfermedad inflamatoria intestinal. Med Clin (Barc) 2008; 131:609-11. [DOI: 10.1157/13127918] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Hansen KK, Oikonomopoulou K, Li Y, Hollenberg MD. Proteinases, proteinase-activated receptors (PARs) and the pathophysiology of cancer and diseases of the cardiovascular, musculoskeletal, nervous and gastrointestinal systems. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2008; 377:377-92. [PMID: 17952408 DOI: 10.1007/s00210-007-0194-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Accepted: 09/19/2007] [Indexed: 12/31/2022]
Abstract
Proteinases like thrombin, trypsin and tissue kallikreins are now known to regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1 to 4) via exposure of a 'tethered' receptor-triggering ligand. On their own, short synthetic peptides based on the 'tethered ligand' sequences of the PARs (PAR-APs) can, in the absence of receptor proteolysis, selectively activate PARs 1, 2 and 4 and cause physiological responses both in vitro and in vivo. Using the PAR-APs as probes in vivo, it has been found that PAR activation can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (both central and peripheral) and can promote cancer metastasis and invasion. The responses triggered by PARs 1, 2 and 4 are in keeping with an innate immune inflammatory response, ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased nociception. Thus, PARs have been implicated in a number of disease states including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. Furthermore, PAR-regulating proteinases have been implicated in pathogen-induced inflammation. The identities of the proteinases that regulate PARs in these pathological settings in vivo have yet to be explored in depth. In addition to activating or dis-arming PARs, proteinases can also cause hormone-like effects by signaling mechanisms that do not involve the PARs and that may be as important as the activation of PARs. Thus, the working hypotheses of this article are: (1) that proteinases in general must now be considered as 'hormone-like' messengers that can signal either via PARs or other mechanisms and (2) that the PARs themselves, their activating serine proteinases and their associated signaling pathways can be considered as attractive targets for therapeutic drug development.
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Affiliation(s)
- Kristina K Hansen
- Department of Pharmacology & Therapeutics, Canadian Institutes of Health Research, Proteinases and Inflammation Network, Faculty of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada.
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Synthesis and pharmacological evaluation of peptide-mimetic protease-activated receptor-1 antagonists containing novel heterocyclic scaffolds. Bioorg Med Chem 2008; 16:6009-20. [PMID: 18477511 DOI: 10.1016/j.bmc.2008.04.059] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2007] [Revised: 04/15/2008] [Accepted: 04/23/2008] [Indexed: 11/23/2022]
Abstract
Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by alpha-thrombin and other proteases. In this paper we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1-16) characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted in some cases (compounds 1 and 4) more potent than the reference. The compounds, tested on aortic rings, confirmed the results obtained in the aggregation assay.
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Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br J Pharmacol 2007; 153 Suppl 1:S263-82. [PMID: 18059329 DOI: 10.1038/sj.bjp.0707507] [Citation(s) in RCA: 215] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Proteinases like thrombin, trypsin and tissue kallikreins are now known to regulate cell signaling by cleaving and activating a novel family of G-protein-coupled proteinase-activated receptors (PARs 1-4) via exposure of a tethered receptor-triggering ligand. On their own, short synthetic PAR-selective PAR-activating peptides (PAR-APs) mimicking the tethered ligand sequences can activate PARs 1, 2 and 4 and cause physiological responses both in vitro and in vivo. Using the PAR-APs as sentinel probes in vivo, it has been found that PAR activation can affect the vascular, renal, respiratory, gastrointestinal, musculoskeletal and nervous systems (both central and peripheral nervous system) and can promote cancer metastasis and invasion. In general, responses triggered by PARs 1, 2 and 4 are in keeping with an innate immune inflammatory response, ranging from vasodilatation to intestinal inflammation, increased cytokine production and increased or decreased nociception. Further, PARs have been implicated in a number of disease states, including cancer and inflammation of the cardiovascular, respiratory, musculoskeletal, gastrointestinal and nervous systems. In addition to activating PARs, proteinases can cause hormone-like effects by other signalling mechanisms, like growth factor receptor activation, that may be as important as the activation of PARs. We, therefore, propose that the PARs themselves, their activating serine proteinases and their associated signalling pathways can be considered as attractive targets for therapeutic drug development. Thus, proteinases in general must now be considered as 'hormone-like' messengers that can signal either via PARs or other mechanisms.
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Kawada M, Arihiro A, Mizoguchi E. Insights from advances in research of chemically induced experimental models of human inflammatory bowel disease. World J Gastroenterol 2007; 13:5581-93. [PMID: 17948932 PMCID: PMC4172737 DOI: 10.3748/wjg.v13.i42.5581] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), the most important being Crohn's disease and ulcerative colitis, results from chronic dysregulation of the mucosal immune system in the gastrointestinal tract. Although the pathogenesis of IBD remains unclear, it is widely accepted that genetic, environmental, and immunological factors are involved. Recent studies suggest that intestinal epithelial defenses are important to prevent inflammation by protecting against microbial pathogens and oxidative stresses. To investigate the etiology of IBD, animal models of experimental colitis have been developed and are frequently used to evaluate new anti-inflammatory treatments for IBD. Several models of experimental colitis that demonstrate various pathophysiological aspects of the human disease have been described. In this manuscript, we review the characteristic features of IBD through a discussion of the various chemically induced experimental models of colitis (e.g., dextran sodium sulfate-, 2,4,6-trinitrobenzene sulfonic acid-, oxazolone-, acetic acid-, and indomethacin-induced models). We also summarize some regulatory and pathogenic factors demonstrated by these models that can, hopefully, be exploited to develop future therapeutic strategies against IBD.
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Kawabata A, Matsunami M, Sekiguchi F. Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol 2007; 153 Suppl 1:S230-40. [PMID: 17994114 DOI: 10.1038/sj.bjp.0707491] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
It has been almost a decade since the molecular cloning of all four members of the proteinase-activated receptor (PAR) family was completed. This unique family of G protein-coupled receptors (GPCRs) mediates specific cellular actions of various endogenous proteinases including thrombin, trypsin, tryptase, etc. and also certain exogenous enzymes. Increasing evidence has been clarifying the emerging roles played by PARs in health and disease. PARs, particularly PAR1 and PAR2, are distributed throughout the gastrointestinal (GI) tract, modulating various GI functions. One of the most important GI functions of PARs is regulation of exocrine secretion in the salivary glands, pancreas and GI mucosal epithelium. PARs also modulate motility of GI smooth muscle, involving multiple mechanisms. PAR2 appears to play dual roles in pancreatitis and related pain, being pro-inflammatory/pro-nociceptive and anti-inflammatory/anti-nociceptive. Similarly, dual roles for PAR1 and PAR2 have been demonstrated in mucosal inflammation/damage throughout the GI tract. There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases.
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Affiliation(s)
- A Kawabata
- Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
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Shpacovitch V, Feld M, Bunnett NW, Steinhoff M. Protease-activated receptors: novel PARtners in innate immunity. Trends Immunol 2007; 28:541-50. [PMID: 17977790 DOI: 10.1016/j.it.2007.09.001] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Revised: 09/08/2007] [Accepted: 09/19/2007] [Indexed: 11/17/2022]
Abstract
Protease-activated receptors (PARs) belong to a family of G protein-coupled receptors activated by serine proteases via proteolytic cleavage. PARs are expressed on epithelial cells, endothelial cells, and leukocytes, indicating a role in controlling barrier function against external danger. During inflammation, microorganisms as well as host immune cells release various proteases activating PARs. Thus, PARs can be viewed as an integral component of the host antimicrobial alarm system. When stimulated, PARs regulate various functions of leukocytes in vivo and in vitro, revealing a novel pathway by which proteases affect innate immune responses. Understanding protease-immune interactions could lead to novel strategies for the treatment of infectious and immune-related diseases.
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Affiliation(s)
- V Shpacovitch
- Department of Dermatology and Ludwig Boltzmann Institute for Cell Biology of the Skin, University of Münster, D-48149 Münster, Germany
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Naldini A, Morena E, Filippi I, Pucci A, Bucci M, Cirino G, Carraro F. Thrombin Inhibits IFN-γProduction in Human Peripheral Blood Mononuclear Cells by Promoting a Th2 Profile. J Interferon Cytokine Res 2006; 26:793-9. [PMID: 17115897 DOI: 10.1089/jir.2006.26.793] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Thrombin, the key enzyme of the coagulation cascade, is involved in inflammation. It was proposed recently that thrombin activity may play an important role in allergic inflammation. Interferon-gamma (IFN-gamma) is a potent Th1-related cytokine secreted by activated T cells and is usually downregulated in allergic inflammation. We recently demonstrated that thrombin enhances interleukin-10 (IL-10) in peripheral blood mononuclear cells (PBMC). Thus, we hypothesized that thrombin may promote a Th2 profile. We here report that human alpha- thrombin downregulates IFN-gamma expression at both protein and mRNA levels in activated PBMCs. The use of proteolytically inactive thrombin and of the specific thrombin receptor agonist peptide, SFLLRN, shows that this downregulation is thrombin specific and requires thrombin proteolytic activity. The addition of an anti- IL-10 monoclonal antibody (mAb) to thrombin-treated PBMCs abolishes IFN-gamma downregulation, suggesting that thrombin exerts its effect through IL-10, a Th2-related cytokine. Furthermore, IFN-gamma reduction was accompanied by increased IL-4 release, as well as by an increase in the proinflammatory cytokine IL-1. In conclusion, the observation that thrombin affects the production of IFN-gamma (Th1 profile) and IL-4 (Th2 profile) provides further evidence for the role played by thrombin in modulating Th1/Th2 cytokine balance, which could be particularly relevant in allergic inflammation.
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