|
1
|
Kronsten VT, Shawcross DL. Clinical Implications of Inflammation in Patients With Cirrhosis. Am J Gastroenterol 2025; 120:65-74. [PMID: 39194320 PMCID: PMC11676607 DOI: 10.14309/ajg.0000000000003056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.
Collapse
Affiliation(s)
- Victoria T. Kronsten
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
| | - Debbie L. Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London
| |
Collapse
|
|
2
|
Gao J, Lan T, Kostallari E, Guo Y, Lai E, Guillot A, Ding B, Tacke F, Tang C, Shah VH. Angiocrine signaling in sinusoidal homeostasis and liver diseases. J Hepatol 2024; 81:543-561. [PMID: 38763358 PMCID: PMC11906189 DOI: 10.1016/j.jhep.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 04/29/2024] [Accepted: 05/10/2024] [Indexed: 05/21/2024]
Abstract
The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases.
Collapse
Affiliation(s)
- Jinhang Gao
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Lan
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yangkun Guo
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Enjiang Lai
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Bisen Ding
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Chengwei Tang
- Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
3
|
ten Hove M, Smyris A, Booijink R, Wachsmuth L, Hansen U, Alic L, Faber C, Hӧltke C, Bansal R. Engineered SPIONs functionalized with endothelin a receptor antagonist ameliorate liver fibrosis by inhibiting hepatic stellate cell activation. Bioact Mater 2024; 39:406-426. [PMID: 38855059 PMCID: PMC11157122 DOI: 10.1016/j.bioactmat.2024.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/11/2024] Open
Abstract
Endothelin-1/endothelin A receptor (ET-1/ETAR) pathway plays an important role in the progression of liver fibrosis by activating hepatic stellate cells (HSCs) - a key cell type involved in the pathogenesis of liver fibrosis. Inactivating HSCs by blocking the ET-1/ETAR pathway using a selective ETAR antagonist (ERA) represents a promising therapeutic approach for liver fibrosis. Unfortunately, small-molecule ERAs possess limited clinical potential due to poor bioavailability, short half-life, and rapid renal clearance. To improve the clinical applicability, we conjugated ERA to superparamagnetic iron-oxide nanoparticles (SPIONs) and investigated the therapeutic efficacy of ERA and ERA-SPIONs in vitro and in vivo and analyzed liver uptake by in vivo and ex vivo magnetic resonance imaging (MRI), HSCs-specific localization, and ET-1/ETAR-pathway antagonism in vivo. In murine and human liver fibrosis/cirrhosis, we observed overexpression of ET-1 and ETAR that correlated with HSC activation, and HSC-specific localization of ETAR. ERA and successfully synthesized ERA-SPIONs demonstrated significant attenuation in TGFβ-induced HSC activation, ECM production, migration, and contractility. In an acute CCl4-induced liver fibrosis mouse model, ERA-SPIONs exhibited higher liver uptake, HSC-specific localization, and ET-1/ETAR pathway antagonism. This resulted in significantly reduced liver-to-body weight ratio, plasma ALT levels, and α-SMA and collagen-I expression, indicating attenuation of liver fibrosis. In conclusion, our study demonstrates that the delivery of ERA using SPIONs enhances the therapeutic efficacy of ERA in vivo. This approach holds promise as a theranostic strategy for the MRI-based diagnosis and treatment of liver fibrosis.
Collapse
Affiliation(s)
- Marit ten Hove
- Personalized Diagnostics and Therapeutics, Department of Bioengineering Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Andreas Smyris
- Personalized Diagnostics and Therapeutics, Department of Bioengineering Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Richell Booijink
- Personalized Diagnostics and Therapeutics, Department of Bioengineering Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Lydia Wachsmuth
- Clinic of Radiology, University Hospital Muenster, Muenster, Germany
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany
| | - Lejla Alic
- Department of Magnetic Detection and Imaging, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| | - Cornelius Faber
- Clinic of Radiology, University Hospital Muenster, Muenster, Germany
| | - Carsten Hӧltke
- Clinic of Radiology, University Hospital Muenster, Muenster, Germany
| | - Ruchi Bansal
- Personalized Diagnostics and Therapeutics, Department of Bioengineering Technologies, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands
| |
Collapse
|
|
4
|
Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [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: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
Collapse
Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| |
Collapse
|
|
5
|
Madir A, Grgurevic I, Tsochatzis EA, Pinzani M. Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges. World J Gastroenterol 2024; 30:290-307. [PMID: 38313235 PMCID: PMC10835535 DOI: 10.3748/wjg.v30.i4.290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 01/26/2024] Open
Abstract
Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.
Collapse
Affiliation(s)
- Anita Madir
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb 10000, Croatia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb 10000, Croatia
| | - Emmanuel A Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and University College London, London NW3 2PF, United Kingdom
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and University College London, London NW3 2PF, United Kingdom
| |
Collapse
|
|
6
|
Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
7
|
Felli E, Selicean S, Guixé-Muntet S, Wang C, Bosch J, Berzigotti A, Gracia-Sancho J. Mechanobiology of portal hypertension. JHEP Rep 2023; 5:100869. [PMID: 37841641 PMCID: PMC10568428 DOI: 10.1016/j.jhepr.2023.100869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 10/17/2023] Open
Abstract
The interplay between mechanical stimuli and cellular mechanobiology orchestrates the physiology of tissues and organs in a dynamic balance characterized by constant remodelling and adaptative processes. Environmental mechanical properties can be interpreted as a complex set of information and instructions that cells read continuously, and to which they respond. In cirrhosis, chronic inflammation and injury drive liver cells dysfunction, leading to excessive extracellular matrix deposition, sinusoidal pseudocapillarization, vascular occlusion and parenchymal extinction. These pathological events result in marked remodelling of the liver microarchitecture, which is cause and result of abnormal environmental mechanical forces, triggering and sustaining the long-standing and progressive process of liver fibrosis. Multiple mechanical forces such as strain, shear stress, and hydrostatic pressure can converge at different stages of the disease until reaching a point of no return where the fibrosis is considered non-reversible. Thereafter, reciprocal communication between cells and their niches becomes the driving force for disease progression. Accumulating evidence supports the idea that, rather than being a passive consequence of fibrosis and portal hypertension (PH), mechanical force-mediated pathways could themselves represent strategic targets for novel therapeutic approaches. In this manuscript, we aim to provide a comprehensive review of the mechanobiology of PH, by furnishing an introduction on the most important mechanisms, integrating these concepts into a discussion on the pathogenesis of PH, and exploring potential therapeutic strategies.
Collapse
Affiliation(s)
- Eric Felli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sonia Selicean
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Cong Wang
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jaume Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Jordi Gracia-Sancho
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
- Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Spain
| |
Collapse
|
|
8
|
Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics (Basel) 2023; 13:2960. [PMID: 37761327 PMCID: PMC10528663 DOI: 10.3390/diagnostics13182960] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic liver disease (CLD) is a significant global health burden, leading to millions of deaths annually. The gut-liver axis plays a pivotal role in this context, allowing the transport of gut-derived products directly to the liver, as well as biological compounds from the liver to the intestine. The gut microbiota plays a significant role in maintaining the health of the digestive system. A change in gut microbiome composition as seen in dysbiosis is associated with immune dysregulation, altered energy and gut hormone regulation, and increased intestinal permeability, contributing to inflammatory mechanisms and damage to the liver, irrespective of the underlying etiology of CLD. The aim of this review is to present the current knowledge about the composition of the intestinal microbiome in healthy individuals and those with CLD, including the factors that affect this composition, the impact of the altered microbiome on the liver, and the mechanisms by which it occurs. Furthermore, this review analyzes the effects of gut microbiome modulation on the course of CLD, by using pharmacotherapy, nutrition, fecal microbiota transplantation, supplements, and probiotics. This review opens avenues for the translation of knowledge about gut-liver interplay into clinical practice as an additional tool to fight CLD and its complications.
Collapse
Affiliation(s)
- Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagellonian University Medical College, 31-688 Kraków, Poland;
- Department of Endoscopy, University Hospital, 30-688 Kraków, Poland
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
9
|
Claudel SE, Jaganathan J, Patel A, Tapper EB, Verma A. Review article: Practical considerations for fluid resuscitation in cirrhosis. Aliment Pharmacol Ther 2023; 57:1066-1082. [PMID: 36998204 PMCID: PMC11839201 DOI: 10.1111/apt.17458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/25/2022] [Accepted: 02/26/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND Standard clinical methods of assessing volume and providing resuscitation are not always applicable to patients with advanced or decompensated cirrhosis. Despite this being well known from a clinical perspective, there remains relatively little evidence to guide clinicians though fluid management in patients with cirrhosis and, often, multi-organ system dysfunction. AIMS This review summarises the current understanding of the circulatory dysfunction in cirrhosis, modalities for assessing volume status, and considerations for fluid selection. It additionally provides a practical approach to fluid resuscitation. METHODS We review current literature on cirrhosis pathophysiology in steady-state and shock, clinical implications of fluid resuscitation, and strategies to assess intravascular volume. Literature reviewed here was identified by the authors through PubMed search and review of selected papers' references. RESULTS Clinical management of resuscitation in advanced cirrhosis remains relatively stagnant. Although several trials have attempted to establish the superior resuscitative fluid, the lack of improvement in hard clinical outcomes leaves clinicians without clear guidance. CONCLUSIONS The absence of consistent evidence for fluid resuscitation in patients with cirrhosis limits our ability to produce a clearly evidence-based protocol for fluid resuscitation in cirrhosis. However, we propose a preliminary practical guide to managing fluid resuscitation in patients with decompensated cirrhosis. Further studies are needed to develop and validate volume assessment tools in the specific context of cirrhosis, while randomised clinical trials of protocolized resuscitation may improve care of this patient population.
Collapse
Affiliation(s)
- Sophie E. Claudel
- Department of Internal Medicine, Boston Medical Center, Boston, Massachusetts, USA
| | - Jeeva Jaganathan
- Digestive Sciences and Nutrition, University of Kentucky College of Medicine, Lexington, Kentucky, USA
| | - Ankit Patel
- Department of Medicine, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Elliot B. Tapper
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ashish Verma
- Department of Internal Medicine, Section on Nephrology, Boston Medical Center, Boston, Massachusetts, USA
| |
Collapse
|
|
10
|
Gillespie SL, Hanrahan TP, Rockey DC, Majumdar A, Hayes PC. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023; 57:454-463. [PMID: 36691947 DOI: 10.1111/apt.17380] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/03/2022] [Accepted: 12/18/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND Advanced chronic liver disease is an increasing cause of premature morbidity and mortality in the UK. Portal hypertension is the primary driver of decompensation, including the development of ascites, hepatic encephalopathy and variceal haemorrhage. Non-selective beta blockers (NSBB) reduce portal pressure and are well established in the prevention of variceal haemorrhage. Carvedilol, a newer NSBB, is more effective at reducing portal pressure due to additional α-adrenergic blockade and has additional anti-oxidant, anti-inflammatory and anti-fibrotic effects. AIM To summarise the available evidence on the use of beta blockers, specifically carvedilol, in cirrhosis, focussing on when and why to start METHODS: We performed a comprehensive literature search of PubMed for relevant publications. RESULTS International guidelines advise the use of NSBB in primary prophylaxis against variceal haemorrhage in those with high-risk varices, with substantial evidence of efficacy comparable with endoscopic band ligation (EBL). NSBB are also well established in secondary prophylaxis, in combination with EBL. More controversial is their use in patients without large varices, but with clinically significant portal hypertension. However, there is gathering evidence that NSBB, particularly carvedilol, reduce the risk of decompensation and improve survival. While caution is advised in patients with advanced cirrhosis and refractory ascites, recent evidence suggests that NSBB can continue to be used safely, and that premature discontinuation may be detrimental. CONCLUSIONS With increasing evidence of benefit independent of variceal bleeding, namely retardation of decompensation and improvement in survival, it is time to consider whether carvedilol should be offered to all patients with advanced chronic liver disease.
Collapse
Affiliation(s)
| | - Timothy P Hanrahan
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Avik Majumdar
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.,The University of Melbourne, Melbourne, Australia
| | - Peter C Hayes
- Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK.,College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
11
|
Guo T, Wantono C, Tan Y, Deng F, Duan T, Liu D. Regulators, functions, and mechanotransduction pathways of matrix stiffness in hepatic disease. Front Physiol 2023; 14:1098129. [PMID: 36711017 PMCID: PMC9878334 DOI: 10.3389/fphys.2023.1098129] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023] Open
Abstract
The extracellular matrix (ECM) provides physical support and imparts significant biochemical and mechanical cues to cells. Matrix stiffening is a hallmark of liver fibrosis and is associated with many hepatic diseases, especially liver cirrhosis and carcinoma. Increased matrix stiffness is not only a consequence of liver fibrosis but is also recognized as an active driver in the progression of fibrotic hepatic disease. In this article, we provide a comprehensive view of the role of matrix stiffness in the pathological progression of hepatic disease. The regulators that modulate matrix stiffness including ECM components, MMPs, and crosslinking modifications are discussed. The latest advances of the research on the matrix mechanics in regulating intercellular signaling and cell phenotype are classified, especially for hepatic stellate cells, hepatocytes, and immunocytes. The molecular mechanism that sensing and transducing mechanical signaling is highlighted. The current progress of ECM stiffness's role in hepatic cirrhosis and liver cancer is introduced and summarized. Finally, the recent trials targeting ECM stiffness for the treatment of liver disease are detailed.
Collapse
Affiliation(s)
- Ting Guo
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Cindy Wantono
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Yuyong Tan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Tianying Duan
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China
| | - Deliang Liu
- Department of Gastroenterology, The Second Xiangya Hospital of Central South University, Changsha, China,Research Center of Digestive Disease, Central South University, Changsha, China,*Correspondence: Deliang Liu,
| |
Collapse
|
|
12
|
The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
Collapse
|
|
13
|
Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
Collapse
|
|
14
|
Bravo M, Raurell I, Barberá A, Hide D, Gil M, Estrella F, Salcedo MT, Augustin S, Genescà J, Martell M. Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH. Dis Model Mech 2021; 14:268318. [PMID: 34014280 PMCID: PMC8188885 DOI: 10.1242/dmm.048884] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022] Open
Abstract
In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model. Diet-induced NASH rats were treated with atorvastatin (10 mg/kg/day), ambrisentan (30 mg/kg/day or 2 mg/kg/day) or a combination of both for 2 weeks. Hemodynamic parameters were registered and liver histology and serum biochemical determinations analysed. Expression of proteins were studied by immunoblotting. Conditioned media experiments were performed with LSEC. HSCs were characterized by RT-PCR, and a collagen lattice contraction assay was performed. Atorvastatin and ambrisentan act synergistically in combination to completely normalize liver hemodynamics and reverse histological NASH by 75%. Atorvastatin reversed the sinusoidal contractile phenotype, thus improving endothelial function, whereas ambrisentan prevented the contractile response in HSCs by blocking ET-1 response. Additionally, ambrisentan also increased eNOS (also known as Nos3) phosphorylation levels in LSEC, via facilitating the stimulation of endothelin-receptor-B in these cells. Furthermore, the serum alanine aminotransferase of the combined treatment group decreased to normal levels, and this group exhibited a restoration of the HSC quiescent phenotype. The combination of atorvastatin and ambrisentan remarkably improves liver histology and PH in a diet-induced NASH model. By recovering LSEC function, together with inhibiting the activation and contraction of HSC, this combined treatment may be an effective treatment for NASH patients. Summary: Combining atorvastatin with ambrisentan is safe and effective in reducing intrahepatic resistance and portal hypertension in an experimental model of NASH. This liver histology amelioration highlights a promising therapeutic strategy.
Collapse
Affiliation(s)
- Miren Bravo
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Imma Raurell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Aurora Barberá
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Diana Hide
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Mar Gil
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - Federico Estrella
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain
| | - María Teresa Salcedo
- Department of Pathology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona 08035, Spain
| | - Salvador Augustin
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Joan Genescà
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - María Martell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid 28029, Spain
| |
Collapse
|
|
15
|
Maternal microvascular dysfunction during preeclamptic pregnancy. Clin Sci (Lond) 2021; 135:1083-1101. [PMID: 33960392 DOI: 10.1042/cs20200894] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/19/2021] [Accepted: 04/21/2021] [Indexed: 12/15/2022]
Abstract
Preeclampsia is a hypertensive disorder of pregnancy effecting ∼5-8% of pregnancies in the United States, and ∼8 million pregnancies worldwide. Preeclampsia is clinically diagnosed after the 20th week of gestation and is characterized by new onset hypertension accompanied by proteinuria and/or thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. This broad definition emphasizes the heterogeneity of the clinical presentation of preeclampsia, but also underscores the role of the microvascular beds, specifically the renal, cerebral, and hepatic circulations, in the pathophysiology of the disease. While the diagnostic criteria for preeclampsia relies on the development of de novo hypertension and accompanying clinical symptoms after 20-week gestation, it is likely that subclinical dysfunction of the maternal microvascular beds occurs in parallel and may even precede the development of overt cardiovascular symptoms in these women. However, little is known about the physiology of the non-reproductive maternal microvascular beds during preeclampsia, and the mechanism(s) mediating microvascular dysfunction during preeclamptic pregnancy are largely unexplored in humans despite their integral role in the pathophysiology of the disease. Therefore, the purpose of this review is to provide a summary of the existing literature on maternal microvascular dysfunction during preeclamptic pregnancy by reviewing the functional evidence in humans, highlighting potential mechanisms, and providing recommendations for future work in this area.
Collapse
|
|
16
|
Abstract
Cirrhosis is the fifth leading cause of death in adults. Advanced cirrhosis can cause significant portal hypertension (PH), which is responsible for many of the complications observed in patients with cirrhosis, such as varices. If portal pressure exceeds a certain threshold, the patient is at risk of developing life-threatening bleeding from varices. Variceal bleeding has a high incidence among patients with liver cirrhosis and carries a high risk of mortality and morbidity. The management of variceal bleeding is complex, often requiring a multidisciplinary approach involving pharmacological, endoscopic, and radiologic interventions. In terms of management, three stages can be considered: primary prophylaxis, active bleeding, and secondary prophylaxis. The main goal of primary and secondary prophylaxis is to prevent variceal bleeding. However, active variceal bleeding is a medical emergency that requires swift intervention to stop the bleeding and achieve durable hemostasis. We describe the pathophysiology of cirrhosis and PH to contextualize the formation of gastric and esophageal varices. We also discuss the currently available treatments and compare how they fare in each stage of clinical management, with a special focus on drugs that can prevent bleeding or assist in achieving hemostasis.
Collapse
|
|
17
|
The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol 2021; 74:670-685. [PMID: 33301825 DOI: 10.1016/j.jhep.2020.11.048] [Citation(s) in RCA: 263] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022]
Abstract
Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.
Collapse
|
|
18
|
Matyas C, Haskó G, Liaudet L, Trojnar E, Pacher P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat Rev Cardiol 2021; 18:117-135. [PMID: 32999450 DOI: 10.1038/s41569-020-0433-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2020] [Indexed: 12/11/2022]
Abstract
The liver is a crucial metabolic organ that has a key role in maintaining immune and endocrine homeostasis. Accumulating evidence suggests that chronic liver disease might promote the development of various cardiac disorders (such as arrhythmias and cardiomyopathy) and circulatory complications (including systemic, splanchnic and pulmonary complications), which can eventually culminate in clinical conditions ranging from portal and pulmonary hypertension to pulmonary, cardiac and renal failure, ascites and encephalopathy. Liver diseases can affect cardiovascular function during the early stages of disease progression. The development of cardiovascular diseases in patients with chronic liver failure is associated with increased morbidity and mortality, and cardiovascular complications can in turn affect liver function and liver disease progression. Furthermore, numerous infectious, inflammatory, metabolic and genetic diseases, as well as alcohol abuse can also influence both hepatic and cardiovascular outcomes. In this Review, we highlight how chronic liver diseases and associated cardiovascular effects can influence different organ pathologies. Furthermore, we explore the potential roles of inflammation, oxidative stress, vasoactive mediator imbalance, dysregulated endocannabinoid and autonomic nervous systems and endothelial dysfunction in mediating the complex interplay between the liver and the systemic vasculature that results in the development of the extrahepatic complications of chronic liver disease. The roles of ageing, sex, the gut microbiome and organ transplantation in this complex interplay are also discussed.
Collapse
Affiliation(s)
- Csaba Matyas
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Lucas Liaudet
- Department of Intensive Care Medicine and Burn Center, University Hospital Medical Center, Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Eszter Trojnar
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD, USA.
| |
Collapse
|
|
19
|
Nie Y, Liu Q, Zhang W, Wan Y, Huang C, Zhu X. Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis. Gut Microbes 2021; 13:1972746. [PMID: 34530693 PMCID: PMC8451456 DOI: 10.1080/19490976.2021.1972746] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Activation of the NOX4/NLRP3 inflammasome pathway has been associated with fibrosis in other organs. An imbalance in intestinal bacteria is an important driving factor of liver fibrosis through the liver-gut axis. This study aimed to explore whether the effect of ursolic acid (UA) on liver fibrosis was associated with the NOX4/NLRP3 inflammasome pathways and intestinal bacteria. Wild-type (WT), NLRP3-/-, and NOX4-/- mice and AP-treated mice were injected with CCI4 and treated with or without UA. The intestinal contents of the mice were collected and analyzed by 16S rRNA sequencing. UA alleviated liver fibrosis, which manifested as decreases in collagen deposition, liver injury, and the expression of fibrosis-related factors, and the expression of NOX4 and NLRP3 was significantly inhibited by UA treatment. Even after CCI4 injection, liver damage and fibrosis-related factors were significantly decreased in NLRP3-/-, NOX4-/-, and AP-treated mice. Importantly, the expression of NLRP3 was obviously inhibited in NOX4-/- and AP-treated mice. In addition, the diversity of intestinal bacteria and the abundance of probiotics in NLRP3-/- and NOX4-/- mice was significantly higher than those in WT mice, while the abundance of harmful bacteria in NLRP3-/- and NOX4-/- mice was significantly lower than that in WT mice. The NOX4/NLRP3 inflammasome pathway plays a crucial role in liver fibrosis and is closely associated with the beneficial effect of UA. The mechanism by which the NOX4/NLRP3 inflammasome pathway is involved in liver fibrosis may be associated with disordered intestinal bacteria.
Collapse
Affiliation(s)
- Yuan Nie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qi Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yipeng Wan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Chenkai Huang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xuan Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
20
|
Kong H, He J, Guo S, Song Q, Xiang D, Tao R, Yu H, Chen G, Huang Z, Ning Q, Huang J. Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells. PLoS Pathog 2020; 16:e1008947. [PMID: 33075079 PMCID: PMC7595619 DOI: 10.1371/journal.ppat.1008947] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 10/29/2020] [Accepted: 08/31/2020] [Indexed: 12/17/2022] Open
Abstract
Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases. Schistosomiasis is a serious but neglected tropical infectious disease. which can lead to hepatic fibrosis and death. To date, there are still no approved antifibrotic therapies. Hepatic fibrosis results in portal hypertension and variceal bleeding, and it is the primary cause of mortality from schistosomiasis. Splenomegaly and hypersplenism can manifest following the development of portal hypertension. Accumulating evidence suggests that the spleen plays a critical role in the development of hepatic fibrosis. In this study, using Schistosoma (S.) japonicum in both humans and mice, we show that progressive hepatic schistosomiasis caused elevation of endothelin receptors (ETRs) both in liver and spleen tissues, and the endothelin receptor-producing cells are mainly located in splenic B cells. More importantly, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells during infection. Thus, our study highlights the potential of endothelin receptor antagonist as a therapeutic intervention for schistosomiasis and other fibrotic diseases.
Collapse
Affiliation(s)
- Hongyan Kong
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinan He
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shusen Guo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiqin Song
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dandan Xiang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Tao
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haijing Yu
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guang Chen
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Ning
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaquan Huang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- * E-mail:
| |
Collapse
|
|
21
|
Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
Collapse
Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| |
Collapse
|
|
22
|
Alsamman S, Christenson SA, Yu A, Ayad NME, Mooring MS, Segal JM, Hu JKH, Schaub JR, Ho SS, Rao V, Marlow MM, Turner SM, Sedki M, Pantano L, Ghoshal S, Ferreira DDS, Ma HY, Duwaerts CC, Espanol-Suner R, Wei L, Newcomb B, Mileva I, Canals D, Hannun YA, Chung RT, Mattis AN, Fuchs BC, Tager AM, Yimlamai D, Weaver VM, Mullen AC, Sheppard D, Chen JY. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice. Sci Transl Med 2020; 12:eaay8798. [PMID: 32817366 PMCID: PMC7976849 DOI: 10.1126/scitranslmed.aay8798] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 02/11/2020] [Accepted: 06/30/2020] [Indexed: 12/11/2022]
Abstract
Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.
Collapse
Affiliation(s)
- Sarah Alsamman
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Stephanie A Christenson
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Amy Yu
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Nadia M E Ayad
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
- UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Meghan S Mooring
- Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Joe M Segal
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA
| | - Jimmy Kuang-Hsien Hu
- Division of Oral Biology & Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | | | - Steve S Ho
- Pliant Therapeutics, South San Francisco, CA 94080, USA
| | - Vikram Rao
- Pliant Therapeutics, South San Francisco, CA 94080, USA
| | | | | | - Mai Sedki
- Internal Medicine, Kaiser Permanente, San Francisco, CA 94115, USA
| | - Lorena Pantano
- Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
| | - Sarani Ghoshal
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Diego Dos Santos Ferreira
- Athinoula A. Martinos Center for Biomedical Imaging, Institute for Innovation in Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
| | - Hsiao-Yen Ma
- Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Caroline C Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA
- Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Regina Espanol-Suner
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Lan Wei
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Benjamin Newcomb
- Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Izolda Mileva
- Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Daniel Canals
- Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Yusuf A Hannun
- Departments of Medicine and Biochemistry and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Raymond T Chung
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Aras N Mattis
- Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Andrew M Tager
- Division of Pulmonary and Critical Care Medicine, Fibrosis Research Center, and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Dean Yimlamai
- Division of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
- UC Berkeley-UCSF Graduate Program in Bioengineering, San Francisco, CA 94143, USA
- Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA
- Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Alan C Mullen
- Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Dean Sheppard
- Division of Pulmonary, Critical Care, Allergy and Sleep, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
- Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jennifer Y Chen
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94115, USA.
- Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| |
Collapse
|
|
23
|
Gandhi CR. Pro- and Anti-fibrogenic Functions of Gram-Negative Bacterial Lipopolysaccharide in the Liver. Front Med (Lausanne) 2020; 7:130. [PMID: 32373617 PMCID: PMC7186417 DOI: 10.3389/fmed.2020.00130] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/24/2020] [Indexed: 12/14/2022] Open
Abstract
Extensive research performed over several decades has identified cells participating in the initiation and progression of fibrosis, and the numerous underlying inter- and intra-cellular signaling pathways. However, liver fibrosis continues to be a major clinical challenge as the precise targets of treatment are still elusive. Activation of physiologically quiescent perisinusoidal hepatic stellate cells (HSCs) to a myofibroblastic proliferating, contractile and fibrogenic phenotype is a critical event in the pathogenesis of chronic liver disease. Thus, elucidation of the mechanisms of the reversal to quiescence or inhibition of activated HSCs, and/or their elimination via apoptosis has been the focus of intense investigation. Lipopolysaccharide (LPS), a gut-resident Gram-negative bacterial endotoxin, is a powerful pro-inflammatory molecule implicated in hepatic injury, inflammation and fibrosis. In both acute and chronic liver injury, portal venous levels of LPS are elevated due to increased intestinal permeability. LPS, via CD14 and Toll-like receptor 4 (TLR4) and its adapter molecules, stimulates macrophages, neutrophils and several other cell types to produce inflammatory mediators as well as factors that can activate HSCs and stimulate their fibrogenic activity. LPS also stimulates synthesis of pro- and anti-inflammatory cytokines/chemokines, growth mediators and molecules of immune regulation by HSCs. However, LPS was found to arrest proliferation of activated HSCs and to convert them into non-fibrogenic phenotype. Interestingly, LPS can elicit responses in HSCs independent of CD14 and TLR4. Identifying and/or developing non-inflammatory but anti-fibrogenic mimetics of LPS could be relevant for treating liver fibrosis.
Collapse
Affiliation(s)
- Chandrashekhar R Gandhi
- Divisions of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Cincinnati VA Medical Center, Cincinnati, OH, United States
| |
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
Cheng X, Yeung PKK, Zhong K, Zilundu PLM, Zhou L, Chung SK. Astrocytic endothelin-1 overexpression promotes neural progenitor cells proliferation and differentiation into astrocytes via the Jak2/Stat3 pathway after stroke. J Neuroinflammation 2019; 16:227. [PMID: 31733648 PMCID: PMC6858703 DOI: 10.1186/s12974-019-1597-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 09/23/2019] [Indexed: 12/17/2022] Open
Abstract
Background Endothelin-1 (ET-1) is synthesized and upregulated in astrocytes under stroke. We previously demonstrated that transgenic mice over-expressing astrocytic ET-1 (GET-1) displayed more severe neurological deficits characterized by a larger infarct after transient middle cerebral artery occlusion (tMCAO). ET-1 is a known vasoconstrictor, mitogenic, and a survival factor. However, it is unclear whether the observed severe brain damage in GET-1 mice post stroke is due to ET-1 dysregulation of neurogenesis by altering the stem cell niche. Methods Non-transgenic (Ntg) and GET-1 mice were subjected to tMCAO with 1 h occlusion followed by long-term reperfusion (from day 1 to day 28). Neurological function was assessed using a four-point scale method. Infarct area and volume were determined by 2,3,5-triphenyltetra-zolium chloride staining. Neural stem cell (NSC) proliferation and migration in subventricular zone (SVZ) were evaluated by immunofluorescence double labeling of bromodeoxyuridine (BrdU), Ki67 and Sox2, Nestin, and Doublecortin (DCX). NSC differentiation in SVZ was evaluated using the following immunofluorescence double immunostaining: BrdU and neuron-specific nuclear protein (NeuN), BrdU and glial fibrillary acidic protein (GFAP). Phospho-Stat3 (p-Stat3) expression detected by Western-blot and immunofluorescence staining. Results GET-1 mice displayed a more severe neurological deficit and larger infarct area after tMCAO injury. There was a significant increase of BrdU-labeled progenitor cell proliferation, which co-expressed with GFAP, at SVZ in the ipsilateral side of the GET-1 brain at 28 days after tMCAO. p-Stat3 expression was increased in both Ntg and GET-1 mice in the ischemia brain at 7 days after tMCAO. p-Stat3 expression was significantly upregulated in the ipsilateral side in the GET-1 brain than that in the Ntg brain at 7 days after tMCAO. Furthermore, GET-1 mice treated with AG490 (a JAK2/Stat3 inhibitor) sh owed a significant reduction in neurological deficit along with reduced infarct area and dwarfed astrocytic differentiation in the ipsilateral brain after tMCAO. Conclusions The data indicate that astrocytic endothelin-1 overexpression promotes progenitor stem cell proliferation and astr ocytic differentiation via the Jak2/Stat3 pathway.
Collapse
Affiliation(s)
- Xiao Cheng
- Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, 111 Dade Road, Guangzhou, 510120, China. .,School of Biomedical Sciences, The University of Hong Kong, HKSAR, China. .,The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 12 Jichang Road, Guangzhou, 510405, China. .,Guangdong Provincial Chinese Emergency Key Laboratory, Guangzhou, 510120, China. .,State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine, Guangzhou, 510120, China.
| | - Patrick K K Yeung
- School of Biomedical Sciences, The University of Hong Kong, HKSAR, China
| | - Ke Zhong
- Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-Sen University, Guangdong Province, Guangzhou, China
| | - Prince L M Zilundu
- Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-Sen University, Guangdong Province, Guangzhou, China
| | - Lihua Zhou
- Department of Anatomy, Zhong Shan School of Medicine, Sun Yat-Sen University, Guangdong Province, Guangzhou, China
| | - Sookja K Chung
- Faculty of Medicine, Macau University of Science and Technology, Macau, China. .,School of Biomedical Sciences, The University of Hong Kong, HKSAR, China.
| |
Collapse
|
|
26
|
Charni-Natan M, Aloni-Grinstein R, Osher E, Rotter V. Liver and Steroid Hormones-Can a Touch of p53 Make a Difference? Front Endocrinol (Lausanne) 2019; 10:374. [PMID: 31244779 PMCID: PMC6581675 DOI: 10.3389/fendo.2019.00374] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 05/28/2019] [Indexed: 12/12/2022] Open
Abstract
The liver is the main metabolic organ in the body, serving as a significant hormonal secretory gland and functioning to maintain hormone balance and homeostasis. Steroid hormones regulate various biological pathways, mainly in the reproductive system and in many metabolic processes. The liver, as well as steroid hormones, contribute significantly, through functional intertwine, to homeostasis maintenance, and proper responses during stress. Malfunction of either has a significant impact on the other and may lead to severe liver diseases as well as to several endocrine syndromes. Thus, the regulation on liver functions as on steroid hormones levels and activities is well-controlled. p53, the well-known tumor suppressor gene, was recently found to regulate metabolism and general homeostasis processes, particularly within the liver. Moreover, p53 was shown to be involved in steroid hormones regulation. In this review, we discuss the bi-directional regulation of the liver and the steroid hormones pointing to p53 as a novel regulator in this axis. A comprehensive understanding of the molecular mechanisms of this axis may help to prevent and treat related disease, especially with the increasing exposure of the population to environmental steroid hormones and steroid hormone-based medication.
Collapse
Affiliation(s)
- Meital Charni-Natan
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ronit Aloni-Grinstein
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel
| | - Etty Osher
- Sackler Faculty of Medicine, Tel Aviv-Sourasky Medical Center, Institute of Endocrinology Metabolism and Hypertension, Tel Aviv University, Tel Aviv, Israel
| | - Varda Rotter
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| |
Collapse
|
|
27
|
Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats. Front Med 2019; 13:398-408. [DOI: 10.1007/s11684-019-0689-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
|
|
28
|
Okimoto S, Kuroda S, Tashiro H, Kobayashi T, Taogoshi T, Matsuo H, Ohdan H. Vitamin A-coupled liposomal Rho-kinase inhibitor ameliorates liver fibrosis without systemic adverse effects. Hepatol Res 2019; 49:663-675. [PMID: 30675748 DOI: 10.1111/hepr.13317] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 01/13/2019] [Accepted: 01/14/2019] [Indexed: 02/08/2023]
Abstract
AIM Rho-kinase (ROCK) inhibitor could ameliorate liver fibrosis by suppressing hepatic stellate cell (HSC) activation. However, because systemic administration of ROCK inhibitor causes serious adverse effects, we developed a drug delivery system selectively delivering ROCK inhibitor to HSCs. Here, we examined whether our developed vitamin A (VA)-coupled liposomal ROCK inhibitor reduced liver fibrosis in rats without causing systemic adverse effects. METHODS LX-2 HSCs were analyzed for morphological changes and the expression of profibrotic proteins. The inhibitory effects of VA-coupled liposomal ROCK inhibitor on liver fibrosis were confirmed in a rat model of liver fibrosis induced by i.p. injection of carbon tetrachloride. The degree of liver fibrosis, biochemical changes, and survival rates were also investigated. RESULTS Vitamin A-coupled liposomal ROCK inhibitor had an effect at approximately 1/100 the amount of the free ROCK inhibitor for inhibiting the activation of LX-2 cells and caused significant decreases in the expression levels of α-smooth muscle actin (SMA) and transforming growth factor (TGF)-β1. The degree of liver fibrosis was suppressed by treatment with VA-coupled liposomal ROCK inhibitor, and the expression of α-SMA and TGF-β1 in liver tissues was also significantly suppressed. In addition, serum levels of alanine aminotransferase and hyaluronic acid were significantly reduced, and there was no decline in kidney function, which has been noted as a systemic adverse effect of ROCK inhibitor. Furthermore, VA-coupled liposomal ROCK inhibitor improved survival rates in rats with liver fibrosis. CONCLUSION Vitamin A-coupled liposomal ROCK inhibitor efficiently suppressed liver fibrosis without causing systemic adverse effects.
Collapse
Affiliation(s)
- Sho Okimoto
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shintaro Kuroda
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hirotaka Tashiro
- Department of Surgery, National Hospital Organization Kure Medical Center, Hiroshima, Japan
| | - Tsuyoshi Kobayashi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takanori Taogoshi
- Department of Pharmaceutical Services, Hiroshima University, Hiroshima, Japan
| | - Hiroaki Matsuo
- Department of Pharmaceutical Services, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| |
Collapse
|
|
29
|
A Randomized Controlled Trial Comparing Nitazoxanide Plus Lactulose With Lactulose Alone in Treatment of Overt Hepatic Encephalopathy. J Clin Gastroenterol 2019; 53:226-230. [PMID: 29668561 DOI: 10.1097/mcg.0000000000001040] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Hepatic encephalopathy (HE) is a reversible spectrum of neuropsychiatric abnormalities associated with liver dysfunction. Lactulose is a nonabsorbable disaccharide presently used to treat HE. Nitazoxanide (NTZ) has a broad-spectrum activity against urease-producing bacteria, so it decreases ammonia production and is therefore expected to reverse the symptoms of HE. A previous pilot study on HE patients given NTZ and lactulose had encouraging results with regard to amelioration of the clinical picture. Patients showed improvement in mental status and the drug was well-tolerated. Results such as these are encouraging larger studies. The aim of this study was to compare the safety and adequacy of NTZ plus lactulose versus lactulose and placebo in management of overt HE. METHODS In total, 120 cirrhotic patients suffering from overt HE were randomly designated to take either NTZ plus lactulose (n=60) or lactulose and placebo (n=60). The Clinical Hepatic Encephalopathy Staging Scale (CHESS) score was assessed for all patients on inclusion to the study and 1 week from the start of treatment. RESULTS Both groups evinced an improvement in CHESS score at 1 week, yet the improvement was significantly better in the NTZ group as the score decreased from 4.15±2.09 to 0.00±0.00 compared with 4.96±2.29 to 1.28±0.91 in patients receiving lactulose and placebo (P-value <0.001). CONCLUSIONS NTZ significantly decreases the CHESS score and improves mental status in the form of patient alertness, orientation, response to stimulation, and ability to talk. NTZ is safe and well-tolerated apart from infrequent epigastric pain.
Collapse
|
|
30
|
Ortiz GA, Garcia-Tsao G. Future Pharmacological Therapies of Portal Hypertension. CURRENT HEPATOLOGY REPORTS 2019; 18:36-48. [PMID: 35722634 PMCID: PMC9205466 DOI: 10.1007/s11901-019-00448-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
PURPOSE OF REVIEW To provide an overview of recent pharmacological treatments for portal hypertension evaluated in early clinical trials, with particular emphasis on the pathophysiological basis of their use. RECENT FINDINGS In patients with compensated cirrhosis, even small decreases in portal pressure (as small as 1 mmHg) are associated with a lower probability of decompensation. In patients with decompensated cirrhosis, portal pressure "response" to non-selective beta-blocker (NSBB) therapy is associated with a lower mortality. When present, significant portal hypertension persists even after elimination of the etiology of cirrhosis and this justifies the continued development of new drugs that target portal hypertension. SUMMARY Over several decades we have gained great depth in the understanding of portal hypertension, its mechanisms and complications. NSBBs, which act by reducing portal venous inflow (an extrahepatic target), are effective in reducing portal pressure and have been the mainstay of therapy for portal hypertension in the last 35 years -being effective in preventing decompensation and variceal hemorrhage. However, because not all patients will have a sufficient response to NSBB and some may be intolerant to NSBB, alternative drugs or drugs that will augment the effect of NSBB on portal pressure are being tested in pre-clinical and early-clinical trials. Many of these drugs target more than one of the intrahepatic or extrahepatic mechanisms implicated in the pathogenesis of portal hypertension in cirrhosis. Out of these proposed therapies, statins have emerged as the most promising new pharmacological therapy for the treatment of portal hypertension.
Collapse
Affiliation(s)
- Guillermo A. Ortiz
- Digestive Diseases Section, Department of Medicine, Yale University, New Haven, CT, USA
- Digestive Diseases Section, Department of Internal medicine, VA-CT Healthcare System, West Haven, CT, USA
| | - Guadalupe Garcia-Tsao
- Digestive Diseases Section, Department of Medicine, Yale University, New Haven, CT, USA
- Digestive Diseases Section, Department of Internal medicine, VA-CT Healthcare System, West Haven, CT, USA
| |
Collapse
|
|
31
|
Abd-Elsalam S, El-Kalla F, Kobtan A, Elhendawy M, Badawi R, Mansour L. Response. Gastrointest Endosc 2018; 87:904-905. [PMID: 29454457 DOI: 10.1016/j.gie.2017.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 12/05/2017] [Indexed: 02/08/2023]
Affiliation(s)
- Sherief Abd-Elsalam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ferial El-Kalla
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdelrahman Kobtan
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elhendawy
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rehab Badawi
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Loai Mansour
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| |
Collapse
|
|
32
|
Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
33
|
Plumbagin Alleviates Capillarization of Hepatic Sinusoids In Vitro by Downregulating ET-1, VEGF, LN, and Type IV Collagen. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5603216. [PMID: 28770223 PMCID: PMC5523349 DOI: 10.1155/2017/5603216] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/28/2017] [Accepted: 06/05/2017] [Indexed: 12/19/2022]
Abstract
Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.
Collapse
|
|
34
|
Omar R, Yang J, Liu H, Davies NM, Gong Y. Hepatic Stellate Cells in Liver Fibrosis and siRNA-Based Therapy. Rev Physiol Biochem Pharmacol 2017; 172:1-37. [PMID: 27534415 DOI: 10.1007/112_2016_6] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatic fibrosis is a reversible wound-healing response to either acute or chronic liver injury caused by hepatitis B or C, alcohol, and toxic agents. Hepatic fibrosis is characterized by excessive accumulation and reduced degradation of extracellular matrix (ECM). Excessive accumulation of ECM alters the hepatic architecture leading to liver fibrosis and cirrhosis. Cirrhosis results in failure of common functions of the liver. Hepatic stellate cells (HSC) play a major role in the development of liver fibrosis as HSC are the main source of the excessive production of ECM in an injured liver. RNA interference (RNAi) is a recently discovered therapeutic tool that may provide a solution to manage multiple diseases including liver fibrosis through silencing of specific gene expression in diseased cells. However, gene silencing using small interfering RNA (siRNA) is encountering many challenges in the body after systemic administration. Efficient and stable siRNA delivery to the target cells is a key issue for the development of siRNA therapeutic. For that reason, various viral and non-viral carriers for liver-targeted siRNA delivery have been developed. This review will cover the current strategies for the treatment of liver fibrosis as well as discussing non-viral approaches such as cationic polymers and lipid-based nanoparticles for targeted delivery of siRNA to the liver.
Collapse
Affiliation(s)
- Refaat Omar
- College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5
| | - Jiaqi Yang
- College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5
| | - Haoyuan Liu
- College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5
| | - Neal M Davies
- College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5
- Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, 8613-114 Street, Edmonton, AB, Canada, T6G 2H1
| | - Yuewen Gong
- College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, Canada, R3E 0T5.
| |
Collapse
|
|
35
|
Simões e Silva AC, Miranda AS, Rocha NP, Teixeira AL. Renin angiotensin system in liver diseases: Friend or foe? World J Gastroenterol 2017; 23:3396-3406. [PMID: 28596676 PMCID: PMC5442076 DOI: 10.3748/wjg.v23.i19.3396] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/17/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
In the last three decades, the understanding of the renin angiotensin system (RAS) has been changed by the discoveries of functional local systems, novel biologically active peptides, additional specific receptors, alternative pathways of angiotensin (Ang) II generation, and new roles for enzymes and precursor components other than those in Ang II synthesis. In this regard, the discovery that Ang-(1-7) opposes the pressor, proliferative, pro-fibrotic, and pro-inflammatory effects mediated by Ang II has contributed to the realization that the RAS is composed of two axes. The first axis consists of the angiotensin-converting enzyme (ACE), with Ang II as the end product, and the angiotensin type 1 (AT1) receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to the production of Ang-(1-7), with the Mas receptor as the main effector conveying the vasodilatory, anti-proliferative, anti-fibrotic, and anti-inflammatory effects of Ang-(1-7). Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases. In this manuscript, we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications, including hemodynamic changes and hepatorenal syndrome. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.
Collapse
|
|
36
|
Chen JY, Newcomb B, Zhou C, Pondick JV, Ghoshal S, York SR, Motola DL, Coant N, Yi JK, Mao C, Tanabe KK, Bronova I, Berdyshev EV, Fuchs BC, Hannun Y, Chung RT, Mullen AC. Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Sci Rep 2017; 7:44867. [PMID: 28322247 PMCID: PMC5359599 DOI: 10.1038/srep44867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 02/15/2017] [Indexed: 12/21/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.
Collapse
Affiliation(s)
- Jennifer Y Chen
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Benjamin Newcomb
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Chan Zhou
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Joshua V Pondick
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Sarani Ghoshal
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | - Samuel R York
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Daniel L Motola
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Nicolas Coant
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Jae Kyo Yi
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Cungui Mao
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | | | | | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA USA
| | - Yusuf Hannun
- Health Science Center, Stony Brook University, Stony Brook, NY USA
| | - Raymond T Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Alan C Mullen
- Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA.,Harvard Stem Cell Institute, Cambridge, MA 02138 USA
| |
Collapse
|
|
37
|
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.
Collapse
|
|
38
|
Chang CC, Lee WS, Chuang CL, Hsin IF, Hsu SJ, Chang T, Huang HC, Lee FY, Lee SD. Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats. Eur J Pharmacol 2017; 802:36-43. [PMID: 28238769 DOI: 10.1016/j.ejphar.2017.02.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/22/2017] [Accepted: 02/22/2017] [Indexed: 01/13/2023]
Abstract
Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.
Collapse
Affiliation(s)
- Ching-Chih Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Wen-Shin Lee
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - I-Fang Hsin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Ting Chang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Cheng-Hsin General Hospital, Taipei, Taiwan
| |
Collapse
|
|
39
|
Ma H, Gao M, Li J, Zhou L, Guo J, Liu J, Han X, Zhai L, Wu T. Re-recognizing serological change patterns and antiviral therapy opportunity of patients with acute hepatitis B through highly sensitive detection technology. Clin Res Hepatol Gastroenterol 2016; 40:584-589. [PMID: 27055389 DOI: 10.1016/j.clinre.2016.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 01/31/2016] [Accepted: 02/11/2016] [Indexed: 02/04/2023]
Abstract
OBJECTIVE This study was conducted to re-recognize serological change patterns of patients with acute hepatitis B (AHB) by a highly sensitive detection technology, as well as to explore methods to select the optimal treatment opportunity. METHODS The biochemical and virological parameters of 558 AHB patients were analyzed retrospectively. The serological markers of hepatitis B virus and HBV DNA were detected by electrochemiluminescence immunoassay and automatic real-time fluorescent quantitative PCR, respectively. RESULTS At baseline, the positive rate of hepatitis B surface antigen (HBsAg) (86.2%) was significantly higher than the positive rate of HBV DNA (51.9%). Among the 58 patients with HBsAg-negative AHB, 16 were detected with trace amounts of HBV DNA at baseline. At 12 weeks, the HBsAg of 43 cases remained positive, and the mean level of HBsAg was 587.5IU/mL±313.4IU/mL. A total of 18 patients with HBsAg levels greater than 1500IU/mL at 12 weeks received interferon α-1b treatment and achieved HBsAg clearance within 24 weeks. CONCLUSIONS Unlike traditional changing patterns, the clearance of HBV DNA in peripheral circulation for a few patients with AHB occurred later than HBsAg clearance. Detection of HBV DNA in peripheral circulation by highly sensitive detection technology could provide a diagnostic basis for those AHB patients who rapidly achieved HBsAg clearance before achieving HBV DNA clearance in their peripheral circulation and prevent misdiagnosis. Dynamic monitoring of the changes in HBsAg levels through highly sensitive detection technology could be used as a guide for the timely adoption of antiviral treatment with interferon and then AHB chronicity would be prevented.
Collapse
Affiliation(s)
- Haixia Ma
- Graduate School, Tianjin Medical University, Tianjin, China; Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Min Gao
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Jia Li
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China.
| | - Li Zhou
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Jie Guo
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Junjuan Liu
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Xu Han
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Lu Zhai
- Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| | - Ting Wu
- Graduate School, Tianjin Medical University, Tianjin, China; Tianjin Second People's Hospital, Tianjin Institute of Hepatology, No. 75, Sudi Road, 300192 Nankai District, Tianjin, China
| |
Collapse
|
|
40
|
Hsu SJ, Lin TY, Wang SS, Chuang CL, Lee FY, Huang HC, Hsin IF, Lee JY, Lin HC, Lee SD. Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats. Eur J Clin Invest 2016; 46:572-80. [PMID: 27091078 DOI: 10.1111/eci.12636] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Accepted: 04/17/2016] [Indexed: 12/21/2022]
Abstract
BACKGROUND Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension. DESIGN This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque-Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ETA R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated. RESULTS In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups. CONCLUSIONS In rats with liver cirrhosis, both nonselective and selective ETA R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis.
Collapse
Affiliation(s)
- Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Te-Yueh Lin
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Sun-Sang Wang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - I-Fang Hsin
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jing-Yi Lee
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
| |
Collapse
|
|
41
|
Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ. Endothelin. Pharmacol Rev 2016; 68:357-418. [PMID: 26956245 PMCID: PMC4815360 DOI: 10.1124/pr.115.011833] [Citation(s) in RCA: 523] [Impact Index Per Article: 58.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.
Collapse
Affiliation(s)
- Anthony P Davenport
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Kelly A Hyndman
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Neeraj Dhaun
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Christopher Southan
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Donald E Kohan
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Jennifer S Pollock
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - David M Pollock
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - David J Webb
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| | - Janet J Maguire
- Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom (A.P.D., J.J.M.); IUPHAR/BPS Guide to PHARMACOLOGY, Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, Edinburgh, United Kingdom (C.S.); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah (D.E.K.); Cardio-Renal Physiology & Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (K.A.H., J.S.P., D.M.P.); and Department of Renal Medicine, Royal Infirmary of Edinburgh (N.D.) and University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute (D.J.W.N.D.), Edinburgh, Scotland, United Kingdom
| |
Collapse
|
|
42
|
Bocca C, Novo E, Miglietta A, Parola M. Angiogenesis and Fibrogenesis in Chronic Liver Diseases. Cell Mol Gastroenterol Hepatol 2015; 1:477-488. [PMID: 28210697 PMCID: PMC5301407 DOI: 10.1016/j.jcmgh.2015.06.011] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 06/02/2015] [Indexed: 12/12/2022]
Abstract
Pathologic angiogenesis appears to be intrinsically associated with the fibrogenic progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several laboratories have suggested that this association is relevant for chronic liver disease progression, with angiogenesis proposed to sustain fibrogenesis. This minireview offers a synthesis of relevant findings and opinions that have emerged in the last few years relating liver angiogenesis to fibrogenesis. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role of hypoxia and hypoxia-inducible factors and assess the evidence supporting a clear relationship between angiogenesis and fibrogenesis. A section is dedicated to the critical interactions between liver sinusoidal endothelial cells and either quiescent hepatic stellate cells or myofibroblast-like stellate cells. Finally, we introduce the unusual, dual (profibrogenic and proangiogenic) role of hepatic myofibroblasts and emerging evidence supporting a role for specific mediators like vasohibin and microparticles and microvesicles.
Collapse
Key Words
- ANGPTL3, angiopoietin-like-3 peptide
- Akt, protein kinase B
- Ang-1, angiopoietin-1
- CCL2, chemokine ligand 2
- CCR, chemokine receptor
- CLD, chronic liver disease
- ET-1, endothelin 1
- HCC, hepatocellular carcinoma
- HIF, hypoxia-inducible factor
- HSC, hepatic stellate cell
- HSC/MFs, myofibroblast-like cells from activated hepatic stellate cells
- Hh, Hedgehog
- Hypoxia
- LSEC, liver sinusoidal endothelial cell
- Liver Angiogenesis
- Liver Fibrogenesis
- MF, myofibroblast
- MP, microparticle
- Myofibroblasts
- NAFLD, nonalcoholic fatty liver disease
- NASH, nonalcoholic steatohepatitis
- NO, nitric oxide
- PDGF, platelet-derived growth factor
- ROS, reactive oxygen species
- VEGF, vascular endothelial growth factor
- VEGF-R2, vascular endothelial growth factor receptor type 2
- eNOS, endothelial nitric oxide synthase
- α-SMA, α-smooth muscle actin
Collapse
Affiliation(s)
| | | | | | - Maurizio Parola
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, School of Medicine, University of Torino, Torino, Italy
| |
Collapse
|
|
43
|
Abstract
Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A2, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to be clinically effective in two randomized controlled trials. Splanchnic hyperemia can be counteracted by nonselective β-blockers (NSBBs), vasopressin analogs and somatostatin analogs, drugs that until recently were the only available treatments for portal hypertension, but that are not very effective in the initial stages of cirrhosis. There is experimental and clinical evidence indicating that a more effective reduction of portal pressure is obtained by combining agents acting on these different pathways. It is likely that the treatment of portal hypertension will evolve to use etiological treatments together with antifibrotic agents and/or drugs improving sinusoidal endothelial function in the initial stages of cirrhosis (preprimary prophylaxis), while NSBBs will be added in advanced stages of the disease.
Collapse
Affiliation(s)
- Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS, Hospital Clinic de Barcelona, CIBEREHD, Barcelona, Spain
| | | | | |
Collapse
|
|
44
|
Yanguas SC, Cogliati B, Willebrords J, Maes M, Colle I, van den Bossche B, de Oliveira CPMS, Andraus W, Alves VAF, Leclercq I, Vinken M. Experimental models of liver fibrosis. Arch Toxicol 2015; 90:1025-1048. [PMID: 26047667 DOI: 10.1007/s00204-015-1543-4] [Citation(s) in RCA: 238] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 05/28/2015] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.
Collapse
Affiliation(s)
- Sara Crespo Yanguas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Joost Willebrords
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Michaël Maes
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Isabelle Colle
- Department of Hepato-Gastroenterology, Algemeen Stedelijk Ziekenhuis, Aalst, Belgium
| | - Bert van den Bossche
- Department of Abdominal Surgery and Hepato-Pancreatico-Biliary Surgery, Algemeen Stedelijk Ziekenhuis, Aalst, Belgium
| | | | - Wellington Andraus
- Laboratory of Medical Investigation, Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | - Isabelle Leclercq
- Laboratoire d'Hépato-Gastro-Entérologie, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| |
Collapse
|
|
45
|
Wang X, Zhao W, Wang J, Shi K, Qin X, Kong Q, Wang G, Mu L, Li H, Sun B, Shi L. Bone Marrow Stromal Cells Inhibit the Activation of Liver Cirrhotic Fat-Storing Cells via Adrenomedullin Secretion. Dig Dis Sci 2015; 60:1325-34. [PMID: 25445161 DOI: 10.1007/s10620-014-3423-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 10/30/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cirrhosis, or liver fibrosis, which is mainly triggered by cirrhosis fat-storing cells (CFSCs) activation, has traditionally been considered an irreversible disease. However, recent observations indicate that even advanced fibrosis is still reversible by removing the causative agents. Anti-fibrotic effects of bone marrow-derived stromal cells (BMSCs) have been demonstrated by inhibiting CFSCs via cytokines secretion; however, the mechanisms are still unclear. AIMS The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated CFSCs. METHODS After the co-culture of CFSCs with BMSCs supernatants with or without the addition of recombinant rat adrenomedullin (AM)/AM-specific siRNA, western blot analysis was mainly used to detect the differences of relative protein expression on CFSCs. RESULTS BMSC-secreted adrenomedullin (AM) effectively inhibited the proliferation and activation of CFSCs by suppressing the expression of Ang II and its binding receptor, AT1, which resulted in a reduction of p47-phox formation. CONCLUSIONS Our data suggested that BMSCs inhibited CFSC activation in vitro via the AM-Ang II-p47-phox signaling pathway, and since CFSC activation is an essential part of hepatic fibrosis process, this inhibition by BMSCs implies us new insights into the potential treatment of hepatic fibrosis via BMSCs.
Collapse
Affiliation(s)
- Xiaodong Wang
- Emergency Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Bao Jian Road, Nangang District, Harbin, 150086, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Gracia-Sancho J, Maeso-Díaz R, Fernández-Iglesias A, Navarro-Zornoza M, Bosch J. New cellular and molecular targets for the treatment of portal hypertension. Hepatol Int 2015; 9:183-91. [PMID: 25788198 DOI: 10.1007/s12072-015-9613-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 02/10/2015] [Indexed: 12/12/2022]
Abstract
Portal hypertension (PH) is a common complication of chronic liver disease, and it determines most complications leading to death or liver transplantation in patients with liver cirrhosis. PH results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (a) distortion of the liver vascular architecture and (b) hepatic microvascular dysfunction. Increment in hepatic resistance is latterly accompanied by splanchnic vasodilation, which further aggravates PH. Hepatic microvascular dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSEC). The cross-talk between LSEC and hepatic stellate cells induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis. Therapy for PH aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments, while architectural disruption and fibrosis can be ameliorated by a variety of anti-fibrogenic drugs and anti-angiogenic strategies. Sinusoidal endothelial dysfunction is ameliorated by statins and other drugs increasing NO availability. Splanchnic hyperemia can be counteracted by non-selective beta-blockers (NSBBs), vasopressin analogs and somatostatin analogs. Future treatment of portal hypertension will evolve to use etiological treatments together with anti-fibrotic agents and/or drugs improving microvascular function in initial stages of cirrhosis (pre-primary prophylaxis), while NSBBs will be added in advanced stages of the disease.
Collapse
Affiliation(s)
- Jordi Gracia-Sancho
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of Barcelona, Rosselló 149, 4th Floor, 08036, Barcelona, Spain,
| | | | | | | | | |
Collapse
|
|
47
|
Lee JY, Lee FY, Huo TI, Wang SS, Huang HC, Lin HC, Chuang CL, Lee SD. Diabetes enhances the intrahepatic vascular response to endothelin-1 in cirrhotic rats: association with the ETA receptor and pERK up-regulation. Liver Int 2015; 35:704-12. [PMID: 24636620 DOI: 10.1111/liv.12527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Accepted: 03/05/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Cirrhosis is characterized by increased intrahepatic vascular resistance and enhanced vasocontractile responsiveness that impedes portal inflow and elevates portal pressure, in which endothelin-1 (ET-1) plays a role. Diabetes and glucose influence vasoresponsiveness but their impact on the intrahepatic vascular bed in cirrhosis is unknown. To investigate intrahepatic ET-1 vasoresponsiveness in cirrhotic rats with and without diabetes and to explore the underlying mechanisms. METHODS Spraque-Dawley rats received common bile-duct ligation (BDL) to induce cirrhosis. Streptozotocin was injected to induce diabetes in the BDL rats (BDL/STZ). In situ liver perfusion was performed to obtain the ET-1 concentration-response curves. The basic hemodynamics and hepatic protein expressions of ET-1 receptors, pERK, ERK, pAkt, Akt, iNOS, eNOS, peNOS and calmodulin were evaluated. The circulating concentrations of N-terminal pro-brain natriuretic peptide (NT-ProBNP), blood urea nitrogen (BUN) and creatinine were also determined. RESULTS Body weight, mean arterial pressure, heart rate and survival rate were significantly decreased in the BDL/STZ rats. The perfusion pressure changes in response to ET-1 were higher in the BDL/STZ group for all perfusates. ETA receptor and pERK expressions were enhanced in the BDL/STZ group. The circulating concentrations of NT-ProBNP, BUN and creatinine, as well as SMA flow, were not significantly different between the BDL and BDL/STZ groups. CONCLUSION Cirrhotic rats with diabetes showed higher intrahepatic ET-1 vasoresponsiveness than normoglycemic cirrhotic rats. This effect is not affected by changes in perfused glucose concentration and may be related, at least in part, to intrahepatic ETA R receptor and pERK over-expression.
Collapse
Affiliation(s)
- Jing-Yi Lee
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Kawada N, Parola M. Interactions of Stellate Cells with Other Non-Parenchymal Cells. STELLATE CELLS IN HEALTH AND DISEASE 2015:185-207. [DOI: 10.1016/b978-0-12-800134-9.00012-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
49
|
|
|
50
|
Liu D, Qian L, Wang J, Hu X, Qiu L. Hepatic perfusion parameters of contrast-enhanced ultrasonography correlate with the severity of chronic liver disease. ULTRASOUND IN MEDICINE & BIOLOGY 2014; 40:2556-2563. [PMID: 25218453 DOI: 10.1016/j.ultrasmedbio.2014.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 05/08/2014] [Accepted: 05/14/2014] [Indexed: 06/03/2023]
Abstract
In the study described here, we introduced a new ratio acquired with contrast-enhanced ultrasonography (CEUS): a liver parenchyma blood supply ratio that differentiates arterial and portal phases. Our purpose was to determine whether this ratio and other liver parenchyma perfusion parameters acquired with CEUS can be correlated with the severity of chronic liver disease. Twelve patients with non-cirrhotic chronic liver disease, 35 patients with cirrhosis (child class A: n = 10; child class B: n = 13; child class C: n = 12) and 21 healthy volunteers were examined by CEUS. Time-intensity curves were drawn for regions of interest located in liver parenchyma and right kidney cortex using QLAB quantification software. The arterial and portal phases were differentiated by the time to the maximum enhancement of right kidney and liver parenchyma perfusion data acquired from the time-intensity curves: the intensity of liver parenchyma perfused by hepatic arterial flow (I(ap)), the intensity of total perfusion of liver parenchyma (I(peak)), the intensity of liver parenchyma perfused by portal venous flow (I(pp)) and the ratio of portal perfusion to total perfusion of liver parenchyma expressed by the parameters I(pp)/I(peak), I(peak), I(pp) and I(pp)/I(peak) significantly decreased in patients with cirrhosis and in patients with non-cirrhotic chronic liver disease, whereas Iap increased. The parameters I(pp), I(peak), I(pp)/I(peak) and Iap correlated with the severity of chronic liver disease (r = -0.938, p < 0.001; r = -0.790, p < 0.001; r = -0.931 p < 0.001; r = 0.31, p < 0.05). The diagnostic accuracy rates for cirrhosis expressed as areas under receiver operating characteristic curves were 0.93 for I(peak), 0.98 for I(pp), 0.98 for I(pp)/I(peak), and 0.69 for I(ap). Liver parenchyma perfusion parameters obtained by CEUS were correlated with the severity of chronic liver disease and have the potential to assess cirrhosis non-invasively.
Collapse
Affiliation(s)
- Dong Liu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Linxue Qian
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Jinrui Wang
- Department of Ultrasound, Peking University Third Hospital, Beijing, China
| | - Xiangdong Hu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lanyan Qiu
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| |
Collapse
|