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Kwanten W(WJ, Francque SM. The liver sinusoid in chronic liver disease: NAFLD and NASH. SINUSOIDAL CELLS IN LIVER DISEASES 2024:263-284. [DOI: 10.1016/b978-0-323-95262-0.00012-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Wang XK, Peng ZG. Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:655557. [PMID: 33935770 PMCID: PMC8082362 DOI: 10.3389/fphar.2021.655557] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.
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Affiliation(s)
- Xue-Kai Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Biotechnology of Antibiotics, National Health and Family Planning Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Stewart RK, Dangi A, Huang C, Murase N, Kimura S, Stolz DB, Wilson GC, Lentsch AB, Gandhi CR. A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury. J Hepatol 2014; 60:298-305. [PMID: 24060854 PMCID: PMC4195246 DOI: 10.1016/j.jhep.2013.09.013] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Revised: 08/05/2013] [Accepted: 09/03/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver. METHODS We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment. RESULTS CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice. CONCLUSIONS HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.
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Affiliation(s)
- Rachel K. Stewart
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
| | - Anil Dangi
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213,Department of Surgery University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, OH, USA and Cincinnati Veterans Administration, Cincinnati, OH, USA
| | - Chao Huang
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
| | - Noriko Murase
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
| | - Shoko Kimura
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
| | - Donna B. Stolz
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gregory C. Wilson
- Department of Surgery University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, OH, USA and Cincinnati Veterans Administration, Cincinnati, OH, USA
| | - Alex B. Lentsch
- Department of Surgery University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, OH, USA and Cincinnati Veterans Administration, Cincinnati, OH, USA
| | - Chandrashekhar R. Gandhi
- Thomas E. Starzl Transplantation Institute and Departments of Surgery, University of Pittsburgh, Pittsburgh, PA 15213,Department of Surgery University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, OH, USA and Cincinnati Veterans Administration, Cincinnati, OH, USA,Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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Yirmibeşoğlu O, Büyükgebiz O, Ars D, Unay Ö, Çevik D. Lisinopril Inhibits Endothelin-1 in the Early Period of Hepatic Reperfusion Injury in a Partial Hepatectomy Model. Transplant Proc 2011; 43:2524-30. [DOI: 10.1016/j.transproceed.2011.06.043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Revised: 05/14/2011] [Accepted: 06/13/2011] [Indexed: 10/17/2022]
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Kwok W, Lee SH, Culberson C, Korneszczuk K, Clemens MG. Caveolin-1 mediates endotoxin inhibition of endothelin-1-induced endothelial nitric oxide synthase activity in liver sinusoidal endothelial cells. Am J Physiol Gastrointest Liver Physiol 2009; 297:G930-9. [PMID: 20501440 PMCID: PMC2777454 DOI: 10.1152/ajpgi.00106.2009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Endothelin-1 (ET-1) plays a key role in the regulation of endothelial nitric oxide synthase (eNOS) activation in liver sinusoidal endothelial cells (LSECs). In the presence of endotoxin, an increase in caveolin-1 (Cav-1) expression impairs ET-1/eNOS signaling; however, the molecular mechanism is unknown. The objective of this study was to investigate the molecular mechanism of Cav-1 in the regulation of LPS suppression of ET-1-mediated eNOS activation in LSECs by examining the effect of caveolae disruption using methyl-beta-cyclodextrin (CD) and filipin. Treatment with 5 mM CD for 30 min increased eNOS activity (+255%, P < 0.05). A dose (0.25 microg/ml) of filipin for 30 min produced a similar effect (+111%, P < 0.05). CD induced the perinuclear localization of Cav-1 and eNOS and stimulated NO production in the same region. Readdition of 0.5 mM cholesterol to saturate CD reversed these effects. Both the combined treatment with CD and ET-1 (CD + ET-1) and with filipin and ET-1 stimulated eNOS activity; however, pretreatment with endotoxin (LPS) abrogated these effects. Following LPS pretreatment, CD + ET-1 failed to stimulate eNOS activity (+51%, P > 0.05), which contributed to the reduced levels of eNOS-Ser1177 phosphorylation and eNOS-Thr495 dephosphorylation, the LPS/CD-induced overexpression and translocation of Cav-1 in the perinuclear region, and the increased perinuclear colocalization of eNOS with Cav-1. These results supported the hypothesis that Cav-1 mediates the action of endotoxin in suppressing ET-1-mediated eNOS activation and demonstrated that the manipulation of caveolae produces significant effects on ET-1-mediated eNOS activity in LSECs.
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Affiliation(s)
- Willson Kwok
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
| | - Sang Ho Lee
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
| | - Cathy Culberson
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
| | - Katarzyna Korneszczuk
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
| | - Mark G. Clemens
- Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina
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Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006; 10:76-99. [PMID: 16563223 PMCID: PMC3933103 DOI: 10.1111/j.1582-4934.2006.tb00292.x] [Citation(s) in RCA: 604] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
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Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University - HospitalAachen, Germany
- *Correspondence to: A. M. GRESSNER/R. WEISKIRCHEN Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany. Tel.: +49-241-8088678/9 Fax: +49-241-8082512 E-mails:
| | - R Weiskirchen
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University - HospitalAachen, Germany
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Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006. [PMID: 16563223 DOI: 10.1634/stemcells.2007-0252"> [doi: 10.1111/j.1582-4934.2006.tb00292.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
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Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University--Hospital, D-52074 Aachen, Germany.
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Gressner AM, Weiskirchen R. Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 2006. [PMID: 16563223 DOI: 10.1111/j.1528-4934.2006.th00292.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-beta1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-beta were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-beta and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.
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Affiliation(s)
- A M Gressner
- Institute of Clinical Chemistry and Pathobiochemistry, RWTH Aachen University--Hospital, D-52074 Aachen, Germany.
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Guo CY, Wu JY, Wu YB, Zhong MZ, Lu HM. Effects of endothelin-1 on hepatic stellate cell proliferation, collagen synthesis and secretion, intracellular free calcium concentration. World J Gastroenterol 2004; 10:2697-700. [PMID: 15309721 PMCID: PMC4572195 DOI: 10.3748/wjg.v10.i18.2697] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To explore the effects of endothelin-1 (ET-1) on hepatic stellate cells (HSCs) DNA uptake, DNA synthesis, collagen synthesis and secretion, inward whole-cell calcium concentration ([Ca2+]i) as well as the blocking effect of verapamil on ET-1-stimulated release of inward calcium (Ca2+) of HSC in vitro.
METHODS: Rat hepatic stellate cells (HSCs) were isolated and cultivated. 3H-TdR and 3H-proline incorporation used for testing DNA uptake and synthesis, collagen synthesis and secretion of HSCs cultured in vitro; Fluorescent calcium indicator Fura-2/AM was used to measure [Ca2+]i inward HSCs.
RESULTS: ET-1 at the concentration of 5 × 10-8 mol/L, caused significant increase both in HSC DNA synthesis (2247 ± 344 cpm, P < 0.05) and DNA uptake (P < 0.05) when compared with the control group. ET-1 could also increase collagen synthesis (P < 0.05 vs control group) and collagen secretion (P < 0.05 vs control group). Besides, inward HSC [Ca2+] i reached a peak concentration (422 ± 98 mol/L, P < 0.001) at 2 min and then went down slowly to165 ± 51 mol/L (P < 0.01) at 25 min from resting state (39 ± 4 mol/L) after treated with ET-1. Verapamil (5 mol/L) blocked ET-1-activated [Ca2+]i inward HSCs compared with control group (P < 0.05). Fura-2/AM loaded HSC was suspended in no Ca2+ buffer containing 1 mol/L EGTA, 5 min later, 10-8 mol/L of ET-1 was added, [Ca2+]i inward HSCs rose from resting state to peak 399 ± 123 mol/L, then began to come down by the time of 20 min. It could also raise [Ca2+]i inward HSCs even without Ca2+ in extracellular fluid, and had a remarkable dose-effect relationship (P < 0.05). Meanwhile, verapamil could restrain the action of ET-1 (P < 0.05).
CONCLUSION: Actions of ET-1 on collagen metabolism of HSCs may depend on the transportation of inward whole-cell calcium.
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Affiliation(s)
- Chuan-Yong Guo
- Department of Gastroenterology, Shanghai Tenth People Hospital of Tongji University, Shanghai 200072, China.
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Uhlmann D, Pietsch UC, Ludwig S, Hess J, Armann B, Gaebel G, Escher E, Schaffranietz L, Tannapfel A, Fiedler M, Hauss J, Witzigmann H. Assessment of hepatic ischemia-reperfusion injury by simultaneous measurement of tissue pO2, pCO2, and pH. Microvasc Res 2004; 67:38-47. [PMID: 14709401 DOI: 10.1016/j.mvr.2003.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
INTRODUCTION The objective of this study was to determine whether the simultaneous measurement of tissue pH, pCO(2), and pO(2) with a multiple-parameter fiberoptic sensor (Paratrend 7) can be used for continuous monitoring of hepatic microperfusion in a pig model of hepatic ischemia given endothelin(A) receptor antagonist (ET(A)-RA) or isotonic saline. METHODS Fourteen anesthetized swine were subjected to 2 h of hepatic vascular exclusion. The animals were randomized into two groups: control group (n = 7, saline solution iv) and therapy group (n = 7, ET(A)-RA). For evaluation of ischemia-reperfusion injury, the data of the multiple-parameter sensor (pO(2para), pCO(2para), and pH(para)) were compared with partial oxygen pressure in tissue (p(ti)O(2)), laser Doppler flow, and systemic hemodynamic, metabolic data, and time course of transaminases. RESULTS In the control group 30 and 60 min after reperfusion, the following values were measured: p(ti)O(2): 34.0 +/- 8.6 / 36.3 +/- 7.0 mm Hg (P < 0.05 vs. preop.: 49.8 +/- 12.1 mm Hg), laser Doppler area: 133.3 +/- 23.2 / 156.4 +/- 15.4 (P < 0.05 vs. preop.: 215.9 +/- 14.8). Animals in the therapy group revealed significantly improved values (p(ti)O(2): 54.0 +/- 8.6 / 58.1 +/- 7.8 mm Hg, laser Doppler: 210.2 +/- 38.5 / 225.2 +/- 21.3; P < 0.05). Using the Paratrend, also an improvement in the therapy group was seen 30 and 60 min after reperfusion. The values showed a strong correlation with p(ti)O(2) (r = 0.895; P < 0.05) and laser Doppler flow (r = 0.807; P < 0.05). In the treatment group, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutamate dehydrogenase (GLDH) were reduced 6 and 18 h after reperfusion, respectively, indicating hepatoprotection by the therapy (P < 0.05 vs. control). CONCLUSIONS The Paratrend sensor offers the opportunity to study postischemic organ hemodynamics through the simultaneous measurement of interstitial pH, pCO(2), and pO(2) in a small tissue region. This method offers a prognostic tool for the study of the effects of experimental vasoactive therapy on liver microcirculation and perspectives for continuous monitoring of human liver microperfusion after liver surgery and trauma.
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Affiliation(s)
- Dirk Uhlmann
- 2nd Department of Surgery, University of Leipzig, 04103, Leipzig, Germany.
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Uhlmann D, Witzigmann H, Senninger N, Hauss J, Spiegel HU. Protective role of an endothelin-converting enzyme inhibitor (FR901533) in hepatic ischemia/reperfusion injury. Microvasc Res 2001; 62:43-54. [PMID: 11421659 DOI: 10.1006/mvre.2001.2309] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
INTRODUCTION There is evidence that endothelin (ET) contributes to disturbances of the hepatic microcirculation after warm ischemia/reperfusion (I/R) by causing vasoconstriction and by enhancing leukocyte endothelium interactions. The aim of this study was to investigate a possible protective role of the endothelin converting enzyme (ECE) inhibitor FR901533 in this setting. METHODS In an in vivo model (42 Wistar rats), hepatic ischemia was induced for 30 min by Pringle's maneuver. Sham operated (I), untreated ischemic (II), and treatment (III) groups with FR901533 (1 mg/kg bw iv) were investigated. The effect of FR901533 in I/R was assessed by in vivo microscopy (30-90 min after reperfusion), measurement of local tissue pO2 (30 and 60 min after reperfusion), and determination of AST/ALT levels (2 h, 6 h, and 2, 6, and 14 days after reperfusion). RESULTS In the untreated ischemic group (II) sinusoidal constriction to 76.3 +/- 4.2% of basic diameters was observed, leading to significant decreases in perfusion rate (82.3 +/- 3.6% of sham group) and in liver tissue pO(2) (43.5 +/- 3.2% of sham group) (P < 0.05). In addition, we found an increased percentage of stagnant leukocytes in sinusoids (138.3 +/- 9.8) and sticking leukocytes in postsinusoidal venules (155.2 +/- 3.3% of sham group) (P < 0.05). Hepatocellular damage (AST/ALT increase to 430.6 +/- 47.7 U/L/200.2 +/- 23.8 U/L, pre: 27.4 +/- 2.7 U/L/28.1 +/- 2.7 U/L) was detected 6 h after reperfusion (P < 0.05). Administration of the ECE inhibitor before ischemia significantly reduced I/R injury. Sinusoidal diameters were maintained (102.2 +/- 1.7%), while perfusion rate (93.1 +/- 1.8%) and tissue pO2 (105.3 +/- 2.7%) increased significantly (P < 0.05). Hepatocellular damage was decreased (AST/ALT levels after 6 h of reperfusion: 166.6 +/- 26.3 U/L/132.4 +/- 22.5 U/L, P < 0.05) and leukocyte sticking and rolling were significantly reduced (P < 0.05). CONCLUSION Our results provide evidence that the new therapeutic approach with an ECE inhibitor is effective in reducing hepatic I/R injury.
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Affiliation(s)
- D Uhlmann
- Second Department of Surgery, University of Leipzig, Leipzig, 04103, Germany
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Kraus TW, Mehrabi A, Klar E, Arnold J, Sido B, Otto G, Herfarth C. Intraoperative evaluation of big-endothelin plasma levels during liver transplantation in different vascular compartments. Transpl Int 2001; 7 Suppl 1:S144-9. [PMID: 11271188 DOI: 10.1111/j.1432-2277.1994.tb01333.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Endothelin-1 (ET) is derived from its precursor big-ET, secreted by endothelial cells of multiple origin. The role of ET peptides in the physiological responses after orthotopic liver transplantation (OLT) was investigated. Venous big-ET plasma levels were analysed by RIA in 28 patients before and after OLT. Samples for analysis were taken intraoperatively from 12 patients from the caval, portal and hepatic veins and the radial artery at multiple time points. Highest caval levels were found during the anhepatic period and 60 min after reperfusion, followed by a drop and subsequent increase postoperatively. Highest levels in the hepatic and portal veins were detected during explanation and reperfusion. A different pattern was found in the radial artery. Values during rejection and infection were elevated compared with preoperative and postoperative levels. The heterogeneity of the kinetics points to different sites of ET generation, including liver and splanchnic circulation. It suggests a predominant paracrine secretion mode of ET peptides with various stimuli involved. Big-ET levels could reflect endothelial cell damage, as big-ET is generated intracellularly and biological activity is rather weak.
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Affiliation(s)
- T W Kraus
- Surgical Department, University of Heidelberg, Germany
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Gu M, Takada Y, Fukunaga K, Ishiguro S, Taniguchi H, Seino K, Yuzawa K, Otsuka M, Todoroki T, Fukao K. Role of platelet-activating factor in hepatectomy with Pringle's maneuver. J Surg Res 2001; 96:233-8. [PMID: 11266278 DOI: 10.1006/jsre.2000.6067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Interruption of hepatic inflow is commonly used to reduce blood loss during extensive liver resection, but may cause liver dysfunction. The present study investigated the effects of platelet-activating factor (PAF) antagonist E5880 on total liver warm ischemia and 70% hepatectomy. METHODS Rabbits were used in this study and were divided into four groups: group 1, those treated with only 70% hepatectomy; group 2, those treated with only 20 min Pringle's maneuver; group 3, those treated with both Pringle's maneuver and 70% hepatectomy without pretreatment; and group 4, those pretreated with PAF antagonist E5880 (0.3 mg/kg) followed by Pringle's maneuver and 70% hepatectomy. The remnant liver function was then evaluated after reperfusion. RESULTS Seven-day survival rates in both groups 1 and 2 were 100%. E5880 treatment significantly increased 7-day survival rate (group 4: 38% vs group 3: 0%, P < 0.05) after a combination of Pringle's maneuver and 70% hepatectomy. The elevations of serum liver enzymes (GOT, GPT, mGOT, and LDH) were significantly inhibited in group 4 at 1 and 4 h after reperfusion. Portal venous pressure and the energy charge of liver were also significantly improved in group 4, compared with those in group 3. Endothelin-1 levels of arterial and portal venous blood progressively increased after reperfusion; however, there were no significant differences between the two groups. Leukocyte infiltration into the liver was significantly inhibited in group 4. CONCLUSION E5880 pretreatment has protective effects on liver function after 70% hepatectomy with Pringle's maneuver in rabbits.
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Affiliation(s)
- M Gu
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki, 305-8575, Japan
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Kuddus RH, Nalesnik MA, Subbotin VM, Rao AS, Gandhi CR. Enhanced synthesis and reduced metabolism of endothelin-1 (ET-1) by hepatocytes--an important mechanism of increased endogenous levels of ET-1 in liver cirrhosis. J Hepatol 2000; 33:725-32. [PMID: 11097479 DOI: 10.1016/s0168-8278(00)80302-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Hepatic concentration of endothelin-1 (ET-1) is increased in human and experimental liver cirrhosis. Because of its potent actions in the liver, ET-1 has been suggested to play an important role in the pathophysiology of cirrhosis. Since hepatocytes are the major cell type to metabolize ET-1, we investigated whether their reduced capacity to degrade ET-1 is a mechanism of its elevated levels in cirrhosis. METHODS The expression of ET-1 receptors, ET-1 and endothelin converting enzyme (ECE), and metabolism of ET-1 and ECE activity were compared in hepatocytes isolated from control and carbon tetrachloride-induced cirrhotic rats. RESULTS ET-1 receptor density and receptor-mediated internalization of ET-1 were significantly increased in cirrhotic hepatocytes relative to the control cells. However, compared to control hepatocytes, metabolism of ET-1 by the cirrhotic cells was reduced significantly. Interestingly, hepatocytes were found to contain preproET-1 mRNA, ECE-1 mRNA and ET-1. PreproET-1 mRNA and ET-1 levels were increased in cirrhotic hepatocytes but their ECE mRNA and ECE activity were not altered. CONCLUSIONS These results provide the first evidence that hepatocytes have the ability to synthesize ET-1 and demonstrate that decreased metabolism and enhanced synthesis, of ET-1 in hepatocytes are an important mechanism of its elevated levels in cirrhosis.
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Affiliation(s)
- R H Kuddus
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh and Veterans Administration Medical Center, PA 15213, USA
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17
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Gandhi CR, Kuddus RH, Uemura T, Rao AS. Endothelin stimulates transforming growth factor-beta1 and collagen synthesis in stellate cells from control but not cirrhotic rat liver. Eur J Pharmacol 2000; 406:311-8. [PMID: 11040336 DOI: 10.1016/s0014-2999(00)00683-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interactions between hepatic stellate cells and endothelin-1 are implicated in liver fibrosis. We determined endothelin-1, its receptors and its effects on the synthesis of a fibrogenic agent transforming growth factor (TGF)-beta1 and collagen in stellate cells from control and CCl(4)-induced cirrhotic rats. The basal synthesis of endothelin-1, TGF-beta1 and collagen was much higher in cirrhotic stellate cells than in control cells. Endothelin-1 stimulated TGF-beta1 and collagen synthesis via endothelin ET(A) and endothelin ET(B) receptors, respectively, in control stellate cells, but did not elicit these effects in the cirrhotic cells despite increased density of the respective receptor subtypes in them. These results indicate that the actions of endothelin-1 on stellate cells may be an important physiological mechanism in maintenance of hepatic architecture. However, inability of endothelin-1 to stimulate TGF-beta1 and collagen synthesis in cirrhotic stellate cells suggests that it does not influence fibrogenic activity by direct action on them probably because the processes are already maximally activated.
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Affiliation(s)
- C R Gandhi
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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18
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Gu M, Takada Y, Fukunaga K, Ishiguro S, Taniguchi H, Seino K, Yuzawa K, Otsuka M, Todoroki T, Fukao K. Pharmacologic graft protection without donor pretreatment in liver transplantation from non-heart-beating donors. Transplantation 2000; 70:1021-5. [PMID: 11045637 DOI: 10.1097/00007890-200010150-00006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Non-heart-beating donors (NHBDs) are considered potential sources of transplant organs in an effort to alleviate the problem of donor shortage in clinical liver transplantation. We investigated the possibility of pharmacologic protection of hepatic allograft function from NHBDs without donor pretreatment. METHODS Orthotopic liver transplantation was performed using pigs. In donors, cardiac arrest was induced by stopping the respirator. Forty-five minutes after cessation of the respirator, the liver was flushed with cold lactated Ringer's solution including heparin and with the University of Wisconsin (UW) solution, and then preserved for 8 hr at 4 degrees C in the UW solution. The pigs were divided into two groups: a control group and a treated group. In the treated group, an endothelin antagonist TAK-044 was added to the UW solutions (10 mg/L), and TAK-044 (10 mg/kg body weight) and a platelet activating factor antagonist E5880 (0.3 mg/kg body weight) were also administered to the recipients. RESULTS TAK-044 and E5880 treatment significantly increased the 7-day survival rate of the recipients (100% vs. 17%, P<0.05). In the treated group, portal venous pressure immediately after reperfusion of the graft was significantly lower than in the control group, and postoperative increase in serum concentrations of glutamic oxaloacetic transaminase and total bilirubin was attenuated. Moreover, the energy charge and adenosine triphosphate concentration of the liver were rapidly restored after reperfusion. CONCLUSIONS Pharmacologic modulation with TAK-044 and E5880 avoiding donor pretreatment can improve the viability of hepatic allografts procured from NHBDs.
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Affiliation(s)
- M Gu
- Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan
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19
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Kraus T, Mehrabi A, Golling M, Schäffer F, Bud O, Gebhard MM, Herfarth C, Klar E. Effects of exogenous endothelin-1 application on liver perfusion in native and transplanted porcine livers. J Surg Res 2000; 93:272-81. [PMID: 11027470 DOI: 10.1006/jsre.2000.5972] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
PURPOSE This study was designed to assess and differentiate the impact of progressivly increasing portal venous endothelin-1 (ET) plasma concentrations on hepatic micro- and macroperfusion of native porcine livers (Group A) and liver grafts after experimental transplantation (Group B). METHODS A standardized gradual increment in systemic ET plasma concentration (0-58 pg/ml) was induced by continuous ET-1 infusion into the portal vein in both groups (A: n = 10, B: n = 10). Control animals received only saline (n = 5, each group). Hepatic microcirculation (HMC) was quantified by thermodiffusion electrodes, hepatic artery flow (HAF), and portal venous flow (PVF) by Doppler flowmetry. RESULTS No changes in ET or perfusion parameters were observed in controls. The mean ET level after orthotopic liver transplantation (OLT) in Group B was elevated (baseline: 3.8 +/- 2.4 pg/ml) compared with Group A (2.8 +/- 1.9 pg/ml). With rising ET levels HAF decreased progressively in Group A from 205 +/- 97 (baseline) to 160 +/- 72 ml/min, and in Group B from 161 +/- 87 to 146 +/- 68 ml/min. PVF decreased in Group A from 722 +/- 253 to 370 +/- 198 ml/min, and in Group B from 846 +/- 263 to 417 +/- 203 ml/min. Baseline HMC in Group A was 86 +/- 15 and decreased significantly to 29 +/- 9 ml/100 g/min, and baseline MC in Group B was 90 +/- 22 and decreased to 44 +/- 32 ml/100 g/min. No significant alteration in systemic circulation was noted at the ET concentrations investigated. CONCLUSIONS Significant impairment of hepatic micro- and macrocirculation was detected after induction of systemic ET levels above 9.4 pg/ml both in native and in transplanted livers. Disturbance of HMC was caused predominantly by reduction of portal venous flow, while the effect of ET on HAF was less pronounced. Characteristics of flow impairment in transplanted and native livers were analogous after short cold ischemic graft storage (6 h).
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Affiliation(s)
- T Kraus
- Department of Surgery, University of Heidelberg, Heidelberg, Germany.
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20
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Gandhi CR, Uemura T, Kuddus R. Endotoxin causes up-regulation of endothelin receptors in cultured hepatic stellate cells via nitric oxide-dependent and -independent mechanisms. Br J Pharmacol 2000; 131:319-27. [PMID: 10991926 PMCID: PMC1572329 DOI: 10.1038/sj.bjp.0703577] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2000] [Revised: 07/03/2000] [Accepted: 07/03/2000] [Indexed: 01/14/2023] Open
Abstract
Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and pathology. HSC produce and react to a potent contractile peptide endothelin-1 (ET-1) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulation with endotoxin. However, whether endotoxin affects ET-1 system of HSC and if this is a mechanism of endotoxin-induced hepatic injury is not known. We characterized synthesis of ET-1 and NO and ET-1 receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin (1 - 1000 ng ml(-1)) stimulated synthesis of ET-1 and NO and up-regulated ET-1 receptors in both cell types. Inhibition of NO synthesis by N(G)-monomethyl-L-homoarginine strongly inhibited endotoxin-induced increase in ET-1 receptors in transformed HSC but produced small additional increase in quiescent HSC. Inhibition of soluble guanylyl cyclase by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one blocked the effect of endotoxin on ET-1 receptors in both cell types. Moreover, ET-1 receptors were increased in both cell types during earlier time points (1 - 4 h) of endotoxin treatment in the absence of the stimulation of NO synthesis. These results demonstrate that endotoxin up-regulates ET-1 receptors in HSC by NO-dependent and -independent mechanisms. Such effects of endotoxin can be of importance in acute endotoxemia and during chronic injury of the liver.
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Affiliation(s)
- C R Gandhi
- Department of Surgery, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, Pennsylvania, PA 15213, USA.
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21
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Rothermund L, Leggewie S, Schwarz A, Thöne-Reinecke C, Cho JJ, Bauer C, Paul M, Neumayer HH, Schuppan D, Hocher B. Regulation of the hepatic endothelin system in advanced biliary fibrosis in rats. Clin Chem Lab Med 2000; 38:507-12. [PMID: 10987198 DOI: 10.1515/cclm.2000.074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The aim of the present study was to analyze the hepatic endothelin system and its regulation in liver cirrhosis due to bile duct obstruction. Wistar rats were subjected for 6 weeks to: 1) sham operation; 2) bile duct obstruction; 3) bile duct obstruction and the selective oral endothelin A receptor antagonist LU 135252; 4) bile duct obstruction and oral silymarin, a hepatoprotective and antifibrotic compound. We determined tissue concentrations of endothelin-1 and big-endothelin-1 by ELISA and the density of both endothelin receptor subtypes in plasma membrane fractions by Scatchard analysis. The hepatic endothelin system in liver cirrhosis due to chronic bile duct obstruction is characterized by a simultaneous up-regulation of both endothelin-1 tissue concentration (7.2 fold compared to sham operation; p<0.001) as well as the density of both endothelin receptor subtypes (ET(A) 7.4-fold, ET(B) 4.9-fold, p<0.001, respectively) suggesting a synergistic activation of the hepatic endothelin system in this rat model of non-inflammatory cirrhosis. Treatment with proven antifibrotic agents such as silymarin or a selective endothelin-A-receptor blocker (LU 135252) did not reduce the activity of the hepatic endothelin system, suggesting that the hepatic endothelin system is not activated by the fibrotic process itself.
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Affiliation(s)
- L Rothermund
- Medizinische Klinik mit Schwerpunkt Nephrologie der Charité, Humboldt Universität zu Berlin, Germany
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22
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Cui TX, Iwai M, Hamai M, Shimazu T. Receptor subtype mediating the action of circulating endothelin on glucose metabolism and hemodynamics in perfused rat liver. REGULATORY PEPTIDES 1999; 83:117-22. [PMID: 10511465 DOI: 10.1016/s0167-0115(99)00058-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The subtype of endothelin receptor that mediates metabolic and hemodynamic effects of circulating endothelin was explored using perfused rat liver. Infusion of endothelin (ET)-1 or ET-3 into the portal vein at a concentration of 0.3 nM increased glucose and lactate output and decreased perfusion flow, although ET-3 was less effective than ET-1. The metabolic effects of ET-1 were observed even under costant-flow perfusion. Infusion of either sarafotoxin S6b or S6c, an ET(A)- or ET(B)-receptor agonist, mimicked the actions of ET-1 to an equal extent. The flow reduction and glucose production induced by ET-1 were partly attenuated by the ET(A)-receptor antagonist BQ485. By contrast, ET(B)-receptor antagonist BQ788 enhanced glucose production caused by ET-1 and ET-3 without affecting the hemodynamic change. The effects of ET-1 and ET-3 were almost totally inhibited by the combination of BQ485 and BQ788. These results suggest that both ET(A) and ET(B) receptors are involved in the metabolic and hemodynamic effects of circulating endothelin in rat liver, while the ET(A)-receptor-mediated action appears to be dominant.
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Affiliation(s)
- T X Cui
- Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Japan
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23
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Gabriel A, Kuddus RH, Rao AS, Gandhi CR. Down-regulation of endothelin receptors by transforming growth factor beta1 in hepatic stellate cells. J Hepatol 1999; 30:440-50. [PMID: 10190727 DOI: 10.1016/s0168-8278(99)80103-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND/AIMS Hepatic endothelin-1 (ET-1) receptor density as well as the levels of both ET-1 and transforming growth factor beta1 (TGF-beta1) increase in liver cirrhosis. Considering their potent contractile (ET-1) and fibrogenic (TGF-beta1) actions on myofibroblastic stellate cells found in the fibrotic/cirrhotic liver, we aimed to investigate the effects of TGF-beta1 on ET-1 receptors and ET-1 synthesis in these cells. METHODS Stellate cells isolated from rat liver by enzymatic digestion were cultured and subjected to TGF-beta1 treatment. Cellular ET-1 receptors and ET-1 released in the medium were determined. RESULTS TGF-beta1 treatment produced time- and dose-dependent decrease in ET-1 binding sites, but did not affect the affinity of the receptors for ET-1. TGF-beta1 also stimulated the release of ET-1 from stellate cells. The extent of TGF-beta1-induced inhibition of [125I]ET-1 binding was much greater for ETB subtype (73+/-18% inhibition), which comprised a major portion (78+/-12%) of the total ET-1 receptors, than for ETA subtype (35+/-11% inhibition). The mRNA expression of the ET-1 receptors also was reduced by TGF-beta1 treatment. TGF-beta1-induced reduction in ET-1 receptor density was coupled to the inhibition of ET-1-stimulated release of [3Hlarachidonic acid from the prelabeled cells. The effects of TGF-beta1 were inhibited by a TGF-beta1 neutralizing monoclonal antibody. CONCLUSIONS These results suggest that the TGF-beta1-induced decrease in ET-1 receptor density may be an important mechanism in limiting the pathologic actions of ET-1 on stellate cells in chronic liver disease.
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Affiliation(s)
- A Gabriel
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA 15213, USA
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24
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Mitsuoka H, Suzuki S, Sakaguchi T, Baba S, Miwa M, Konno H, Nakamura S. Contribution of endothelin-1 to microcirculatory impairment in total hepatic ischemia and reperfusion injury. Transplantation 1999; 67:514-20. [PMID: 10071019 DOI: 10.1097/00007890-199902270-00004] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Endothelin (ET)-1 may have a role in hepatic polymorphonuclear leukocyte infiltration as well as microcirculatory disturbance during hepatic ischemia-reperfusion (HIR) injury. This study was conducted to investigate the influence of ET-1 on the hepatic microcirculation after total HIR and to evaluate the effect of a nonselective ET receptor antagonist under these conditions. METHODS Male rats pretreated with either normal saline (NS group) or TAK-044, a nonselective ET receptor antagonist (TAK group), were subjected to 120 min of total hepatic ischemia with extracorporeal portosystemic shunting. RESULTS Plasma ET-1 levels increased significantly from 1 to 6 hr after reperfusion in the NS group when compared with the nonischemic control. In the early phase of reperfusion, the NS group showed significantly narrower sinusoids, lower hepatic tissue blood flow, a lower hepatic tissue oxy-hemoglobin concentration, and more hepatic neutrophil infiltration than the TAK group (P<0.05). Pretreatment with TAK-044 improved hepatic microcirculatory derangement, and resulted in significantly better 7-day survival (61.5%) with more bile production after reperfusion when compared with the NS group (P<0.01). CONCLUSIONS The present study demonstrated that ET-1 is involved in the development of HIR injury by causing deterioration of the hepatic microcirculation. A nonselective ET receptor antagonist successfully ameliorated HIR injury through improvement of hepatic oxygenation and of the microcirculation along with reduced hepatic neutrophil infiltration.
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Affiliation(s)
- H Mitsuoka
- The Second Department of Surgery, Hamamatsu University School of Medicine, Japan
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25
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Cui TX, Iwai M, Yamauchi T, Shimazu T. Aggravating action of zymosan on acute liver damage in perfused liver of rats treated with D-galactosamine. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:G1361-6. [PMID: 9843773 DOI: 10.1152/ajpgi.1998.275.6.g1361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
To study the role of Kupffer cells in the aggravation of liver injury, effects of zymosan on acute liver damage were explored using perfused livers of rats 24 h after intraperitoneal injection of D-galactosamine (800 mg/kg). The leakage of lactate dehydrogenase and aspartate aminotransferase into the effluent was used to indicate acute liver damage. Infusion of zymosan (30 microgram/ml) into the portal vein rapidly increased the leakage of lactate dehydrogenase and aspartate aminotransferase from galactosamine-treated liver with decreased perfusion flow. Pretreatment of animals with gadolinium, which diminished an immunostaining of resident macrophages in the injured liver, significantly attenuated the flow reduction induced by zymosan, whereas it did not affect the increases in enzyme leakage. Infusions of PGF2alpha, PGE2, and leukotriene D4, the eicosanoids mainly produced by Kupffer cells, decreased perfusion flow without rapid augmentation of enzyme leakage from galactosamine-treated liver. These results indicate that zymosan potentiates acute liver damage after galactosamine injection and suggest that certain types of nonparenchymal cells other than Kupffer cells are mainly involved in the action of zymosan.
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Affiliation(s)
- T X Cui
- Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan
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26
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Reinehr RM, Kubitz R, Peters-Regehr T, Bode JG, Häussinger D. Activation of rat hepatic stellate cells in culture is associated with increased sensitivity to endothelin 1. Hepatology 1998; 28:1566-77. [PMID: 9828221 DOI: 10.1002/hep.510280617] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The effect of endothelin (ET) 1 on intracellular Ca2+ transients in cultured rat hepatic stellate cells (HSCs) during transformation was studied by use of single-cell fluorescence. Regardless of the duration of HSC culture, ET-1 caused a BQ-123-sensitive but IRL-1038-insensitive elevation of [Ca2+]i, indicating the involvement of ETA but not ETB receptors. HSCs in early culture ("quiescent HSCs") were mildly responsive to ET-1: the ET-1 concentration required to obtain a [Ca2+]i transient in 50% of the cells (RC50) was 7 nmol/L, and all cells responded to ET-1 concentrations above 40 nmol/L. With culture time, -smooth muscle actin (-SMA) expression increased, as did the ET-1 sensitivity of cells, resulting in a shift of the RC50 value from 7 nmol/L to 13 pmol/L within 8 days. Independent of the duration of culture, ET-1 sensitivity was higher in -SMA-expressing cells. On the other hand, sensitivity of HSCs to produce a [Ca2+]i response to extracellular uridin 5'-triphosphate (UTP) or phenylephrine did not change during the activation process. There was no difference between quiescent and activated HSCs with respect to the sharing of intracellular Ca2+ stores, which could be mobilized by ET-1, UTP, and phenylephrine, respectively. The data suggest three conclusions. (1) A marked increase in ET-1 sensitivity of HSCs during the activation process suggests a potentiation of autocrine/paracrine stimulation. (2) HSCs are susceptible to -adrenergic and purinergic stimulation, but sensitivity to phenylephrine and UTP is not affected during the transformation process. (3) The ET-1-mobilizable Ca2+ store is contained in and is smaller than the Ca2+ pool, which is mobilized by phenylephrine or UTP.
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Affiliation(s)
- R M Reinehr
- Medizinische Einrichtungen der Heinrich-Heine-Universität, Klinik f ur Gastroenterologie, Hepatologie und Infektiologie, Düsseldorf, Germany
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27
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Caligiuri A, Glaser S, Rodgers RE, Phinizy JL, Robertson W, Papa E, Pinzani M, Alpini G. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:G835-46. [PMID: 9756516 DOI: 10.1152/ajpgi.1998.275.4.g835] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We studied the expression of endothelin-1 (ET-1) receptors (ETA and ETB) and the effects of ET-1 on cholangiocyte secretion. The effects of ET-1 on cholangiocyte secretion were assessed in normal and bile duct-ligated (BDL) rats by measuring 1) basal and secretin-induced choleresis in vivo, 2) secretin receptor gene expression and cAMP levels in small and large cholangiocytes, and 3) luminal expansion in response to secretin in intrahepatic bile duct units (IBDU). ETA and ETB receptors were expressed by small and large cholangiocytes. ET-1 had no effect on basal bile flow or bicarbonate secretion in normal or BDL rats but decreased secretin-induced bicarbonate-rich choleresis in BDL rats. ET-1 decreased secretin receptor gene expression and secretin-stimulated cAMP synthesis in large cholangiocytes and secretin-induced luminal expansion in IBDU from normal or BDL rats. The inhibitory effects of ET-1 on secretin-induced cAMP synthesis and luminal duct expansion were blocked by specific inhibitors of the ETA (BQ-610) receptor. ET-1 inhibits secretin-induced ductal secretion by decreasing secretin receptor and cAMP synthesis, two important determinants of ductal secretion.
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Affiliation(s)
- A Caligiuri
- Department of Internal Medicine and Medical Physiology, Scott and White Hospital and Texas A&M University Health Science Center College of Medicine, Temple, Texas 76504, USA
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28
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Iwai M, Yamauchi T, Shimazu T. Endothelin 1 aggravates acute liver injury in perfused livers of rats after treatment with D-galactosamine. Hepatology 1998; 28:503-9. [PMID: 9696017 DOI: 10.1002/hep.510280230] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with D-galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with D-galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.
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Affiliation(s)
- M Iwai
- Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Japan
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29
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Eakes AT, Olson MS. Regulation of endothelin synthesis in hepatic endothelial cells. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 274:G1068-76. [PMID: 9696707 DOI: 10.1152/ajpgi.1998.274.6.g1068] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Endothelin (ET) stimulates vasoconstriction and glucose production and mediator synthesis in the liver. Only hepatic endothelial cells express ET-1 mRNA, and during endotoxemia in the intact rat, a ninefold increase in hepatic ET-1 mRNA occurs within 3 h of lipopolysaccharide (LPS) infusion [A. T. Eakes, K. M. Howard, J. E.Miller, and M. S. Olson. Am. J. Physiol. 272 (Gastrointest. Liver Physiol. 35): G605-G611, 1997]. The present study defines the mechanism by which hepatic ET production is enhanced during endotoxin exposure. Culture media conditioned by exposure to endotoxin-treated Kupffer cells stimulated a twofold increase in immunoreactive ET-1 (irET-1) secretion by liver endothelial cells. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), LPS, and platelet-activating factor (PAF) were tested for their ability to stimulate cultured liver endothelial cells to secrete irET-1. Although TNF-alpha, LPS, and PAF had no significant effect on ET-1 synthesis, TGF-beta increased ET-1 mRNA expression and irET-1 secretion. In coculture experiments, treating Kupffer cells with endotoxin caused a doubling of the ET-1 mRNA level in the liver endothelial cells.This increase in ET-1 mRNA was attenuated by a TGF-beta-neutralizing antibody. Hence, a paracrine signaling mechanism operates between Kupffer cells that release TGF-beta on endotoxin challenge and hepatic endothelial cells in which TGF-beta stimulates ET-1 mRNA expression and ET-1 secretion; this intercellular signaling relationship is an important component in the hepatic responses to endotoxin exposure.
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Affiliation(s)
- A T Eakes
- Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78284-7760, USA
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30
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Gandhi CR, Nemoto EM, Watkins SC, Subbotin VM. An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats. LIVER 1998; 18:39-48. [PMID: 9548266 DOI: 10.1111/j.1600-0676.1998.tb00125.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl4)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl4-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl4 (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl4 treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl4 administration, and progressively thereafter during the development of cirrhosis. The acute CCl4-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7+/-1.8 to 17.6+/-3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62+/-8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6+/-2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.
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MESH Headings
- Animals
- Carbon Tetrachloride/toxicity
- Cells, Cultured
- Endothelin Receptor Antagonists
- Endothelin-1/antagonists & inhibitors
- Endothelin-1/metabolism
- Hypertension, Portal/chemically induced
- Hypertension, Portal/pathology
- Hypertension, Portal/prevention & control
- Liver/drug effects
- Liver/metabolism
- Liver Cirrhosis, Experimental/chemically induced
- Liver Cirrhosis, Experimental/pathology
- Liver Cirrhosis, Experimental/prevention & control
- Male
- Peptides, Cyclic/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Endothelin/metabolism
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Affiliation(s)
- C R Gandhi
- Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA
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31
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Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, Housset C. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27:472-80. [PMID: 9462646 DOI: 10.1002/hep.510270222] [Citation(s) in RCA: 174] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Endothelin (ET) peptides have been implicated in the pathogenesis of several biological processes within the liver. ET levels are elevated in the circulation of patients with cirrhosis, and recent data suggest that ET may be overproduced in the liver itself in this condition. The aims of the current study were to elucidate the cellular source and expression of endothelin-1 (ET-1) in normal and injured liver, and to investigate its biological effects on stellate cells, the primary target of ETs in the liver. In normal hepatic cells, preproET-1 messenger RNA (mRNA) was detected in only nonparenchymal cells, predominantly in sinusoidal endothelial cells. After biliary fibrosis and early cirrhosis induced by bile duct ligation, preproET-1 mRNA and immunoreactive ET levels increased with progressive injury in whole liver extracts, as well as in isolated stellate and endothelial cell fractions. Eight days after bile duct ligation, the relative increase in preproET-1 mRNA was 1.6- and 7.6-fold above normal in sinusoidal endothelial and stellate cells, respectively. Additionally, immunoreactive ET peptide levels increased by 60% +/- 27% over basal values in sinusoidal endothelial cells and 98% +/- 40% in stellate cells. Cultured stellate cells responded dramatically to exogenous ET-1 by the spreading and up-regulation of smooth muscle alpha actin expression. Furthermore, in early culture before cellular activation, ET-1 (10 nmol/L) caused over a twofold increase in [3H]thymidine incorporation, while activated cells (i.e., those cultured for >1 week) exposed to ET-1 exhibited up to a fivefold decrease in [3H]thymidine incorporation. The data indicate that not only is ET-1 overproduced by both sinusoidal endothelial and stellate cells during liver injury, but that it also has potent effects on features of stellate cell activation. We conclude that autocrine and paracrine production of ET-1 is prominent and is likely to be important in the pathogenesis of hepatic diseases.
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Affiliation(s)
- D C Rockey
- Liver Centers and the Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
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32
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Eakes AT, Harvey SA, Olson MS. Endothelin association with cultured rat hepatic endothelial cells: functional characterization. BIOCHIMICA ET BIOPHYSICA ACTA 1997; 1359:153-64. [PMID: 9409812 DOI: 10.1016/s0167-4889(97)00084-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Endothelin is a potent vasoactive peptide whose concentration increases in a number of pathophysiological states. In the intact animal, the liver is known to sequester approximately 12% of an injected bolus of [125I]endothelin-1 ([125I]ET-1). Endothelial cells (ECs) isolated from rat liver were maintained in culture in order to examine their role in ET sequestration. LECs were shown to express predominantly ET(B) receptors both by association assays and by Northern blot analysis. In these cells the reaction between [125I]ET-1 and its receptor was essentially irreversible. Ligand binding experiments performed at 4 degrees C showed that LECs in early culture (approximately 3 h) had 4.3 +/- 0.8 fmol of ET receptors per 10(6) cells; this number fell progressively to < or = 1 fmol/10(6) cells during 24 h of culture. The decrease in receptor numbers could be blocked by maintaining the cells at 4 degrees C. Northern blot analysis showed that relative to freshly isolated cells, mRNA for the ET(B) receptor decreased 4-fold in early culture, and recovered somewhat at 24 h. At 37 degrees C [125I]ET-1 bound by the cells was rapidly internalized, with concomitant down-regulation of ET receptors. Recovery of down-regulated ET receptors was sensitive to cycloheximide, making short-term receptor recycling unlikely. Metabolism of [125I]ET-1 was low at short (< 4 h) exposure times, and at 24 h showed a concentration dependence similar to that of ligand association, suggesting that ET-1 metabolism primarily was intracellular. ET stimulation of Kupffer cells and other hepatic cell types is known to activate phosphoinositide signaling, but no such activation was seen in LECs. Moreover, ET did not appear to stimulate protein tyrosine kinase activity in LECs. While hepatic LECs may lack some of the ET-dependent responses seen in other cell types, they likely contribute substantially to the liver's previously reported ability to sequester systemically administered ET.
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Affiliation(s)
- A T Eakes
- Department of Biochemistry, The University of Texas Health Science Center at San Antonio, 78284-7760, USA
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33
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Abstract
During immune injury, activation of endothelial cells by inflammatory cytokines stimulates leukocyte adhesion to the endothelium, turns the endothelium from an anticoagulant surface to one that is frankly procoagulant, and results in the release of vasoactive mediators and growth factors. Cytokine activation of endothelial cells also results in increased endothelial cell TGF-beta 1 synthesis and enhanced activation of latent TGF-beta, the latter involving a shift of plasmin production from the apical to subendothelial surface. In cytokine-stimulated endothelial cells, TGF-beta hinders leukocyte adhesion and transmigration via inhibition of IL-8 and E-selectin expression. TGF-beta also profoundly diminishes cytokine-stimulated inducible nitric oxide synthase production and instead augments endothelial nitric oxide synthase expression. Thus, some of the TGF-beta actions on endothelium during immune activation can viewed as immunosuppressive. TGF-beta also influences mechanisms of vascular remodeling during the healing phase of immune injury. It stimulates PDGF-B synthesis by endothelial cells, causes bFGF release from subendothelial matrix, and promotes VEGF synthesis by non-endothelial cells. Together these mediators control angiogenesis, a critical component of the vascular repair phenomenon. Further, endothelial cell derived PDGF-B and bFGF influence the proliferation and migration of neighboring cells. Thus, endothelial cells and TGF-beta actions on the endothelium play important roles both during the initial phase of immune injury and during the later remodeling phase.
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Affiliation(s)
- P Pintavorn
- Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
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34
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Elliot AJ, Vo LT, Grossman VL, Bhathal PS, Grossman HJ. Endothelin-induced vasoconstriction in isolated perfused liver preparations from normal and cirrhotic rats. J Gastroenterol Hepatol 1997; 12:314-8. [PMID: 9195372 DOI: 10.1111/j.1440-1746.1997.tb00427.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Isolated, perfused rat liver preparations (IPRL), obtained from rats with carbon tetrachloride-induced cirrhosis and normal controls, were used to investigate responses to the vasoactive peptide endothelin-1 (ET-1). The mean perfusion resistance (R) of cirrhotic IPRL was significantly greater than that of controls (2.63 +/- 0.24 vs 1.54 +/- 0.14 mmHg/mL per min per g; P < 0.01). Both control and cirrhotic IPRL demonstrated a concentration-related increase in resistance (delta R) in response to ET-1, with a minimum effective concentration of approximately 3 x 10(-11) mol/L. The EC50 (-log of the 50% effective concentration) was not significantly different between cirrhotic and control IPRL (8.48 +/- 0.19 and 8.79 +/- 0.11, respectively); however, the maximum response to ET-1 was significantly greater in cirrhotic preparations (R: 10.4 +/- 2.2 vs 4.4 +/- 0.5 mmHg/mL per min per g, P < 0.01; DR, 7.8 +/- 2.1 vs 2.8 +/- 0.4 mmHg/mL per min per g, P < 0.01). Following maximal stimulation by ET-1, the mean portal-hepatic venous pressure gradient at a physiological flow rate of 1 mL/min per g was approximately 90% greater across cirrhotic IPRL than that across normal IPRL (11.2 +/- 2.0 vs 5.9 +/- 0.9 mmHg, respectively; P < 0.05). These results support the hypothesis that endogenously released ET-1 has a significant influence on the portal vascular resistance of cirrhotic liver in vivo and has an important role in the pathogenesis of portal hypertension.
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Affiliation(s)
- A J Elliot
- Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
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35
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Gandhi CR, Kang Y, De Wolf A, Madariaga J, Aggarwal S, Scott V, Fung J. Altered endothelin homeostasis in patients undergoing liver transplantation. LIVER TRANSPLANTATION AND SURGERY : OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES AND THE INTERNATIONAL LIVER TRANSPLANTATION SOCIETY 1996; 2:362-9. [PMID: 9346677 DOI: 10.1002/lt.500020506] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The liver is a major site of synthesis, clearance, and actions of the powerful vasoactive peptide endothelin-1 (ET-1). We investigated the role of the liver in ET-1 homeostasis by comparing circulating and hepatic ET-1 levels and hepatic ET receptors in patients undergoing orthotopic liver transplantation (OLTx) for end-stage liver disease (ESLD) with those in patients undergoing liver resection for focal lesions with otherwise normal hepatic synthetic function. Central venous and radial arterial blood was drawn immediately after induction of anesthesia (point I), 10 minutes before beginning of resection or the anhepatic stage (point II), and 30 minutes after completion of resection or reperfusion of the grafted liver (point III). Portal and hepatic venous blood was drawn at points II and III. Plasma ET-1 levels were higher in ESLD patients than in resection patients. Plasma ET-1 levels rose both during resection and transplantation; the increase in ET-1 was more pronounced during transplantation. In ESLD patients, hepatic venous ET-1 was higher than portal venous ET-1, suggesting reduced clearance and/or enhanced synthesis of the peptide in the cirrhotic liver. Conversely, hepatic venous ET-1 was lower than portal venous ET-1 in resection patients at all time points and at point III in the ESLD patients. Hepatic concentration of ET-1 was greater and the capacity of the liver to catabolize ET-1 was reduced in ESLD patients as compared to the resection patients. Further, hepatic ET receptor density was higher in ESLD than in resection patients. These results suggest that the cirrhotic liver may contribute to elevated plasma ET-1 in ESLD. Considering its potent hemodynamic and metabolic effects in the liver, increased hepatic ET-1 and ET receptors and plasma ET-1 could play a role in the pathophysiology of liver disease and perioperative complications of OLTx.
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Affiliation(s)
- C R Gandhi
- Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, PA 15261, USA
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36
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Affiliation(s)
- A Mallat
- Unité INSERM 99, Hôpital Henri Mondor, Créteil, France
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37
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Abstract
The experimental data reviewed in this study tend to indicate that the hepatic sinusoidal endothelial cell (SEC) is, chronologically, the first hepatic cell that undergoes pathologic changes in alcoholemia. Due to its strategic position in the liver sinusoid, SEC dysfunction and structural alterations have far-reaching repercussions for the whole liver. The authors gather experimental evidence suggesting that alcohol-induced SEC alterations are mostly due to Kupffer cell activation induced by alcohol rather than to a direct action of alcohol on SEC. Once activated, the Kupffer cell secretes a spectrum of mediators that affect both function and structure of SEC. Kupffer cell activation is regarded as a result of both direct and indirect actions of alcohol on the cell. The indirect action of alcohol is ascribed to alcohol-induced elevated plasma levels of Gram-negative bacterial lipopolysaccharide (LPS), a strong activator of Kupffer cell. However, a comparison of alcohol and LPS effects on SEC functions and structure reveals that these two agents may have, under many circumstances, different actions on the SEC, at least in laboratory animals. However, this issue continues to be a matter of debate. Also the review presents justification for the necessity to extend research on mechanisms underlying alcoholic liver disease to the effects of alcohol on the SEC. Finally, several future research directions are suggested in this review to better understand the mechanisms underlying alcohol-induced liver dysfunction.
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Affiliation(s)
- I V Deaciuc
- Department of Physiology, Louisiana State University Medical Center, New Orleans 70112-1393, USA
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38
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Hocher B, Zart R, Diekmann F, Slowinski T, Thöne-Reineke C, Lutz J, Bauer C. Role of the paracrine liver endothelin system in the pathogenesis of CCl4-induced liver injury. Eur J Pharmacol 1995; 293:361-8. [PMID: 8748689 DOI: 10.1016/0926-6917(95)90056-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
This study analyzed if the paracrine liver endothelin system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar Kyoto rats were divided into four groups: a bosentan (mixed endothelin ETA and ETB receptor antagonist) treated group with CCl4 intoxication, a vehicle treated group with CCl4 intoxication, a nontreated control group and a bosentan treated control group. Hepatotoxicity was assessed by determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) followed by histopathological examinations. Tissue endothelin-1 concentrations and expression of endothelin receptor subtypes were analyzed. The tissue levels of endothelin-1 in the liver of rats with CCl4 intoxication were significantly higher than those in normal rats. Scatchard analysis revealed no differences in the density and binding constant of endothelin ETA and ETB receptor between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in a significant protection against elevation of ALT, AST, LDH and bilirubin. Histopathological examination of live sections for necrotic, swollen and lipid-laden cells revealed findings that were in agreement with the serum enzyme data. In conclusion, this study showed that the paracrine endothelin system is involved in the pathogenesis of CCl4-induced hepatotoxicity and that the blockade of the stimulated liver endothelin systems reduces CCl4-induced liver injury.
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Affiliation(s)
- B Hocher
- Department of Nephrology, Universitätsklinikum Benjamin Franklin, Free University of Berlin, Germany
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39
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Kawada N, Kuroki T, Kobayashi K, Inoue M, Kaneda K, Decker K. Action of endothelins on hepatic stellate cells. J Gastroenterol 1995; 30:731-8. [PMID: 8963390 DOI: 10.1007/bf02349639] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To elucidate the role played by hepatic sinusoidal cells in the regulation of the circulatory status in the liver, the effect of endothelins (ETs) on primary-cultured stellate cells was examined. Kinetic analysis with 125I-labeled ET-1 revealed that stellate cells have ET receptors with a Kd value of 141 pM and a Bmax of 12.3 fmol/10(5) cells. ET-1, -2, and -3 dose-dependently increased inositol monophosphate (InsP) levels in stellate cells with an EC50 of 0.53, 1.63, and 1.88nM, respectively. Binding of 125I-labeled ET-1 to stellate cells and the ET-enhanced InsP formation were suppressed by preincubating the cells with 10 nM of unlabeled ET-1 or ET-3 for more than 3 h, indicating down-regulation and desensitization of ET receptors by homologous ligands. Binding of ETs to surface receptors induced a marked contraction of stellate cells. Stellate cells rapidly reacted to ETs, as detected by the flexible silicone-rubber-membrane method; 78%, 73%, and 58% of the stellate cells contracted 2.5 min after the addition of 10 nM of ET-1, ET-2, or ET-3, respectively. On the other hand, ETs also triggered a long-lasting contraction of the cells, as revealed with hydrated collagen gels. The ET-induced contraction of stellate cells decreased the diameter of the collagen lattice by about 60%, and this action was inhibited either by cytochalasin B or by H-7, a protein kinase C inhibitor. These and other results suggest that ETs induced cell contraction by some mechanism that involved protein kinase C.
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Affiliation(s)
- N Kawada
- Third Department of Internal Medicine, Osaka City University Medical School, Japan
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40
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Gandhi CR, Sproat LA, Subbotin VM. Increased hepatic endothelin-1 levels and endothelin receptor density in cirrhotic rats. Life Sci 1995; 58:55-62. [PMID: 8628111 DOI: 10.1016/0024-3205(95)02255-4] [Citation(s) in RCA: 80] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Endothelin-1 (ET-1), the most powerful agent to cause constriction of the hepatic vasculature, is synthesized in the liver by sinusoidal endothelial cells. Circulating ET-1 levels have been shown to increase in liver cirrhosis. As liver could be a major source of increased plasma ET-1 as well as a target for its pathologic actions, this study was designed to determine hepatic ET-1 and ET receptor(s) in experimental liver cirrhosis. Cirrhosis was induced in rats by intraperitoneal administration of carbon tetrachloride for 8 weeks. Hepatic ET-1 was measured by radioimmunoassay and ET receptors were determined by radioligand competition binding procedure. A four fold increase in ET-1 concentration accompanied by a 65% increase in ET-receptor density was observed in the cirrhotic liver. There was no change in the ET receptor affinity. The capacity of the liver to metabolize ET-1 was reduced significantly in cirrhosis. Interestingly, transforming growth factor-beta, hepatic levels of which increase in cirrhosis, stimulated ET-1 synthesis in cultured Ito cells. It has been shown that ET-1 is a potent constrictor of Ito cells that proliferate and transform into highly contractile myofibroblasts in liver cirrhosis. Thus, interactions between ET-1 and Ito cells may have significant implications in the pathogenesis and complications of liver cirrhosis.
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Affiliation(s)
- C R Gandhi
- Department of Anesthesiology/Critical Care Medicine, University of Pittsburgh, Pennsylvania, USA
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41
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Yokomori H, Oda M, Han JY, Ogi M, Motoori T, Kamegaya Y, Kazamoto S, Tsukada N, Akiba Y, Nakamura M, Ishii H. NG-L monomethyl arginine (L-NMMA) enhances bile canalicular contractions in cultured rat hepatocytes. Med Mol Morphol 1995. [DOI: 10.1007/bf02348022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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42
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Affiliation(s)
- W E Lands
- Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland 20892-7003, USA
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43
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Mallat A, Fouassier L, Préaux AM, Gal CS, Raufaste D, Rosenbaum J, Dhumeaux D, Jouneaux C, Mavier P, Lotersztajn S. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway. J Clin Invest 1995; 96:42-9. [PMID: 7615814 PMCID: PMC185171 DOI: 10.1172/jci118052] [Citation(s) in RCA: 92] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sarafotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibroblastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis and proliferation of cells stimulated with either human serum or platelet-derived growth factor -BB (PDGF-BB). PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect. SRTX-C was as potent as ET-1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysis of the intermediate steps leading to growth-inhibition by ET-1 revealed that activation of mitogen-activated protein kinase by serum or PDGF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimulated cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos or krox 24 mRNA expression were not affected. We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, ET-1 may also exert negative control of growth on specific cells.
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Affiliation(s)
- A Mallat
- Unité INSERM 99, Hôpital Henri Mondor, Créteil, France
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44
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Suzuki H, Menegazzi M, Carcereri de Prati A, Mariotto S, Armato U. Nitric oxide in the liver: physiopathological roles. ADVANCES IN NEUROIMMUNOLOGY 1995; 5:379-410. [PMID: 8746512 DOI: 10.1016/0960-5428(95)00024-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Many of the known roles of arginine (e.g. in immune function, wound healing, and protection against ammonia intoxication) are mediated by a metabolic pathway synthesising nitric oxide (NO) in the liver. Contrary to some of the current views, liver-produced NO may be basically beneficial, as it exerts both protective actions against tissue injury and cytotoxic effects on invading microorganisms, parasites, or tumor cells. An ongoing equilibrium between NO and other NO-reactive compounds (e.g. O2 and non-heme iron-sulphur-containing moieties) appears to be important in this respect, even under critical conditions. Thus, NO may prevent liver tissue harm from oxidant stress. Only when this putative counterbalance is upset by an uncontrolled, prolonged and/or massive production of NO, liver tissue damage may occur leading to hepatic inflammation or even tumor development. Moreover, the currently available data support the working hypothesis that hepatocytes partake not only to immunoregulatory processes, but even to immune defence mechanisms. Thus, the liver constitutes an excellent model for investigations into the crosstalks regulating the production of NO which take place among not only the various networks operating inside a single hepatic cell, but even the individual types of liver cells.
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Affiliation(s)
- H Suzuki
- Istituto di Chimica Biologica, Università di Verona, Italy
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45
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Dore-Duffy P, Balabanov R, Washington R, Swanborg RH. Transforming growth factor beta 1 inhibits cytokine-induced CNS endothelial cell activation. MOLECULAR AND CHEMICAL NEUROPATHOLOGY 1994; 22:161-75. [PMID: 7993525 DOI: 10.1007/bf03160103] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Postcapillary endothelium at the sites of inflammation undergoes a series of changes collectively termed endothelial cell activation. Activated endothelium expresses immunologically relevant surface proteins that include MHC class II antigens (Ags) and adhesion proteins, as well as exhibits a number of functional changes. Endothelial activation has not been thoroughly studied in CNS endothelium. We have examined cytokine-mediated endothelial activation in isolated rat CNS microvessels. Freshly isolated rat CNS microvessels are viable in culture for at least 72 h. Untreated microvessels express no endothelial activation antigens, but do exhibit constitutive expression of the transferrin receptor (tfR). INF gamma induces a dose-dependent increase in both MHC class II antigens and tfR measured by immunofluorescent staining and quantitated by laser cytometry. IFN gamma-mediated endothelial cell activation could be inhibited with as little as 2 ng/mL TGF-beta 1. although 100% inhibition was seen with 10 ng/mL TGF-beta 1. Cytokine-preactivated endothelial expression of class II Ag and tfR could also be inhibited by TGF-beta 1. TGF-beta 1-treated microvessels become anergic to IFN gamma stimulation. Results suggest that TGF-beta 1 may have a regulatory role in endothelial activation.
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Affiliation(s)
- P Dore-Duffy
- Wayne State University Multiple Sclerosis Research Center, Department of Neurology, Detroit, MI
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46
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Abstract
Plasma lysozyme levels are elevated in several different pathological conditions. In our study we show that well differentiated human hepatoma cells Hep3B and HepG2 are active synthesis sites of lysozyme and that this synthesis can be modulated by acute phase mediators. The production and modulation of lysozyme synthesis was studied by means of Northern-blot analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a specific bioassay after treatment of the cells with interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha. Hep3B and HepG2 cells constitutively synthesize high amounts of lysozyme. Lysozyme synthesis and secretion were found to be augmented by interleukin-1 beta and tumor necrosis factor-alpha in both cell lines. Interleukin-6 caused an increase in lysozyme production in Hep3B but a decrease in the HepG2 cells. As expected, the synthesis of albumin was decreased in both cell lines. Furthermore we demonstrated that HepG2 and Hep3B cells produce a biologically active form of the enzyme as measured by a specific bioassay. The results demonstrate that lysozyme is constitutively synthesized by Hep3B and HepG2 hepatoma cell lines and that lysozyme synthesis is modulated by acute-phase mediators. Well differentiated human hepatoma cells may respond differently to different cytokines.
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Affiliation(s)
- N Köbsel
- Abteilung Gastroenterologie und Endokrinologie, Georg-August-Universität Göttingen, Germany
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47
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Sakamoto M, Ueno T, Kin M, Ohira H, Torimura T, Inuzuka S, Sata M, Tanikawa K. Ito cell contraction in response to endothelin-1 and substance P. Hepatology 1993; 18:978-83. [PMID: 7691708 DOI: 10.1002/hep.1840180432] [Citation(s) in RCA: 98] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The contractile response of cultured Ito cells to endothelin-1 and substance P was examined. Ito cells were obtained from rat liver by perfusion with collagenase, followed by separation through centrifugal elutriation, and were cultured for 24 hr. The area of the Ito cells was measured after treatment with endothelin-1 or substance P at various concentrations in the culture medium. The area of the cells decreased dose dependently after treatment with endothelin-1 or substance P. The area of Ito cells before addition of interleukin-1 or substance P was defined as 100%. The area of the cells after treatment with endothelin-1 or substance P medium was expressed as the percentage against the area before treatment with endothelin-1 or substance P. The percentage in area after treatment with 200 nmol/L endothelin-1 was as follows: 81% +/- 13% at 30 min, 77% +/- 15% at 60 min, 87% +/- 15% at 120 min and 99% +/- 18% at 180 min. The maximal decrease in area occurred at 60 min after treatment. The percentage values for 200 nmol/L substance P were as follows: 88% +/- 15% at 10 min, 95% +/- 17% at 30 min and 101% +/- 17% at 60 min. The maximal decrease in area was noted at 10 min. Thus Ito cells contracted in response to treatment with endothelin-1 or substance P. The mode of the extent and onset of the contraction was different for the two peptides. These findings suggest that Ito cells are involved in the regulation of the hepatic sinusoidal microcirculation.
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Affiliation(s)
- M Sakamoto
- Second Department of Medicine, Kurume University School of Medicine, Japan
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48
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Bluhm RE, Frazer MG, Vore M, Pinson CW, Badr KF. Endothelins 1 and 3: potent cholestatic agents secreted and excreted by the liver that interact with cyclosporine. Hepatology 1993; 18:961-8. [PMID: 8406372 DOI: 10.1002/hep.1840180430] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Autoradiographic studies have shown that the liver accumulates endothelin. High-affinity binding sites for endothelin have been identified on rat liver plasma membranes. We investigated the role of endothelin isopeptides as mediators of cholestasis with isolated rat liver perfused by a recirculating solution of buffer and blood. These studies demonstrated that endothelin-1, as measured by means of radioimmunoassay, was cleared from the perfusate by the liver and that the liver concentrated both endothelin-1 and endothelin-3 in bile. Addition of endothelin-1 to the liver perfusate solution increased the concentration of endothelin-3 measured in the perfusate, suggesting that endothelin-1 caused release or secretion of endothelin-3. Both endothelin-1 and endothelin-3 at 5 nmol/L caused almost complete cessation of bile flow, but this effect was more prolonged after endothelin-1 than after endothelin-3 administration. Because it has been reported that cyclosporine increases endothelin levels, we studied the interaction of these two compounds. Cyclosporine (100 mumol/L) also produced cholestasis. Endothelin-3 secretion in bile, however, was decreased in livers perfused with cyclosporine compared with secretion in controls. Simultaneous addition of endothelin-1 and cyclosporine that on their own were not significantly cholestatic produced cholestasis. In conclusion, endothelin is a potent cholestatic agent secreted and excreted by the liver. It may potentiate the cholestatic action of cyclosporine.
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Affiliation(s)
- R E Bluhm
- Department of Medicine, Vanderbilt University, School of Medicine, Nashville, Tennessee 37207
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Kawada N, Tran-Thi TA, Klein H, Decker K. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. EUROPEAN JOURNAL OF BIOCHEMISTRY 1993; 213:815-23. [PMID: 7682947 DOI: 10.1111/j.1432-1033.1993.tb17824.x] [Citation(s) in RCA: 268] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
We have studied the contractility of liver sinusoidal stellate (Ito) cells stimulated with endothelin 1, nitric-oxide donors and eicosanoids. Contraction and relaxation of stellate cells were detected by the use of a silicone-rubber method that revealed the traction forces exerted by these cells. Endothelin 1 was a strong elicitor for stellate-cell contraction. 78, 55, 59 and 56% of stellate cells were contracted 2.5, 5, 10 and 20 min, respectively, after exposure to 10 nM endothelin 1. The effect of endothelin 1 was dose dependent and still detectable at an endothelin 1 concentration of 100 pM. Concomitantly, an endothelin-dependent formation of inositol phosphates was apparent; values of InsP, InsP2, and InsP3 were 881 +/- 99%, 1965 +/- 368%, and 791 +/- 120% of control, respectively, 20 min after addition of 10 nM endothelin 1. In addition, endothelin 1 caused a transient increase of [Ca2+]i in stellate cells from a basal value of 121 +/- 9 nM to maximal 1015 +/- 86 nM. These endothelin-1 effects were much stronger than those of the thromboxane-A2 analogue U46619 and of prostaglandin F2 alpha. In contrast, Iloprost, prostaglandin E2, and sodium nitroprusside promoted stellate-cell relaxation; for example, 82, 83 and 71% of stellate cells relaxed 5, 10, and 20 min, respectively, after addition of 500 microM sodium nitroprusside to contacted cells. Prostaglandin E2 and Iloprost led to elevation of cAMP levels in stellate cells from a basal value of 9.2 +/- 0.8 pmol/well to 55.1 +/- 8.0 and 122.2 +/- 12.2 pmol/well 10 min after addition of prostaglandin E2 (5 microM) and Iloprost (5 microM), respectively, in the presence of 3-isobutyl-1-methylxanthine (0.5 mM). However, sodium nitroprusside was a trigger for cGMP accumulation. Intracellular cGMP increased from a basal value of 0.9 +/- 0.07 pmol/well to 13.4 +/- 6.7 pmol/well 10 min after addition of 500 microM sodium nitroprusside into the medium. It is interesting that Iloprost and sodium nitroprusside also induced the disappearance of actin stress fibers in contracted cells; F-actin stress fibers became less numerous and de-aggregated; more than 90% of stellate cells were void of stress fibers after 10 microM Iloprost treatment for 30 min. Thus, endothelin 1, eicosanoids and sodium nitroprusside are able to modulate the contractility of stellate cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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Affiliation(s)
- N Kawada
- Biochemisches Institut, Universität Freiburg, Germany
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Oshita M, Takei Y, Kawano S, Yoshihara H, Hijioka T, Fukui H, Goto M, Masuda E, Nishimura Y, Fusamoto H. Roles of endothelin-1 and nitric oxide in the mechanism for ethanol-induced vasoconstriction in rat liver. J Clin Invest 1993; 91:1337-42. [PMID: 8473486 PMCID: PMC288104 DOI: 10.1172/jci116334] [Citation(s) in RCA: 79] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
This study was designed to investigate the mechanism for ethanol-induced hepatic vasoconstriction in isolated perfused rat liver. Upon initiation of ethanol infusion into the portal vein at concentrations ranging from 25 to 100 mM, portal pressure began to increase in a concentration-dependent manner and reached maximal levels in 2-5 min (initial phase), followed by a gradual decrease over the period of ethanol infusion (escape phenomenon). Endothelin-1 antiserum significantly inhibited this ethanol-induced hepatic vasoconstriction by 45-80%. Cessation of infusion of endothelin-1 antiserum was followed by a subsequent increase in portal pressure. On the other hand, when a nitric oxide synthesis inhibitor, NG-monomethyl-L-arginine (L-NMMA), was infused into the portal vein simultaneously with ethanol, the initial phase of the response of portal pressure to ethanol was not altered and the peak values of portal pressure remained unchanged. However, after the peak increase in portal pressure, the rate of decrease was less than in the absence of L-NMMA. Thus, L-NMMA diminished the escape phenomenon and sustained the vasoconstriction. This study supports the hypothesis that two endothelium-derived vasoactive factors, endothelin-1 and nitric oxide, regulate hepatic vascular tone in the presence of ethanol.
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Affiliation(s)
- M Oshita
- First Department of Medicine, Osaka University Medical School, Japan
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