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von Meijenfeldt FA, Lisman T, Pacheco A, Zen Y, Bernal W. Histologic evidence of neutrophil extracellular traps and fibrin(ogen) deposition in liver biopsies from patients with inflammatory liver disease. Res Pract Thromb Haemost 2025; 9:102666. [PMID: 39959636 PMCID: PMC11830338 DOI: 10.1016/j.rpth.2024.102666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 02/18/2025] Open
Abstract
Background Liver disease is often characterized by the activation of coagulation and inflammation. Experimental studies suggest that the interaction between neutrophils and platelets with local activation of coagulation could contribute to liver injury progression, but there have been limited studies in humans. Objectives We studied the hemostatic components and neutrophil extracellular traps (NETs) in liver biopsies from patients with different inflammatory liver diseases. Methods Liver biopsies from patients with inflammatory liver disease (alcoholic steatohepatitis [ASH], autoimmune hepatitis, primary sclerosing cholangitis, metabolic-associated steatohepatitis, and allograft ischemia-reperfusion injury (IRI), each n = 20) were stained for fibrin(ogen), platelets, and NETs. The correlation of NET formation with deposition of hemostatic components and laboratory measures of disease severity was investigated. Results In 75% of the liver biopsies, no fibrin(ogen) was detectable, and only 20% of the biopsies showed minimal deposition. Overall, 50% of liver biopsies stained positive for NETs. Platelet deposition and NET formation were highest in IRI, where it correlated with histologic severity of injury (r = .61 [95% CI, .22-.84]; P < .01) and ASH. Platelet deposition was associated with NET formation (r = .44 [95% CI, .27-.59]; P < .001) and colocalized in the biopsies. NET formation, but not fibrin and platelet deposition, was moderately associated with the model of end-stage liver disease score (r = .29 [95% CI, .07-.49]; P < .01). Conclusion In contrast to experimental studies, we demonstrated minimal intrahepatic fibrin(ogen) deposition in different types of human inflammatory liver disease. Histologic evidence for intrahepatic NETs was common and most pronounced in acute ASH and IRI and was associated with platelet deposition and disease severity.
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Affiliation(s)
- Fien A. von Meijenfeldt
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Alessandra Pacheco
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - Yoh Zen
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom
| | - William Bernal
- Institute of Liver Studies, King’s College Hospital, London, United Kingdom
- Liver Intensive Care Unit, Institute of Liver Studies, King’s College Hospital, London, United Kingdom
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Tarchi SM, Salvatore M, Lichtenstein P, Sekar T, Capaccione K, Luk L, Shaish H, Makkar J, Desperito E, Leb J, Navot B, Goldstein J, Laifer S, Beylergil V, Ma H, Jambawalikar S, Aberle D, D'Souza B, Bentley-Hibbert S, Marin MP. Radiology of fibrosis part III: genitourinary system. J Transl Med 2024; 22:616. [PMID: 38961396 PMCID: PMC11223291 DOI: 10.1186/s12967-024-05333-1] [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: 02/12/2024] [Accepted: 05/20/2024] [Indexed: 07/05/2024] Open
Abstract
Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.
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Affiliation(s)
- Sofia Maria Tarchi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA.
| | - Mary Salvatore
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Philip Lichtenstein
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Thillai Sekar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Kathleen Capaccione
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Lyndon Luk
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Hiram Shaish
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jasnit Makkar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Elise Desperito
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jay Leb
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Benjamin Navot
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jonathan Goldstein
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Sherelle Laifer
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Volkan Beylergil
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Hong Ma
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Sachin Jambawalikar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Dwight Aberle
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Belinda D'Souza
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Stuart Bentley-Hibbert
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Monica Pernia Marin
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
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Tarchi SM, Salvatore M, Lichtenstein P, Sekar T, Capaccione K, Luk L, Shaish H, Makkar J, Desperito E, Leb J, Navot B, Goldstein J, Laifer S, Beylergil V, Ma H, Jambawalikar S, Aberle D, D'Souza B, Bentley-Hibbert S, Marin MP. Radiology of fibrosis part II: abdominal organs. J Transl Med 2024; 22:610. [PMID: 38956593 PMCID: PMC11218138 DOI: 10.1186/s12967-024-05346-w] [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: 02/12/2024] [Accepted: 05/25/2024] [Indexed: 07/04/2024] Open
Abstract
Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.
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Affiliation(s)
- Sofia Maria Tarchi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA.
| | - Mary Salvatore
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Philip Lichtenstein
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Thillai Sekar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kathleen Capaccione
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Lyndon Luk
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hiram Shaish
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jasnit Makkar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Elise Desperito
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jay Leb
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Benjamin Navot
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Jonathan Goldstein
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sherelle Laifer
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Volkan Beylergil
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Hong Ma
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Sachin Jambawalikar
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Dwight Aberle
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | - Belinda D'Souza
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Monica Pernia Marin
- Department of Radiology, Columbia University Irving Medical Center, New York, NY, USA
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Tarchi SM, Salvatore M, Lichtenstein P, Sekar T, Capaccione K, Luk L, Shaish H, Makkar J, Desperito E, Leb J, Navot B, Goldstein J, Laifer S, Beylergil V, Ma H, Jambawalikar S, Aberle D, D'Souza B, Bentley-Hibbert S, Marin MP. Radiology of fibrosis. Part I: Thoracic organs. J Transl Med 2024; 22:609. [PMID: 38956586 PMCID: PMC11218337 DOI: 10.1186/s12967-024-05244-1] [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: 02/12/2024] [Accepted: 04/27/2024] [Indexed: 07/04/2024] Open
Abstract
Sustained injury from factors such as hypoxia, infection, or physical damage may provoke improper tissue repair and the anomalous deposition of connective tissue that causes fibrosis. This phenomenon may take place in any organ, ultimately leading to their dysfunction and eventual failure. Tissue fibrosis has also been found to be central in both the process of carcinogenesis and cancer progression. Thus, its prompt diagnosis and regular monitoring is necessary for implementing effective disease-modifying interventions aiming to reduce mortality and improve overall quality of life. While significant research has been conducted on these subjects, a comprehensive understanding of how their relationship manifests through modern imaging techniques remains to be established. This work intends to provide a comprehensive overview of imaging technologies relevant to the detection of fibrosis affecting thoracic organs as well as to explore potential future advancements in this field.
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Affiliation(s)
- Sofia Maria Tarchi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA.
| | - Mary Salvatore
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Philip Lichtenstein
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Thillai Sekar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Kathleen Capaccione
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Lyndon Luk
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Hiram Shaish
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jasnit Makkar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Elise Desperito
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jay Leb
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Benjamin Navot
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Jonathan Goldstein
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Sherelle Laifer
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Volkan Beylergil
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Hong Ma
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Sachin Jambawalikar
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Dwight Aberle
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Belinda D'Souza
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Stuart Bentley-Hibbert
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
| | - Monica Pernia Marin
- Department of Radiology, Columbia University Irving Medical Center, 630 W 168th Street, New York, NY, 10032, USA
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Heidari Z, Naeimzadeh Y, Fallahi J, Savardashtaki A, Razban V, Khajeh S. The Role of Tissue Factor In Signaling Pathways of Pathological Conditions and Angiogenesis. Curr Mol Med 2024; 24:1135-1151. [PMID: 37817529 DOI: 10.2174/0115665240258746230919165935] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 10/12/2023]
Abstract
Tissue factor (TF) is an integral transmembrane protein associated with the extrinsic coagulation pathway. TF gene expression is regulated in response to inflammatory cytokines, bacterial lipopolysaccharides, and mechanical injuries. TF activity may be affected by phosphorylation of its cytoplasmic domain and alternative splicing. TF acts as the primary initiator of physiological hemostasis, which prevents local bleeding at the injury site. However, aberrant expression of TF, accompanied by the severity of diseases and infections under various pathological conditions, triggers multiple signaling pathways that support thrombosis, angiogenesis, inflammation, and metastasis. Protease-activated receptors (PARs) are central in the downstream signaling pathways of TF. In this study, we have reviewed the TF signaling pathways in different pathological conditions, such as wound injury, asthma, cardiovascular diseases (CVDs), viral infections, cancer and pathological angiogenesis. Angiogenic activities of TF are critical in the repair of wound injuries and aggressive behavior of tumors, which are mainly performed by the actions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF1-α). Pro-inflammatory effects of TF have been reported in asthma, CVDs and viral infections, including COVID-19, which result in tissue hypertrophy, inflammation, and thrombosis. TF-FVII induces angiogenesis via clotting-dependent and -independent mechanisms. Clottingdependent angiogenesis is induced via the generation of thrombin and cross-linked fibrin network, which facilitate vessel infiltration and also act as a reservoir for endothelial cells (ECs) growth factors. Expression of TF in tumor cells and ECs triggers clotting-independent angiogenesis through induction of VEGF, urokinase-type plasminogen activator (uPAR), early growth response 1 (EGR1), IL8, and cysteine-rich angiogenic inducer 61 (Cyr61).
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Affiliation(s)
- Zahra Heidari
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahid Razban
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahar Khajeh
- Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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6
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Swan D, Lisman T, Tripodi A, Thachil J. The prothrombotic tendency of metabolic-associated fatty liver disease. J Thromb Haemost 2023; 21:3045-3055. [PMID: 37353082 DOI: 10.1016/j.jtha.2023.06.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 06/12/2023] [Indexed: 06/25/2023]
Abstract
Our understanding of the function of the liver has evolved over the centuries. Early theories proposing that the liver could be used to divine the future have been superseded by our current knowledge of the importance of the liver in processes such as digestion and detoxification. Similarly, although liver disease was previously associated with only an increased risk of bleeding, there is now a substantial body of evidence demonstrating an increased thrombotic potential in patients with this disease. Metabolic-associated fatty liver disease (MAFLD) is increasing in frequency and is likely to overtake alcoholic liver disease as the primary indication for liver transplant in the future. In this review, we discuss the evidence linking liver disease, and MAFLD in particular, with arterial and venous thromboembolic disease. We review the safety and efficacy of anticoagulation in advanced liver disease and consider whether antithrombotic agents could slow or halt the progression of fibrosis in MAFLD.
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Affiliation(s)
- Dawn Swan
- Department of Haematology, Beaumont Hospital, Dublin, Ireland.
| | - Ton Lisman
- Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Armando Tripodi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Luigi Villa, Milano, Italy
| | - Jecko Thachil
- Department of Haematology, Manchester University Hospitals, Oxford Road, Manchester, UK
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Wu X, Zhu Y, Guo Y, Zhao Z, Li Z. Grb2-related adaptor protein GRAP is a novel regulator of liver fibrosis. Life Sci 2023; 327:121861. [PMID: 37343720 DOI: 10.1016/j.lfs.2023.121861] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/07/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
AIMS Excessive liver fibrosis is frequently observed in chronic liver diseases and associated with decline of liver functions. Hepatic stellate cells (HSCs) are considered the principal mediator of liver fibrosis by trans-differentiating into myofibroblasts. In the present study we investigated the role of Grb2-related adaptor protein (GRAP) in HSC activation and liver fibrosis. METHODS AND MATERIALS Liver fibrosis was induced by carbon tetrachloride (CCl4) injection. Gene expression was examined by quantitative PCR. Cell proliferation was evaluated by EdU incorporation. DNA-protein interaction was examined by chromatin immunoprecipitation (ChIP). KEY FINDINGS GRAP expression was up-regulated during HSC-myofibroblast transition both in vivo and in vitro. Mechanistically, serum response factor (SRF) and myocardin-related transcription factor A (MRTF-A) formed a complex to bind to the GRAP promoter and activate GRAP transcription. Small interfering RNA (siRNA) mediated GRAP silencing blocked HSC-myofibroblast transition in vitro. Importantly, adeno-associated virus 6 (AAV6) mediated GRAP knockdown in myofibroblasts attenuated liver fibrosis in mice. Of note, inhibition of ERK signaling abrogated enhancement of HSC-myofibroblast transition by GRAP over-expression. SIGNIFICANCE Our data suggest that GRAP, possibly via ERK activation, regulates HSC-myofibroblast transition and contributes to liver fibrosis. Screening for small-molecule GRAP inhibitors may yield novel therapeutic solutions against liver fibrosis.
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Affiliation(s)
- Xiaoyan Wu
- School of Sports and Health, Nanjing Sport Institute, Nanjing, China.
| | - Yuwen Zhu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yan Guo
- Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Zhigang Zhao
- Department of Rehabilitation, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zheng Li
- Department of Rehabilitation, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
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Yang X, Ou Y, Yang Y, Wang L, Zhang Y, Zhao F, Shui P, Qing J. Targeting endothelial coagulation signaling ameliorates liver obstructive cholestasis and dysfunctional angiogenesis. Exp Biol Med (Maywood) 2023; 248:1242-1253. [PMID: 37644866 PMCID: PMC10621472 DOI: 10.1177/15353702231191190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 05/08/2023] [Indexed: 08/31/2023] Open
Abstract
Cholestatic fibrogenesis is a pathobiological process in which cumulative injury to the bile ducts coincides with progressive liver fibrosis. The pathobiologic mechanisms underlying fibrogenesis and disease progression remain poorly understood. Currently, there is no effective treatment for liver fibrosis. In this study, we discovered that components of the coagulation cascade were associated with the advanced progression of obstructive cholestasis, and anticoagulant therapy could improve liver cholestasis-induced fibrosis. In a mouse model of common bile duct ligation (BDL), which mimics cholestatic liver injury, RNA sequencing analysis revealed an increased expression of coagulation factors in endothelial cells. Pharmacological targeting of the coagulation signaling by hirudin, an anticoagulatory antagonist of thrombin, ameliorated obstructive cholestasis, and attenuated liver fibrosis symptoms. Hirudin attenuated fibrosis-associated angiogenesis, endothelial-to-mesenchymal transition (EndMT), and tissue hypoxia and reduced liver inflammation after BDL. Furthermore, hirudin suppressed YAP (Yes-associated protein) signaling and its downstream effectors in vascular endothelial cells, which are considered with profibrotic characteristics. In conclusion, we demonstrated that pharmacological targeting of coagulation signaling by hirudin has the potential to alleviate liver obstructive cholestasis and fibrosis.
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Affiliation(s)
- Xue Yang
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
- Department of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Yangying Ou
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
| | - Ying Yang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
| | - Lu Wang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yuwei Zhang
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
| | - Fulan Zhao
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
| | - Pixian Shui
- Department of Pharmacy, Southwest Medical University, Luzhou 646000, China
| | - Jie Qing
- National Traditional Chinese Medicine Clinical Research Base and Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China
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Airola C, Pallozzi M, Cerrito L, Santopaolo F, Stella L, Gasbarrini A, Ponziani FR. Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications. Cells 2023; 12:1712. [PMID: 37443746 PMCID: PMC10341358 DOI: 10.3390/cells12131712] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.
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Affiliation(s)
- Carlo Airola
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Maria Pallozzi
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Lucia Cerrito
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Francesco Santopaolo
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Leonardo Stella
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
| | - Antonio Gasbarrini
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Hepatology Unit, CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy; (C.A.); (M.P.); (L.C.); (F.S.); (L.S.); (A.G.)
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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10
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Xiao T, Ren S, Bao J, Gao D, Sun R, Gu X, Gao J, Chen S, Jin J, Wei L, Wu C, Yang C, Yang G, Zhou H. Vorapaxar proven to be a promising candidate for pulmonary fibrosis by intervening in the PAR1/JAK2/STAT1/3 signaling pathway-an experimental in vitro and vivo study. Eur J Pharmacol 2023; 943:175438. [PMID: 36682482 DOI: 10.1016/j.ejphar.2022.175438] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 11/20/2022] [Accepted: 11/28/2022] [Indexed: 01/21/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease, and its 5-year mortality rate is even higher than the mortality rate of some cancers. Fibrosis can cause irreversible damage to lung structure and function. Treatment options for IPF remain limited, and there is an urgent need to develop effective therapeutic drugs. Protease activated receptor-1 (PAR-1) is a G-protein-coupled receptor and is considered a potential target for the treatment of fibrotic diseases. Vorapaxar is a clinically approved PAR-1 antagonist for cardiovascular protection. The purpose of this study was to explore the potential effect and mechanism of Vorapaxar on pulmonary fibrosis in vivo and in vitro. In the experimental animal model, Vorapaxar can effectively alleviate bleomycin (BLM)-induced pulmonary fibrosis. Treatment with 2.5, 5 or 10 mg/kg Vorapaxar once a day reduced the degree of fibrosis in a dose-dependent manner. The expression of fibronectin, collagen and α smooth muscle actin decreased significantly at the messenger RNA (mRNA) and protein levels in treated mice. In vitro, our results showed that Vorapaxar could inhibit the activation of fibroblasts induced by thrombin in a dose-dependent manner. In terms of mechanism, Vorapaxar inhibits the signal transduction of JAK2/STAT1/3 by inhibiting the activation of protease activated receptor 1, which reduces the expression of HSP90β and the interaction between HSP90β and transforming growth factor-β (TGFβ) receptor II and inhibits the TGFβ/Smad signaling pathway. In conclusion, Vorapaxar inhibits the activation of pulmonary fibroblasts induced by thrombin by targeting protease activated receptor 1 and alleviates BLM-induced pulmonary fibrosis in mice.
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Affiliation(s)
- Ting Xiao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
| | - Shanfa Ren
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
| | - Jiali Bao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
| | - Dandi Gao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China; Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China
| | - Ronghao Sun
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China
| | - Xiaoting Gu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China
| | - Jingjing Gao
- Tianjin Jikun Technology Co., Ltd, Tianjin, 301700, China
| | - Shanshan Chen
- The First Affiliated Hospital of Zhengzhou University, 1 Longhu Middle Ring Road, Zhengzhou, Jinshui District, Henan Province, China
| | - Jin Jin
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Beijing, 100730, China
| | - Luqing Wei
- Tianjin Beichen Hospital, No. 7, Beiyi Road, Beichen District, Tianjin, 300400, China
| | - Chunwa Wu
- Tianjin Beichen Hospital, No. 7, Beiyi Road, Beichen District, Tianjin, 300400, China
| | - Cheng Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
| | - Guang Yang
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
| | - Honggang Zhou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, China.
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11
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Bitto N, Ghigliazza G, Lavorato S, Caputo C, La Mura V. Improving Management of Portal Hypertension: The Potential Benefit of Non-Etiological Therapies in Cirrhosis. J Clin Med 2023; 12:934. [PMID: 36769582 PMCID: PMC9917703 DOI: 10.3390/jcm12030934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Niccolò Bitto
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Gabriele Ghigliazza
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Sub-Intensive Care Medicine, 20122 Milan, Italy
| | - Stanislao Lavorato
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Camilla Caputo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Vincenzo La Mura
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
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12
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Multi-target-based polypharmacology prediction (mTPP): An approach using virtual screening and machine learning for multi-target drug discovery. Chem Biol Interact 2022; 368:110239. [DOI: 10.1016/j.cbi.2022.110239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/19/2022] [Accepted: 10/21/2022] [Indexed: 11/23/2022]
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13
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Osteogenesis in human periodontal ligament stem cell sheets is enhanced by the protease-activated receptor 1 (PAR1) in vivo. Sci Rep 2022; 12:15637. [PMID: 36117187 PMCID: PMC9482923 DOI: 10.1038/s41598-022-19520-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
Human periodontal ligament stem cells (PDLSCs) have been studied as a promising strategy in regenerative approaches. The protease-activated receptor 1 (PAR1) plays a key role in osteogenesis and has been shown to induce osteogenesis and increase bone formation in PDLSCs. However, little is known about its effects when activated in PDLSCs as a cell sheet construct and how it would impact bone formation as a graft in vivo. Here, PDLSCs were obtained from 3 patients. Groups were divided into control, osteogenic medium and osteogenic medium + PAR1 activation by TFLLR-NH2 peptide. Cell phenotype was determined by flow cytometry and immunofluorescence. Calcium deposition was quantified by Alizarin Red Staining. Cell sheet microstructure was analyzed through light, scanning electron microscopy and histology and transplanted to Balb/c nude mice. Immunohistochemistry for bone sialoprotein (BSP), integrin β1 and collagen type 1 and histological stains (H&E, Van Giesson, Masson’s Trichrome and Von Kossa) were performed on the ex-vivo mineralized tissue after 60 days of implantation in vivo. Ectopic bone formation was evaluated through micro-CT. PAR1 activation increased calcium deposition in vitro as well as BSP, collagen type 1 and integrin β1 protein expression and higher ectopic bone formation (micro-CT) in vivo.
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14
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Sakamori R, Yamada R, Tahata Y, Kodama T, Hikita H, Tatsumi T, Yamada T, Takehara T. The absence of warfarin treatment and situs inversus are associated with the occurrence of hepatocellular carcinoma after Fontan surgery. J Gastroenterol 2022; 57:111-119. [PMID: 35064829 DOI: 10.1007/s00535-021-01842-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 12/05/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a long-term complication of Fontan-associated liver disease (FALD). However, risk factors for HCC in patients with FALD remain unclear. This study aimed to identify factors associated with HCC development post-Fontan procedure. METHODS We retrospectively examined 103 post-Fontan patients who underwent hepatic imaging at our institution. HCC incidence and patient characteristics were analyzed. A Cox proportional hazards model was used to identify risk factors for HCC. RESULTS The median interval between Fontan surgery and final hepatic imaging was 19.6 (1.0-37.7) years. Among 103 patients, nine developed HCC. The cumulative incidence rates of HCC at 10, 20, and 30 years postoperatively were 0%, 7%, and 13%, respectively. In the univariate analysis, age at Fontan surgery, situs inversus, and warfarin absence were associated with HCC occurrence. The multivariate analysis identified the warfarin absence (adjusted hazard ratio [aHR], 22.71; 95% confidence interval: 3.29-507.1; p = 0.0005) and situs inversus (aHR, 14.36; 95% confidence interval: 2.75-105.5; p = 0.002) as risk factors. The prevalence of situs inversus and the warfarin absence was 12% and 50%, respectively. The 20- and 30-year incidence rates of HCC among patients who received warfarin were 0% and 7%, respectively, while those among patients who did not receive warfarin were 14% and 21%, respectively. HCC incidence was significantly higher in the non-warfarin group than in the warfarin group (p = 0.006) and among patients with situs inversus than among those with situs solitus (p = 0.004). CONCLUSIONS Warfarin absence and situs inversus were associated with HCC development post-Fontan procedure.
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Affiliation(s)
- Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuki Tahata
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomomi Yamada
- Department of Medical Innovation, Osaka University Hospital, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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15
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Lucchesi A, Napolitano R, Bochicchio MT, Giordano G, Napolitano M. Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The "Circulating Wound" Model. Int J Mol Sci 2021; 22:ijms222111343. [PMID: 34768772 PMCID: PMC8583863 DOI: 10.3390/ijms222111343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient's demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs-rich in tissue factor (TF)-in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a "circulating wound", as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications.
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MESH Headings
- Animals
- Biological Assay
- Blood Platelets/metabolism
- Humans
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/drug therapy
- Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/metabolism
- Models, Biological
- Receptors, Fibrinogen/metabolism
- Thrombin/antagonists & inhibitors
- Thrombin/biosynthesis
- Thrombophilia/physiopathology
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Affiliation(s)
- Alessandro Lucchesi
- Hematology Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Roberta Napolitano
- Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
- Correspondence:
| | - Maria Teresa Bochicchio
- Biosciences Laboratory, IRCCS Istituto Scientifico Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Giulio Giordano
- Internal Medicine Division, Hematology Service, Regional Hospital “A. Cardarelli”, 86100 Campobasso, Italy;
| | - Mariasanta Napolitano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties and Infectious Disease Unit, University Hospital “P. Giaccone”, 90127 Palermo, Italy;
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16
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Seo Y, Heo Y, Jo S, Park SH, Lee C, Chang J, Jeon DK, Kim TG, Han G, Namkung W. Novel positive allosteric modulator of protease-activated receptor 1 promotes skin wound healing in hairless mice. Br J Pharmacol 2021; 178:3414-3427. [PMID: 33837955 DOI: 10.1111/bph.15489] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 02/04/2021] [Accepted: 03/29/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Protease-activated receptor 1 (PAR1) is a GPCR expressed in several skin cell types, including keratinocyte and dermal fibroblast. PAR1 activation plays a crucial role in the process of skin wound healing such as thrombosis, inflammation, proliferation and tissue repair. In the present study, we identified a novel positive allosteric modulator of PAR1, GB83, and investigated its effect on skin wound healing. EXPERIMENTAL APPROACH The enhancement of PAR1 activity by GB83 was measured using Fluo-4 calcium assay. In silico docking analysis of GB83 in PAR1 was performed using dock ligands method (CDOCKER) with CHARMm force field. Effects of GB83 on cell viability and gene expression were observed using MTS assay and quantitative real-time PCRs, respectively. SKH-1 hairless mice were used to investigate the wound healing effect of GB83. KEY RESULTS We demonstrated that GB83 did not activate PAR1 by itself but strongly enhanced PAR1 activation by thrombin and PAR1-activating peptide (AP). In silico docking analysis revealed that GB83 can bind to the PAR1 binding site of vorapaxar. GB83 significantly promoted PAR1-mediated cell viability and migration. In addition, the enhancement of PAR1 activity by GB83 strongly increased gene expression of TGF-β, fibronectin and type I collagen in vitro and promoted skin wound healing in vivo. CONCLUSION AND IMPLICATIONS Our results revealed that GB83 is the first positive allosteric modulator of PAR1 and it can be a useful pharmacological tool for studying PAR1 and a potential therapeutic agent for skin wound healing.
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Affiliation(s)
- Yohan Seo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.,Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea.,New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Yunkyung Heo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Sungwoo Jo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - So-Hyeon Park
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon, Republic of Korea
| | - Chulho Lee
- Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea.,Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jiwon Chang
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Dong-Kyu Jeon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea
| | - Tae Gun Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Gyoonhee Han
- Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea.,Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Wan Namkung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.,Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Republic of Korea
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17
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Shouman MM, Abdelsalam RM, Tawfick MM, Kenawy SA, El-Naa MM. Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway. Front Pharmacol 2021; 12:676608. [PMID: 34045968 PMCID: PMC8144514 DOI: 10.3389/fphar.2021.676608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/27/2021] [Indexed: 11/13/2022] Open
Abstract
Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant pathways involved in different pathological conditions such as angiogenesis, inflammation and fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense oligodeoxynucleotides are strong modulators of gene expression. In the present study, antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via suppression of TF gene expression. Liver fibrosis was induced in rats by a single administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction, liver TF expression was significantly upregulated along with liver enzymes activities and liver histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth factor-1beta (TGF-1β) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline content and collagen deposition were significantly elevated in the liver. Blocking of TF expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly restored liver enzymes activities and improved histopathological features along with decreasing the elevated α-SMA, TGF-1β, TNF-α, hydroxyproline and collagen. Moreover, TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform on which recovery from liver fibrosis could be mediated through targeting TF expression.
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Affiliation(s)
- Maha M Shouman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern Sciences and Arts University (MSA), Giza, Egypt
| | - Rania M Abdelsalam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,Department of Biology, Faculty of Pharmacy, New Giza University, Giza, Egypt
| | - Mahmoud M Tawfick
- Department of Microbiology and Immunology, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mona M El-Naa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
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18
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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis? Clin Sci (Lond) 2020; 134:2189-2201. [PMID: 32844997 DOI: 10.1042/cs20191102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 08/16/2020] [Accepted: 08/18/2020] [Indexed: 12/13/2022]
Abstract
Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis - the chronic nature of insult required and the liver's unique ability to regenerate - give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.
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19
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A direct thrombin inhibitor, dabigatran etexilate protects from renal fibrosis by inhibiting protease activated receptor-1. Eur J Pharmacol 2020; 893:173838. [PMID: 33359646 DOI: 10.1016/j.ejphar.2020.173838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/16/2020] [Accepted: 12/22/2020] [Indexed: 11/23/2022]
Abstract
Chronic kidney disease (CKD) involves interstitial fibrosis as an influential underlying pathological process associated with compromised renal function regardless of etiological cause of the injury. The tubulointerstitial fibrosis is found to be well correlated with declining renal function and its subsequent culmination into renal failure. Given the prominent role of thrombin in multiple diseases, it was tempting for us to investigate the outcome of a direct thrombin inhibitor in renal injury. We investigated the involvement of thrombin in renal injury and fibrosis by using an FDA approved orally active, direct thrombin inhibitor, dabigatran etexilate (DB). We used a robust experimental model of unilateral ureteral obstruction (UUO)-induced renal injury which shows progressive tubulointerstitial fibrosis (TIF) along with tubular injury and inflammation. The obstructed kidney showed severe TIF as compared to control kidneys. The administration of DB significantly inhibited UUO-induced collagen-1 and TIF by inhibition of thrombin activated protease activated receptor (PAR)-1 expression in fibrotic kidney. In addition, DB administration improved histoarchitecture of obstructed kidney, inhibited TGF-β and SNAI2-induced epithelial-mesenchymal transition (EMT) program. Our study highlights the importance of thrombin signalling in TIF and provides strong evidences to support the notion that a direct thrombin inhibitor ameliorates TIF by PAR-1 mediated mechanism.
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20
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Poole LG, Pant A, Cline‐Fedewa HM, Williams KJ, Copple BL, Palumbo JS, Luyendyk JP. Liver fibrosis is driven by protease-activated receptor-1 expressed by hepatic stellate cells in experimental chronic liver injury. Res Pract Thromb Haemost 2020; 4:906-917. [PMID: 32685902 PMCID: PMC7354391 DOI: 10.1002/rth2.12403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 05/14/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Blood coagulation protease activity is proposed to drive hepatic fibrosis through activation of protease-activated receptors (PARs). Whole-body PAR-1 deficiency reduces experimental hepatic fibrosis, and in vitro studies suggest a potential contribution by PAR-1 expressed by hepatic stellate cells. However, owing to a lack of specific tools, the cell-specific role of PAR-1 in experimental hepatic fibrosis has never been formally investigated. Using a novel mouse expressing a conditional PAR-1 allele, we tested the hypothesis that PAR-1 expressed by hepatic stellate cells contributes to hepatic fibrosis. METHODS PAR-1flox/flox mice were crossed with mice expressing Cre recombinase controlled by the lecithin retinol acyltransferase (LRAT) promoter, which induces recombination in hepatic stellate cells. Male PAR-1flox/flox/LRATCre and PAR-1flox/flox mice were challenged twice weekly with carbon tetrachloride (CCl4, 1 mL/kg i.p.) for 6 weeks to induce liver fibrosis. RESULTS PAR-1 mRNA levels were reduced (>95%) in hepatic stellate cells isolated from PAR-1flox/flox/LRATCre mice. Hepatic stellate cell activation was evident in CCl4-challenged PAR-1flox/flox mice, indicated by increased α-smooth muscle actin labeling and induction of several profibrogenic genes. CCl4-challenged PAR-1flox/flox mice displayed robust hepatic collagen deposition, indicated by picrosirius red staining and type I collagen immunolabeling. Notably, stellate cell activation and collagen deposition were significantly reduced (>30%) in PAR-1flox/flox/LRATCre mice. Importantly, the reduction in liver fibrosis was not a consequence of reduced acute CCl4 hepatotoxicity in PAR-1flox/flox/LRATCre mice. CONCLUSIONS The results constitute the first direct experimental evidence that PAR-1 expressed by stellate cells directly promotes their profibrogenic phenotype and hepatic fibrosis in vivo.
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Affiliation(s)
- Lauren G. Poole
- Institute for Integrative ToxicologyMichigan State UniversityEast LansingMIUSA
- Department of Pathobiology & Diagnostic InvestigationMichigan State UniversityEast LansingMIUSA
| | - Asmita Pant
- Department of Pathobiology & Diagnostic InvestigationMichigan State UniversityEast LansingMIUSA
| | - Holly M. Cline‐Fedewa
- Department of Pathobiology & Diagnostic InvestigationMichigan State UniversityEast LansingMIUSA
| | - Kurt J. Williams
- Department of Pathobiology & Diagnostic InvestigationMichigan State UniversityEast LansingMIUSA
| | - Bryan L. Copple
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
| | - Joseph S. Palumbo
- Cancer and Blood Diseases InstituteCincinnati Children’s Hospital Medical Center and the University of Cincinnati College of MedicineCincinnatiOHUSA
| | - James P. Luyendyk
- Institute for Integrative ToxicologyMichigan State UniversityEast LansingMIUSA
- Department of Pathobiology & Diagnostic InvestigationMichigan State UniversityEast LansingMIUSA
- Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingMIUSA
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21
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Maruyama S, Kono H, Furuya S, Shimizu H, Saito R, Shoda K, Akaike H, Hosomura N, Kawaguchi Y, Amemiya H, Kawaida H, Sudo M, Inoue S, Shirai T, Suzuki-Inoue K, Ichikawa D. Platelet C-Type Lectin-Like Receptor 2 Reduces Cholestatic Liver Injury in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1833-1842. [PMID: 32473917 DOI: 10.1016/j.ajpath.2020.05.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Cholestatic liver injury leads to liver dysfunction. The available evidence suggests that platelets can either promote or reduce liver injury and fibrosis. This study focused on the functions of the C-type lectin-like receptor 2 (CLEC-2), a new special platelet receptor that binds with podoplanin-activating platelets. The role of CLEC-2 and podoplanin in cholestatic liver injury was investigated. Mice were injected intraperitoneally with weekly doses of anti-CLEC-2 antibody (2A2B10) to achieve effective CLEC-2 inhibition in their platelets. Next, left and middle hepatic bile duct ligation (BDL) procedures were performed, and mice were euthanized 1 week later (2A2B10-BDL group). In addition, mice were prepared for control groups, and relevant histological and laboratory variables were compared among these groups. The inhibition of CLEC-2 resulted in increasing hepatocellular necrosis, hepatic inflammation, and liver fibrosis. In addition, podoplanin was strongly expressed in hepatic sinusoidal endothelial cells in BDL-treated mice. Moreover, in 2A2B10-BDL mice, total plasma bile acid levels were significantly increased. In summary, podoplanin is expressed on hepatic sinusoidal endothelial cells upon BDL. Platelets bind with podoplanin via CLEC-2 and become activated. As a result, the total bile acid pool is decreased. Therefore, the CLEC-2-podoplanin interaction promotes liver protection and inhibits liver fibrosis after cholestatic liver injury.
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Affiliation(s)
- Suguru Maruyama
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Hiroshi Kono
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan.
| | - Shinji Furuya
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Hiroki Shimizu
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Ryo Saito
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Katsutoshi Shoda
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Hidenori Akaike
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Naohiro Hosomura
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Yoshihiko Kawaguchi
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Hidetake Amemiya
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Hiromichi Kawaida
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Makoto Sudo
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Shingo Inoue
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Toshiaki Shirai
- Department of Clinical and Laboratory Medicine, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Katsue Suzuki-Inoue
- Department of Clinical and Laboratory Medicine, Faculty of Medicine University of Yamanashi, Chuo, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine University of Yamanashi, Chuo, Japan
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22
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Lafoz E, Ruart M, Anton A, Oncins A, Hernández-Gea V. The Endothelium as a Driver of Liver Fibrosis and Regeneration. Cells 2020; 9:E929. [PMID: 32290100 PMCID: PMC7226820 DOI: 10.3390/cells9040929] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.
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Affiliation(s)
- Erica Lafoz
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Maria Ruart
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Aina Anton
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Anna Oncins
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
| | - Virginia Hernández-Gea
- Unidad de Hemodinámica Hepática, Servicio de Hepatología, Hospital Clínic, Universidad de Barcelona, Instituto de Investigaciones Biomédicas Augusto Pi Suñer (IDIBAPS), 08036 Barcelona, Spain; (E.L.); (M.R.); (A.A.); (A.O.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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23
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Xie H, Su D, Zhang J, Ji D, Mao J, Hao M, Wang Q, Yu M, Mao C, Lu T. Raw and vinegar processed Curcuma wenyujin regulates hepatic fibrosis via bloking TGF-β/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. JOURNAL OF ETHNOPHARMACOLOGY 2020; 246:111768. [PMID: 30849507 DOI: 10.1016/j.jep.2019.01.045] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Curcuma wenyujin Y.H. (CW), a variety of Curumae Rhizoma, which documented in China Pharmacopeia, has long been used as plant medicine for its traditional effect on promoting Qi, activating blood stagnation and expelling blood stasis. Nowadays, it is often used in clinic for extraordinary effect on liver diseases. It is worthy to be noted that CW processed with vinegar has been applied in clinic for 1500 years which started in the northern and southern dynasties. AIM OF STUDY Liver fibrosis is a worldwide clinical issue. It is worth developing a multi-target and multicellular approach which is high efficiency and low side effects for the treatment of hepatic fibrosis. The anti-hepatic fibrosis molecular mechanisms of CW and vinegar Curcuma wenyujin (VCW) need to be explored and elucidated. Furthermore, the study aimed to discuss the efficiency and mechanism differences between CW and VCW in hepatic fibrosis. METHODS AND RESULTS Biochemical assays and histopathology were adopted to evaluate the anti-hepatic fibrosis effect of CW and VCW. The TGF-β/Smad signaling involving TGF-β1, TGF-βRⅠ, TGF-βRⅡ and Smad2, Smad3, Smad7 in fibrosis is examined, which is a critical step towards the evaluation of anti-hepatic fibrosis agents. Meanwhile, the MMP/TIMP balance is a potential therapy target by modulating extracellular matrix, which is also examined. Both CW and VCW inhibit the activation and proliferation of hepatic stellate cells and induce apoptosis via blocking TGF-β/Smad signaling pathways. Additionally, the level of MMP-2/TIMP-1 regulated significantly, which suggest CW and VCW participate in the degradation process, and maintain the formation and production of extracellular matrix. CONCLUSION Raw and vinegar processed Curcuma wenyujin regulates hepatic fibrosis via bloking TGF-β/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. And VCW has more exhibition than CW.
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Affiliation(s)
- Hui Xie
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - Dan Su
- School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Ji Zhang
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - De Ji
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - Jing Mao
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - Min Hao
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - Qiaohan Wang
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China
| | - Mengting Yu
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China; School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China
| | - Chunqin Mao
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China.
| | - Tulin Lu
- School of Pharmacy, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China.
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24
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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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25
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Rogalski P, Rogalska-Plonska M, Wroblewski E, Kostecka-Roslen I, Dabrowska M, Swidnicka-Siergiejko A, Wasielica-Berger J, Cydzik M, Hirnle T, Flisiak R, Dabrowski A. Laboratory evidence for hypercoagulability in cirrhotic patients with history of variceal bleeding. Thromb Res 2019; 178:41-46. [PMID: 30959281 DOI: 10.1016/j.thromres.2019.03.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 03/01/2019] [Accepted: 03/31/2019] [Indexed: 12/18/2022]
Abstract
AIM We aimed to assess the relationship between procoagulant imbalance and the occurrence of variceal bleeding in patients with liver cirrhosis. METHODS We compared the results of chromogenic assay for the functional evaluation of the Protein C anticoagulant pathway (ThromboPath®), thromboelastometry and the levels of factor VII, VIII, and antithrombin in two groups of cirrhotic patients: Group 1 (n = 25) - patients with moderate or large esophageal or gastric varices, who had never experienced acute gastrointestinal bleeding and Group 2 (n = 24) - patients with a history of variceal bleeding. RESULTS Despite the differences in MELD score and the results of basic laboratory tests indicating more severe cirrhosis and suggesting a greater risk of bleeding in Group 2, the results of thromboelastometry did not differ significantly between groups. The ThromboPath® test results [ThP B: 67.8 ± 13.4 versus 59.09 ± 12.4%, p = 0.023] and factor VII level [69.04 ± 24.16 vs 53.54 ± 25.06, p = 0.032] confirmed greater plasma procoagulant activity in Group 1 compared to Group 2. However, there were no statistically significant differences in thrombin generation after activation of the protein C. Plasma of patients in Group 2 was more resistant to anticoagulation with protein C compared to Group 1 (PICI%: 65.58 ± 7.24 versus 55.64 ± 13.07%, p = 0.001). CONCLUSION The results of our study confirm the lack of influence of coagulation disorders on the occurrence of variceal bleeding. Moreover, the results of ThromboPath® assay indicate hypercoagulability in patients with a history of variceal bleeding and more severe liver cirrhosis, compared to patients who have never bled.
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Affiliation(s)
- Pawel Rogalski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland.
| | - Magdalena Rogalska-Plonska
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Eugeniusz Wroblewski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Ines Kostecka-Roslen
- Department of Hematological Diagnostics, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Milena Dabrowska
- Department of Hematological Diagnostics, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Agnieszka Swidnicka-Siergiejko
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Justyna Wasielica-Berger
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Mariusz Cydzik
- Department of Cardiosurgery, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Tomasz Hirnle
- Department of Cardiosurgery, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
| | - Andrzej Dabrowski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Sklodowskiej - Curie 24a, 15-276 Bialystok, Poland
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26
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Jalal PJ, King BJ, Saeed A, Adedeji Y, Mason CP, Ball JK, Irving WL, McClure CP, Tarr AW. Elevated serum activity of MBL and ficolin-2 as biomarkers for progression to hepatocellular carcinoma in chronic HCV infection. Virology 2019; 530:99-106. [PMID: 30798068 DOI: 10.1016/j.virol.2019.02.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 02/04/2019] [Accepted: 02/04/2019] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is an uncommon but significant outcome of chronic hepatitis C virus (HCV) infection. A serum biomarker for predicting progression to HCC would have a major impact on patient monitoring and clinical management. We explored circulating liver-expressed lectins, ficolin-2, ficolin-3 and mannose binding lectin (MBL), as potential biomarkers for the development of HCC. The activity of these three lectins were analysed in HCV positive patients who developed HCC (n = 31) with comparable HCV-positive HCC-negative patients (n = 106) and healthy controls (n = 79). Serum binding activity of ficolin-2 and MBL were elevated compared to controls. Analysis of pre-HCC onset samples revealed that MBL levels were significantly elevated up to 3 years, and ficolin-2 was elevated up to 1 year, prior to diagnosis of HCC over controls. This preliminary study identifies MBL and ficolin-2 as potential biomarkers for the development of HCC in chronic HCV infection.
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Affiliation(s)
- Paywast J Jalal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; Biology Department, Faculty of Science, University of Sulaimani, Iraq
| | - Barnabas J King
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Amanj Saeed
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; Biology Department, Faculty of Science, University of Sulaimani, Iraq
| | - Yemisi Adedeji
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Christopher P Mason
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK
| | - Jonathan K Ball
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - William L Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - C Patrick McClure
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK
| | - Alexander W Tarr
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, UK; School of Life Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, UK.
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27
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Luyendyk JP, Schoenecker JG, Flick MJ. The multifaceted role of fibrinogen in tissue injury and inflammation. Blood 2019; 133:511-520. [PMID: 30523120 PMCID: PMC6367649 DOI: 10.1182/blood-2018-07-818211] [Citation(s) in RCA: 321] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/26/2018] [Indexed: 02/08/2023] Open
Abstract
The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological end points of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that affect the spectrum of tissue injury, remodeling, and repair. Indeed, fibrin(ogen) deposits are a near-universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor-targeted therapies for a range of tissue injuries and disease.
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Affiliation(s)
- James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation
- Department of Pharmacology and Toxicology, and
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI
| | - Jonathan G Schoenecker
- Department of Orthopaedics
- Department of Pharmacology
- Department of Pediatrics, and
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN; and
| | - Matthew J Flick
- Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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28
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Lee KC, Hsu WF, Hsieh YC, Chan CC, Yang YY, Huang YH, Hou MC, Lin HC. Dabigatran Reduces Liver Fibrosis in Thioacetamide-Injured Rats. Dig Dis Sci 2019; 64:102-112. [PMID: 30288660 DOI: 10.1007/s10620-018-5311-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 09/28/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.
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Affiliation(s)
- Kuei-Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Fan Hsu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hepato-Gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yun-Cheng Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Che-Chang Chan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Ying Yang
- Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan.,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, #201, Section 2, Shih-Pai Road, Taipei 112, Taiwan. .,Department of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
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29
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Poole LG, Pant A, Baker KS, Kopec AK, Cline-Fedewa HM, Iismaa SE, Flick MJ, Luyendyk JP. Chronic liver injury drives non-traditional intrahepatic fibrin(ogen) crosslinking via tissue transglutaminase. J Thromb Haemost 2019; 17:113-125. [PMID: 30415489 PMCID: PMC6322974 DOI: 10.1111/jth.14330] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Indexed: 12/25/2022]
Abstract
Essentials Fibrin clots are often implicated in the progression of liver fibrosis. Liver fibrosis was induced in transgenic mice with defects in clot formation or stabilization. Liver fibrosis and fibrin(ogen) deposition do not require fibrin polymerization or factor XIIIa. Fibrin(ogen) is an in vivo substrate of tissue transglutaminase in experimental liver fibrosis. SUMMARY: Background Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has other downstream targets that promote fibrosis. Therefore, the goal of this study was to determine the precise role of fibrin deposits in experimental hepatic fibrosis. Methods Liver fibrosis was induced in mice expressing mutant fibrinogen insensitive to thrombin-mediated proteolysis (i.e. locked in the monomeric form), termed FibAEK mice, and factor XIII A2 subunit-deficient (FXIII-/- ) mice. Female wild-type mice, FXIII-/- mice and homozygous FibAEK mice were challenged with carbon tetrachloride (CCl4 ) twice weekly for 4 weeks or 6 weeks (1 mL kg-1 , intraperitoneal). Results Hepatic injury and fibrosis induced by CCl4 challenge were unaffected by FXIII deficiency or inhibition of thrombin-catalyzed fibrin polymer formation (in FibAEK mice). Surprisingly, hepatic deposition of crosslinked fibrin(ogen) was not reduced in CCl4 -challenged FXIII-/- mice or FibAEK mice as compared with wild-type mice. Rather, deposition of crosslinked hepatic fibrin(ogen) following CCl4 challenge was dramatically reduced in tissue transglutaminase-2 (TGM2)-deficient (TGM2-/- ) mice. However, the reduction in crosslinked fibrin(ogen) in TGM2-/- mice did not affect CCl4 -induced liver fibrosis. Conclusions These results indicate that neither traditional fibrin clots, formed by the thrombin-activated FXIII pathway nor atypical TGM2-crosslinked fibrin(ogen) contribute to experimental CCl4 -induced liver fibrosis. Collectively, the results indicate that liver fibrosis occurs independently of intrahepatic fibrin(ogen) deposition.
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Affiliation(s)
- L G Poole
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - A Pant
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - K S Baker
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - A K Kopec
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - H M Cline-Fedewa
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
| | - S E Iismaa
- Division of Molecular Cardiology and Biophysics, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia
| | - M J Flick
- Cancer and Blood Diseases Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - J P Luyendyk
- Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
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30
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van Dievoet MA, Leclercq I, Hermans C, Lambert C, Horsmans Y, Jacquemin M, Eeckhoudt S. Does haemophilia slow down the development of liver fibrosis? Haemophilia 2018; 25:e32-e35. [DOI: 10.1111/hae.13630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 09/22/2018] [Accepted: 10/11/2018] [Indexed: 12/17/2022]
Affiliation(s)
| | | | | | | | - Yves Horsmans
- Cliniques Universitaires Saint-Luc; Brussels Belgium
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31
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Pant A, Kopec AK, Luyendyk JP. Role of the blood coagulation cascade in hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2018; 315:G171-G176. [PMID: 29723040 PMCID: PMC6139645 DOI: 10.1152/ajpgi.00402.2017] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 04/19/2018] [Accepted: 04/24/2018] [Indexed: 02/07/2023]
Abstract
Liver is the primary source of numerous proteins that are critical for normal function of the blood coagulation cascade. Because of this, diseases of the liver, particularly when affiliated with severe complications like cirrhosis, are associated with abnormalities of blood clotting. Although conventional interpretation has inferred cirrhosis as a disorder of uniform bleeding risk, it is now increasingly appreciated as a disease wherein the coagulation cascade is precariously rebalanced. Moreover, prothrombotic risk factors are also associated with a more rapid progression of fibrosis in humans, suggesting that coagulation proteases participate in disease pathogenesis. Indeed, strong evidence drawn from experimental animal studies indicates that components of the coagulation cascade, particularly coagulation factor Xa and thrombin, drive profibrogenic events, leading to hepatic fibrosis. Here, we concisely review the evidence supporting a pathologic role for coagulation in the development of liver fibrosis and the potential mechanisms involved. Further, we highlight how studies in experimental animals may shed light on emerging clinical evidence, suggesting that beneficial effects of anticoagulation could extend beyond preventing thrombotic complications to include reducing pathologies like fibrosis.
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Affiliation(s)
- Asmita Pant
- Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, Michigan
- Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan
| | - Anna K Kopec
- Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, Michigan
- Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan
| | - James P Luyendyk
- Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, Michigan
- Institute for Integrative Toxicology, Michigan State University , East Lansing, Michigan
- Department of Pharmacology and Toxicology, Michigan State University , East Lansing, Michigan
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32
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Bitto N, Liguori E, La Mura V. Coagulation, Microenvironment and Liver Fibrosis. Cells 2018; 7:85. [PMID: 30042349 PMCID: PMC6115868 DOI: 10.3390/cells7080085] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/19/2018] [Accepted: 07/20/2018] [Indexed: 12/12/2022] Open
Abstract
Fibrosis is the main consequence of any kind of chronic liver damage. Coagulation and thrombin generation are crucial in the physiological response to tissue injury; however, the inappropriate and uncontrolled activation of coagulation cascade may lead to fibrosis development due to the involvement of several cellular types and biochemical pathways in response to thrombin generation. In the liver, hepatic stellate cells and sinusoidal endothelial cells orchestrate fibrogenic response to chronic damage. Thrombin interacts with these cytotypes mainly through protease-activated receptors (PARs), which are expressed by endothelium, platelets and hepatic stellate cells. This review focuses on the impact of coagulation in liver fibrogenesis, describes receptors and pathways involved and explores the potential antifibrotic properties of drugs active in hemostasis in studies with cells, animal models of liver damage and humans.
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Affiliation(s)
- Niccolò Bitto
- Medicina Interna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Università Degli Studi di Milano, 20097 San Donato Milanese (MI), Italy.
| | - Eleonora Liguori
- Medicina Interna, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Donato, Università Degli Studi di Milano, 20097 San Donato Milanese (MI), Italy.
| | - Vincenzo La Mura
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, UOC Medicina Generale-Emostasi e Trombosi, 20122 Milano, Italy.
- Dipartimento di Scienze biomediche per la Salute, Università degli Studi di Milano, 20122 Milano, Italy.
- A. M. and A. Migliavacca per lo studio delle Malattie del Fegato, 20122 Milano, Italy.
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33
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Horinouchi Y, Ikeda Y, Fukushima K, Imanishi M, Hamano H, Izawa-Ishizawa Y, Zamami Y, Takechi K, Miyamoto L, Fujino H, Ishizawa K, Tsuchiya K, Tamaki T. Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis. Sci Rep 2018; 8:10858. [PMID: 30022146 PMCID: PMC6052035 DOI: 10.1038/s41598-018-29008-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 07/04/2018] [Indexed: 01/25/2023] Open
Abstract
Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis.
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Affiliation(s)
- Yuya Horinouchi
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
| | - Yasumasa Ikeda
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
| | - Keijo Fukushima
- Department of Pharmacology for Life Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Masaki Imanishi
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
| | - Hirofumi Hamano
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
| | - Yuki Izawa-Ishizawa
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yoshito Zamami
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
- Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kenshi Takechi
- Clinical Trial Center for Developmental Therapeutics, Tokushima University Hospital, Tokushima, Japan
| | - Licht Miyamoto
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Hiromichi Fujino
- Department of Pharmacology for Life Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Keisuke Ishizawa
- Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan
- Department of Clinical Pharmacology and Therapeutics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Koichiro Tsuchiya
- Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Toshiaki Tamaki
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
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34
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Dhar A, Sadiq F, Anstee QM, Levene AP, Goldin RD, Thursz MR. Thrombin and factor Xa link the coagulation system with liver fibrosis. BMC Gastroenterol 2018; 18:60. [PMID: 29739329 PMCID: PMC5941658 DOI: 10.1186/s12876-018-0789-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 04/26/2018] [Indexed: 12/16/2022] Open
Abstract
Background Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis. Methods HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated. Results Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/− 4.12) compared to culturing with FXa or thrombin alone (26.90%+/− 8.90, p = 0.02; 13.1%+/− 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001). Conclusions FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.
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Affiliation(s)
- Ameet Dhar
- Department of Surgery and Cancer, Imperial College London, St Mary's Hospital Campus, London, W2 1NY, UK
| | - Fouzia Sadiq
- Department of Surgery and Cancer, Imperial College London, St Mary's Hospital Campus, London, W2 1NY, UK.
| | - Quentin M Anstee
- Institute of Cellular Medicine, Newcastle University, The Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK
| | - Adam P Levene
- Department of Histopathology, Imperial College London, St Mary's Hospital Campus, London, W2 1NY, UK
| | - Robert D Goldin
- Department of Histopathology, Imperial College London, St Mary's Hospital Campus, London, W2 1NY, UK
| | - Mark R Thursz
- Department of Surgery and Cancer, Imperial College London, St Mary's Hospital Campus, London, W2 1NY, UK
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35
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Abstract
Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.
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Affiliation(s)
- Matthew McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 1080 LMP, 333 Cedar St., New Haven, CT, 06520, USA
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 1080 LMP, 333 Cedar St., New Haven, CT, 06520, USA.
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36
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Li X, Zhu L, Wang B, Yuan M, Zhu R. Drugs and Targets in Fibrosis. Front Pharmacol 2017; 8:855. [PMID: 29218009 PMCID: PMC5703866 DOI: 10.3389/fphar.2017.00855] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/08/2017] [Indexed: 01/18/2023] Open
Abstract
Fibrosis contributes to the development of many diseases and many target molecules are involved in fibrosis. Currently, the majority of fibrosis treatment strategies are limited to specific diseases or organs. However, accumulating evidence demonstrates great similarities among fibroproliferative diseases, and more and more drugs are proved to be effective anti-fibrotic therapies across different diseases and organs. Here we comprehensively review the current knowledge on the pathological mechanisms of fibrosis, and divide factors mediating fibrosis progression into extracellular and intracellular groups. Furthermore, we systematically summarize both single and multiple component drugs that target fibrosis. Future directions of fibrosis drug discovery are also proposed.
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Affiliation(s)
- Xiaoyi Li
- Department of Gastroenterology, School of Life Sciences and Technology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Lixin Zhu
- Department of Pediatrics, Digestive Diseases and Nutrition Center, State University of New York at Buffalo, Buffalo, NY, United States
- Genome, Environment and Microbiome Community of Excellence, State University of New York at Buffalo, Buffalo, NY, United States
| | - Beibei Wang
- Department of Gastroenterology, School of Life Sciences and Technology, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Meifei Yuan
- Center for Drug Discovery, SINO High Goal Chemical Technology Co., Ltd., Shanghai, China
| | - Ruixin Zhu
- Department of Gastroenterology, School of Life Sciences and Technology, Shanghai East Hospital, Tongji University, Shanghai, China
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37
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Lisman T, Porte RJ. Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases. Res Pract Thromb Haemost 2017; 1:150-161. [PMID: 30046685 PMCID: PMC6058283 DOI: 10.1002/rth2.12028] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 06/21/2017] [Indexed: 12/14/2022] Open
Abstract
Patients with liver diseases may develop alterations in all components of the hemostatic system. Thrombocytopenia, low levels of coagulation factors and inhibitors, low levels of fibrinolytic proteins, and increased levels of endothelial-derived proteins such as von Willebrand factor are all part of the coagulopathy of liver disease. Due to concomitant changes in pro- and antihemostatic drivers, the net effects of these complex hemostatic changes have long been unclear. According to current concepts, the hemostatic system of patients with liver disease is in an unstable balance, which explains the occurrence of both bleeding and thrombotic complications. This review will discuss etiology and management of bleeding and thrombosis in liver disease and will outline unsolved clinical questions. In addition, we will discuss the role of intrahepatic activation of coagulation for progression of liver disease, a novel paradigm with potential consequences for the general management of patients with liver disease.
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Affiliation(s)
- Ton Lisman
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Robert J. Porte
- Surgical Research Laboratory and Section of Hepatobiliary Surgery and Liver TransplantationDepartment of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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38
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Vilaseca M, García-Calderó H, Lafoz E, García-Irigoyen O, Avila MA, Reverter JC, Bosch J, Hernández-Gea V, Gracia-Sancho J, García-Pagán JC. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65:2031-2044. [PMID: 28142199 DOI: 10.1002/hep.29084] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/29/2016] [Accepted: 01/24/2017] [Indexed: 12/12/2022]
Abstract
UNLABELLED In cirrhosis, increased intrahepatic vascular resistance (IHVR) is the primary factor for portal hypertension (PH) development. Hepatic stellate cells (HSCs) play a major role increasing IHVR because, when activated, they are contractile and promote fibrogenesis. Protease-activated receptors (PARs) can activate HSCs through thrombin and factor Xa, which are known PAR agonists, and cause microthrombosis in liver microcirculation. This study investigates the effects of the oral anticoagulant, rivaroxaban (RVXB), a direct antifactor Xa, on HSC phenotype, liver fibrosis (LF), liver microthrombosis, and PH in cirrhotic rats. Hepatic and systemic hemodynamic, nitric oxide (NO) bioavailability, LF, HSC activation, and microthrombosis were evaluated in CCl4 and thioacetamide-cirrhotic rats treated with RVXB (20 mg/kg/day) or its vehicle for 2 weeks. RVXB significantly decreased portal pressure (PP) in both models of cirrhosis without changes in portal blood flow, suggesting a reduction in IHVR. RVXB reduced oxidative stress, improved NO bioavailability, and ameliorated endothelial dysfunction. Rivaroxaban deactivated HSC, with decreased alpha-smooth muscle actin and mRNA expression of other HSC activation markers. Despite this marked improvement in HSC phenotype, no significant changes in LF were identified. RVXB markedly reduced fibrin deposition, suggesting reduced intrahepatic microthrombosis. CONCLUSION RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031-2044).
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Affiliation(s)
- Marina Vilaseca
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,University of Barcelona Medical School, Barcelona, Spain
| | - Héctor García-Calderó
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - Erica Lafoz
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,University of Barcelona Medical School, Barcelona, Spain
| | - Oihane García-Irigoyen
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.,Centro de Investigación Médica Aplicada (CIMA), Division of Hepatology; University of Navarra, IDISNA (Instituto de Investigacion Sanitaria de Navarra), Pamplona, Spain
| | - Matías A Avila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.,Centro de Investigación Médica Aplicada (CIMA), Division of Hepatology; University of Navarra, IDISNA (Instituto de Investigacion Sanitaria de Navarra), Pamplona, Spain
| | | | - Jaume Bosch
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,University of Barcelona Medical School, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain.,Swiss Liver Centre, Inselspital, Bern University, Switzerland
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,University of Barcelona Medical School, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
| | - Joan Carles García-Pagán
- Barcelona Hepatic Hemodynamic Lab, Liver Unit, Hospital Clínic, Barcelona, Spain, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain.,University of Barcelona Medical School, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
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39
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Shea BS, Probst CK, Brazee PL, Rotile NJ, Blasi F, Weinreb PH, Black KE, Sosnovik DE, Van Cott EM, Violette SM, Caravan P, Tager AM. Uncoupling of the profibrotic and hemostatic effects of thrombin in lung fibrosis. JCI Insight 2017; 2:86608. [PMID: 28469072 PMCID: PMC5414562 DOI: 10.1172/jci.insight.86608] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
Fibrotic lung disease, most notably idiopathic pulmonary fibrosis (IPF), is thought to result from aberrant wound-healing responses to repetitive lung injury. Increased vascular permeability is a cardinal response to tissue injury, but whether it is mechanistically linked to lung fibrosis is unknown. We previously described a model in which exaggeration of vascular leak after lung injury shifts the outcome of wound-healing responses from normal repair to pathological fibrosis. Here we report that the fibrosis produced in this model is highly dependent on thrombin activity and its downstream signaling pathways. Direct thrombin inhibition with dabigatran significantly inhibited protease-activated receptor-1 (PAR1) activation, integrin αvβ6 induction, TGF-β activation, and the development of pulmonary fibrosis in this vascular leak-dependent model. We used a potentially novel imaging method - ultashort echo time (UTE) lung magnetic resonance imaging (MRI) with the gadolinium-based, fibrin-specific probe EP-2104R - to directly visualize fibrin accumulation in injured mouse lungs, and to correlate the antifibrotic effects of dabigatran with attenuation of fibrin deposition. We found that inhibition of the profibrotic effects of thrombin can be uncoupled from inhibition of hemostasis, as therapeutic anticoagulation with warfarin failed to downregulate the PAR1/αvβ6/TGF-β axis or significantly protect against fibrosis. These findings have direct and important clinical implications, given recent findings that warfarin treatment is not beneficial in IPF, and the clinical availability of direct thrombin inhibitors that our data suggest could benefit these patients.
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Affiliation(s)
- Barry S. Shea
- Division of Pulmonary, Critical Care and Sleep Medicine, Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island, USA
- Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases
| | - Clemens K. Probst
- Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases
| | - Patricia L. Brazee
- Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases
| | | | - Francesco Blasi
- A. A. Martinos Center for Biomedical Imaging, Department of Radiology
| | | | - Katharine E. Black
- Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases
| | - David E. Sosnovik
- A. A. Martinos Center for Biomedical Imaging, Department of Radiology
| | - Elizabeth M. Van Cott
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Peter Caravan
- A. A. Martinos Center for Biomedical Imaging, Department of Radiology
| | - Andrew M. Tager
- Division of Pulmonary and Critical Care Medicine and Center for Immunology and Inflammatory Diseases
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40
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Egan K, Dillon A, Dunne E, Kevane B, Galvin Z, Maguire P, Kenny D, Stewart S, Ainle FN. Increased soluble GPVI levels in cirrhosis: evidence for early in vivo platelet activation. J Thromb Thrombolysis 2017; 43:54-59. [PMID: 27416950 DOI: 10.1007/s11239-016-1401-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cirrhosis is a consequence of prolonged liver injury and is characterised by extensive tissue fibrosis: the deposition of collagen-rich extracellular matrix. The haemostatic balance is disordered in cirrhosis and coagulation activation appears to promote fibrosis. In spite of recent studies demonstrating a role for anticoagulant therapy in preventing cirrhosis progression, there has not been a change in clinical practice, suggesting that physicians are reluctant to anticoagulate patients with cirrhosis due to bleeding risks. Platelets play an important role in facilitating coagulation. Glycoprotein VI (GPVI) is a platelet-specific collagen receptor that is shed from the platelet surface in a metalloproteinase-dependent manner in response to GPVI ligation and coagulation activation. Our aim was to use soluble GPVI levels to determine whether there was evidence for collagen and coagulation-induced platelet activation in early, well-compensated cirrhosis. Plasma soluble GPVI levels were quantified in 46 patients with mixed aetiology cirrhosis and 55 healthy controls using an immunoassay. In the cirrhosis group, soluble GPVI levels were significantly increased (5.8 ± 4.4 ng/ml, n = 46) compared to healthy controls (3.3 ± 3.4 ng/ml, n = 55, p < 0.05). This increase in soluble GPVI levels was still evident when levels were adjusted for platelet count (Healthy controls; 0.015 ± 0.018 ng/106 platelets/ml vs. cirrhosis; 0.048 ± 0.04 ng/106 platelets/ml, p < 0.0001). This study provides evidence for early platelet activation in patients with well-compensated cirrhosis. This may have translational implications for prognosis, treatment, and risk stratification.
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Affiliation(s)
- Karl Egan
- School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.,SPHERE Research Group, Conway Institute, University College Dublin, Dublin 4, Ireland
| | - Audrey Dillon
- Department of Hepatology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Eimear Dunne
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Barry Kevane
- School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland.,SPHERE Research Group, Conway Institute, University College Dublin, Dublin 4, Ireland.,Department of Haematology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Zita Galvin
- Department of Hepatology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Patricia Maguire
- SPHERE Research Group, Conway Institute, University College Dublin, Dublin 4, Ireland
| | - Dermot Kenny
- Department of Hepatology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Stephen Stewart
- Department of Hepatology, Mater Misericordiae University Hospital, Dublin 7, Ireland
| | - Fionnuala Ni Ainle
- School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland. .,SPHERE Research Group, Conway Institute, University College Dublin, Dublin 4, Ireland. .,Department of Haematology, Mater Misericordiae University Hospital, Dublin 7, Ireland.
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41
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Lin C, Borensztajn K, Spek CA. Targeting coagulation factor receptors - protease-activated receptors in idiopathic pulmonary fibrosis. J Thromb Haemost 2017; 15:597-607. [PMID: 28079978 DOI: 10.1111/jth.13623] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Indexed: 12/11/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a 5-year mortality rate of > 50% and unknown etiology. Treatment options remain limited and, currently, only two drugs are available, i.e. nintedanib and pirfenidone. However, both of these antifibrotic agents only slow down the progression of the disease, and do not remarkably prolong the survival of IPF patients. Hence, the discovery of new therapeutic targets for IPF is crucial. Studies exploring the mechanisms that are involved in IPF have identified several possible targets for therapeutic interventions. Among these, blood coagulation factor receptors, i.e. protease-activated receptors (PARs), are key candidates, as these receptors mediate the cellular effects of coagulation factors and play central roles in influencing inflammatory and fibrotic responses. In this review, we will focus on the controversial role of the coagulation cascade in the pathogenesis of IPF. In the light of novel data, we will attempt to reconciliate the apparently conflicting data and discuss the possibility of pharmacologic targeting of PARs for the treatment of fibroproliferative diseases.
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Affiliation(s)
- C Lin
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - K Borensztajn
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
- Inserm UMR1152, Medical School Xavier Bichat, Paris, France
- Département Hospitalo-universtaire FIRE (Fibrosis, Inflammation and Remodeling) and LabEx Inflamex, Paris, France
| | - C A Spek
- Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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43
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Doni A, Garlanda C, Mantovani A. Innate immunity, hemostasis and matrix remodeling: PTX3 as a link. Semin Immunol 2016; 28:570-577. [PMID: 27881292 DOI: 10.1016/j.smim.2016.10.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 10/07/2016] [Accepted: 10/12/2016] [Indexed: 12/20/2022]
Abstract
Innate immunity is evolutionarily connected with hemostasis. PTX3 is an essential fluid-phase pattern recognition molecule of the innate immune system that acts as a functional ancestor of antibodies. PTX3 by interacting with defense collagens and fibrinogens amplifies effector functions of the innate immune system. At wound sites, PTX3 regulates the injury-induced thrombotic response and promotes wound healing by favoring timely fibrinolysis. Therefore, PTX3 interacts with ancestral domains conserved in innate immunity, hemostasis and extracellular matrix and exerts functions related to both antimicrobial resistance and tissue repair. These findings strengthen the connection between innate immune system and hemostasis, and suggest that recognition of microbes and extracellular matrix are evolutionarily conserved and integrated functions of the innate immune system.
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Affiliation(s)
- Andrea Doni
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy.
| | - Cecilia Garlanda
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy; Humanitas University, via Manzoni 113, 20089 Rozzano, Italy
| | - Alberto Mantovani
- Istituto Clinico Humanitas IRCCS, via Manzoni 113, 20089 Rozzano, Italy; Humanitas University, via Manzoni 113, 20089 Rozzano, Italy
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Nault R, Fader KA, Kopec AK, Harkema JR, Zacharewski TR, Luyendyk JP. From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis. Toxicol Sci 2016; 154:381-391. [PMID: 27613713 DOI: 10.1093/toxsci/kfw175] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDD-elicited NAFLD. Chronic exposure to TCDD (30 µg/kg every 4 days for 28 days) was associated with intrahepatic coagulation, indicated by increased plasma thrombin-antithrombin levels and hepatic fibrin(ogen) deposition. PAR-1 deficiency diminished TCDD-elicited body weight loss and relative liver weight was reduced in TCDD-exposed PAR-1-/- mice compared with TCDD-exposed wild-type mice. PAR-1 deficiency did not affect TCDD-induced hepatic steatosis or hepatocellular injury, as indicated by serum alanine aminotransferase activity. Despite a lack of effect on these 2 features of NAFLD pathology, PAR-1 deficiency was associated with a reduction in hepatic inflammation evident in liver histopathology, and reflected by a reduction in serum levels of the proinflammatory cytokine interleukin-6. Moreover, TCDD-driven hepatic collagen deposition was markedly reduced in PAR-1-deficient mice. These results indicate that experimental TCDD-elicited steatohepatitis is associated with coagulation cascade activation and PAR-1-driven hepatic inflammation and fibrosis.
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Affiliation(s)
- Rance Nault
- Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.,Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan
| | - Kelly A Fader
- Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.,Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan
| | - Anna K Kopec
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan.,Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Jack R Harkema
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan
| | - Timothy R Zacharewski
- Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, Michigan.,Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan
| | - James P Luyendyk
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan; .,Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan
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Abstract
There is accumulating evidence that the coagulation system is involved in the process of fibrogenesis in chronic liver disease. Recent studies postulated a possible connection between plasmatic hypercoagulability and progression of fibrosis. The aim of the study was to investigate disorders of the coagulation system in patients with chronic hepatitis C having different extent of hepatic fibrosis well defined by liver histology. A total of 62 patients with chronic hepatitis C were recruited and categorized into 2 groups according to their histological fibrosis stage : mild/moderate fibrosis group (F0-F3 group, n = 30) and extensive fibrosis/cirrhosis group (F4-F6 group, n = 32). The control group consisted of 31 healthy individuals. The following hemostatic assays were evaluated: antithrombin III (AT), protein C (PC) activity, activated partial thromboplastin time, prothrombin time, plasma fibrinogen as well as conventional liver function test. The PC level exhibited a significant reduction in both patient groups when compared to the normal control group (89.25% ± 10.05% and 48.33% ± 15.86% vs 111.86 ± 10.90; P < .001 and P < .001). The PC was found to be the strongest associated factor to histological fibrosis stage ( r = –.834; P < .0001). Univariate and multivariate analysis showed that AT ( P = .003) and PC ( P = .0001) were the most important factors associated with advanced fibrosis. The PC ( P = .001) was found to be the only predictor of mild fibrosis. In conclusion, PC deficiency occurs in an early stage of liver fibrosis. The severity of deficiency is proportional to extent of fibrosis. The PC may have a key role in linking hypercoagulability with hepatic fibrogenesis in chronic liver disease.
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46
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Kopec AK, Joshi N, Luyendyk JP. Role of hemostatic factors in hepatic injury and disease: animal models de-liver. J Thromb Haemost 2016; 14:1337-49. [PMID: 27060337 PMCID: PMC5091081 DOI: 10.1111/jth.13327] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Indexed: 12/14/2022]
Abstract
Chronic liver damage is associated with unique changes in the hemostatic system. Patients with liver disease often show a precariously rebalanced hemostatic system, which is easily tipped towards bleeding or thrombotic complications by otherwise benign stimuli. In addition, some clinical studies have shown that hemostatic system components contribute to the progression of liver disease. There is a strong basic science foundation for clinical studies with this particular focus. Chronic and acute liver disease can be modeled in rodents and large animals with a variety of approaches, which span chronic exposure to toxic xenobiotics, diet-induced obesity, and surgical intervention. These experimental approaches have now provided strong evidence that, in addition to perturbations in hemostasis caused by liver disease, elements of the hemostatic system have powerful effects on the progression of experimental liver toxicity and disease. In this review, we cover the basis of the animal models that are most often utilized to assess the impact of the hemostatic system on liver disease, and highlight the role that coagulation proteases and their targets play in experimental liver toxicity and disease, emphasizing key similarities and differences between models. The need to characterize hemostatic changes in existing animal models and to develop novel animal models recapitulating the coagulopathy of chronic liver disease is highlighted. Finally, we emphasize the continued need to translate knowledge derived from highly applicable animal models to improve our understanding of the reciprocal interaction between liver disease and the hemostatic system in patients.
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Affiliation(s)
- Anna K. Kopec
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
| | - Nikita Joshi
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
| | - James P. Luyendyk
- Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48824
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan 48824
- Institute for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824
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Tischendorf M, Miesbach W, Chattah U, Chattah Z, Maier S, Welsch C, Zeuzem S, Lange CM. Differential Kinetics of Coagulation Factors and Natural Anticoagulants in Patients with Liver Cirrhosis: Potential Clinical Implications. PLoS One 2016; 11:e0155337. [PMID: 27171213 PMCID: PMC4865185 DOI: 10.1371/journal.pone.0155337] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 04/27/2016] [Indexed: 11/18/2022] Open
Abstract
Background Advanced liver diseases are associated with profound alterations of the coagulation system increasing the risk not only of bleeding, but also of thromboembolic complications. A recent milestone study has shown that prophylactic anticoagulation in liver cirrhosis patients results in a reduced frequency of hepatic decompensation. Yet, INR measurement, one of the most widely applied tests to assess liver function, only inaccurately predicts the risk of hepatic decompensation related to alterations of the coagulation system. To assess the relationship between selected coagulation factors / natural anticoagulants with INR, MELD score, and hepatic decompensation, we performed the present pilot study. A total number of 92 patients with various stages of liver cirrhosis were included and prospectively followed for at least 6 months. We found that important natural anticoagulants, namely antithrombin and protein C, as well as factor XI (which may also serve as an anticoagulant) decreased earlier and by a larger magnitude than one would expect from classical coagulation test results. The correlation between these factors and INR was only moderate. Importantly, reduced plasma activities of natural anticoagulants but not INR or MELD score were independent predictors of hepatic encephalopathy (P = 0.013 and 0.003 for antithrombin and protein C, respectively). Conclusion In patients with liver cirrhosis plasma activities of several natural anticoagulants are earlier and stronger affected than routine coagulation tests. Reduced activities of natural anticoagulants may be predictive for the development of hepatic encephalopathy.
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Affiliation(s)
- Michael Tischendorf
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Wolfgang Miesbach
- Haemophilia Centre, Medical Clinic III / Institute of Transfusion Medicine, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Umer Chattah
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Zenab Chattah
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Sebastian Maier
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Christoph Welsch
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
| | - Christian M. Lange
- Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, Haus 11, 60590 Frankfurt, Germany
- * E-mail:
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49
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Spronk HMH, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH, Rienstra M, van Hunnik A, Kuiper M, Lumeij S, Zeemering S, Linz D, Kamphuisen PW, Ten Cate H, Crijns HJ, Van Gelder IC, van Zonneveld AJ, Schotten U. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. Eur Heart J 2016; 38:38-50. [PMID: 27071821 DOI: 10.1093/eurheartj/ehw119] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 12/21/2015] [Accepted: 03/02/2016] [Indexed: 01/09/2023] Open
Abstract
AIMS Atrial fibrillation (AF) produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors provokes pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues. We studied the effects of thrombin on atrial fibroblasts and tested the hypothesis that hypercoagulability contributes to the development of a substrate for AF. METHODS AND RESULTS In isolated rat atrial fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signalling molecules Akt and Erk and increased the expression of transforming growth factor β1 (2.7-fold) and the pro-inflammatory factor monocyte chemoattractant protein-1 (6.1-fold). Thrombin also increased the incorporation of 3H-proline, suggesting enhanced collagen synthesis by fibroblasts (2.5-fold). All effects could be attenuated by the thrombin inhibitor dabigatran. In transgenic mice with a pro-coagulant phenotype (TMpro/pro), the inducibility of AF episodes lasting >1 s was higher (7 out of 12 vs. 1 out of 10 in wild type) and duration of AF episodes was longer compared with wild type mice (maximum episode duration 42.8 ± 68.4 vs. 0.23 ± 0.39 s). In six goats with persistent AF treated with nadroparin, targeting Factor Xa-mediated thrombin generation, the complexity of the AF substrate was less pronounced than in control animals (LA maximal activation time differences 23.3 ± 3.1 ms in control vs. 15.7 ± 2.1 ms in nadroparin, P < 0.05). In the treated animals, AF-induced α-smooth muscle actin expression was lower and endomysial fibrosis was less pronounced. CONCLUSION The hypercoagulable state during AF causes pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts. Hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF. In AF goats, nadroparin attenuates atrial fibrosis and the complexity of the AF substrate. Inhibition of coagulation may not only prevent strokes but also inhibit the development of a substrate for AF.
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Affiliation(s)
- Henri M H Spronk
- Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands
| | - Anne Margreet De Jong
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Sander Verheule
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Hetty C De Boer
- Department of Nephrology and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - Alexander H Maass
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dennis H Lau
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Michiel Rienstra
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Arne van Hunnik
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Marion Kuiper
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Stijn Lumeij
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Stef Zeemering
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Dominik Linz
- Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany
| | - Pieter Willem Kamphuisen
- Department of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hugo Ten Cate
- Department of Biochemistry, Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University, Maastricht, The Netherlands
| | - Harry J Crijns
- Department of Cardiology, Academic Hospital Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Isabelle C Van Gelder
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Anton Jan van Zonneveld
- Department of Nephrology and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - Ulrich Schotten
- Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
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50
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Cerini F, Vilaseca M, Lafoz E, García-Irigoyen O, García-Calderó H, Tripathi DM, Avila M, Reverter JC, Bosch J, Gracia-Sancho J, García-Pagán JC. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016; 64:834-42. [PMID: 26686269 DOI: 10.1016/j.jhep.2015.12.003] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 11/30/2015] [Accepted: 12/01/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Increased hepatic vascular resistance due to fibrosis and elevated hepatic vascular tone is the primary factor in the development of portal hypertension. Heparin may decrease fibrosis by inhibiting intrahepatic microthrombosis and thrombin-mediated hepatic stellate cell activation. In addition, heparin enhances eNOS activity, which may reduce hepatic vascular tone. Our study aimed at evaluating the effects of acute, short-, long-term and preventive enoxaparin administration on hepatic and systemic hemodynamics, liver fibrosis and nitric oxide availability in cirrhotic rats. METHODS Enoxaparin (1.8 mg/kg subcutaneously), or its vehicle, was administered to CCl4-cirrhotic rats 24h and 1h before the study (acute), daily for 1 week (short-term) or daily for 3 weeks (long-term) and to thioacetamide-cirrhotic rats daily for 3 weeks with/without thioacetamide (preventive/long-term, respectively). Mean arterial pressure, portal pressure, portal blood flow, hepatic vascular resistance and molecular/cellular mechanisms were evaluated. RESULTS No significant changes in hemodynamic parameters were observed in acute administration. However, one-week, three-week and preventive treatments significantly decreased portal pressure mainly due to a decrease in hepatic vascular resistance without significant changes in mean arterial pressure. These findings were associated with significant reductions in liver fibrosis, hepatic stellate cell activation, and desmin expression. Moreover, a reduction in fibrin deposition was observed in enoxaparin-treated rats, suggesting reduced intrahepatic microthrombosis. CONCLUSION Enoxaparin reduces portal pressure in cirrhotic rats by improving the structural component of increased liver resistance. These findings describe the potentially beneficial effects of enoxaparin beyond the treatment/prevention of portal vein thrombosis in cirrhosis, which deserve further investigation.
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Affiliation(s)
- Federica Cerini
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain
| | - Marina Vilaseca
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Erica Lafoz
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Oihane García-Irigoyen
- Centro de Investigación Médica Aplicada (CIMA), Division of Hepatology and Gene Therapy, Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Héctor García-Calderó
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Dinesh M Tripathi
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Matias Avila
- Centro de Investigación Médica Aplicada (CIMA), Division of Hepatology and Gene Therapy, Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain
| | - Juan Carlos Reverter
- Hemotherapy and Hemostasis Department, Hospital Clínic, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jaime Bosch
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
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