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Wereszczynka-Siemiatkowska U, Swidnicka-Siergiejko A, Siemiatkowski A, Bondyra Z, Wasielica-Berger J, Mroczko B, Janica J, Dabrowski A. Endothelin 1 and transforming growth factor-β1 correlate with liver function and portal pressure in cirrhotic patients. Cytokine 2015; 76:144-151. [PMID: 26144293 DOI: 10.1016/j.cyto.2015.05.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 05/13/2015] [Accepted: 05/25/2015] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The invasive measurement of hepatic venous pressure gradient is the recommended method for the assessment of portal hypertension. We assessed if the mediators that regulate portal hypertension may be used as noninvasive markers of portal hypertension and liver insufficiency. MATERIALS AND METHODS We explored in prospective, observational study the concentration of endothelin-1, nitric oxide, and transforming growth factor-β1/2 in peripheral and hepatic venous blood; their relationship with the values of portal hypertension and liver insufficiency; and their level changes 4-6 months after non-selective beta-blocker therapy in cirrhotic patients with non-bleeding esophageal varices. RESULTS (1) Cirrhotics have significantly increased peripheral endothelin 1 and decreased transforming growth factor-β1 levels; (2) peripheral levels of all factors correlated significantly with their hepatic levels; (3) after therapy, peripheral endothelin-1 levels significantly increased, but transforming growth factor-β2 levels decreased and were lower in patients with pressure gradient value normalization; (4) before and after therapy, peripheral and hepatic endothelin-1, transforming growth factor-β1/2 levels correlated significantly with liver failure indicators (laboratory parameters, Child-Pough and MELD scores) and pressure gradient values. CONCLUSIONS Peripheral endothelin-1 and transforming growth factor-β1 levels, which strongly correlate with their hepatic levels, reflect the stage of portal hypertension and liver insufficiency in cirrhosis.
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Affiliation(s)
- Urszula Wereszczynka-Siemiatkowska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Agnieszka Swidnicka-Siergiejko
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland.
| | - Andrzej Siemiatkowski
- Department of Anaesthesiology and Intensive Therapy, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Zofia Bondyra
- Department of Radiology, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Justyna Wasielica-Berger
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Jacek Janica
- Department of Radiology, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
| | - Andrzej Dabrowski
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, M. Curie-Sklodowskiej 24a, 15276 Bialystok, Poland
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4
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Bellien J, Iacob M, Remy-Jouet I, Lucas D, Monteil C, Gutierrez L, Vendeville C, Dreano Y, Mercier A, Thuillez C, Joannides R. Epoxyeicosatrienoic Acids Contribute With Altered Nitric Oxide and Endothelin-1 Pathways to Conduit Artery Endothelial Dysfunction in Essential Hypertension. Circulation 2012; 125:1266-75. [DOI: 10.1161/circulationaha.111.070680] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background—
We sought to clarify, using functional and biological approaches, the role of epoxyeicosatrienoic acids, nitric oxide (NO)/reactive oxygen species balance, and endothelin-1 in conduit artery endothelial dysfunction during essential hypertension.
Methods and Results—
Radial artery diameter and mean wall shear stress were determined in 28 untreated patients with essential hypertension and 30 normotensive control subjects during endothelium-dependent flow-mediated dilatation induced by hand skin heating. The role of epoxyeicosatrienoic acids and NO was assessed with the brachial infusion of inhibitors of cytochrome P450 epoxygenases (fluconazole) and NO synthase (
N
G
-monomethyl-
l
-arginine [L-NMMA]). Compared with controls, hypertensive patients exhibited a decreased flow-mediated dilatation in response to postischemic hyperemia as well as to heating, as shown by the lesser slope of their diameter–shear stress relationship. In controls, heating-induced flow-mediated dilatation was reduced by fluconazole, L-NMMA, and, to a larger extent, by L-NMMA+fluconazole. In patients, flow-mediated dilatation was not affected by fluconazole and was reduced by L-NMMA and L-NMMA+fluconazole to a lesser extent than in controls. Furthermore, local plasma epoxyeicosatrienoic acids increased during heating in controls (an effect diminished by fluconazole) but not in patients. Plasma nitrite, an indicator of NO availability, increased during heating in controls (an effect abolished by L-NMMA) and, to a lesser extent, in patients, whereas, inversely, reactive oxygen species increased more in patients (an effect diminished by L-NMMA). Plasma endothelin-1 decreased during heating in controls but not in patients.
Conclusions—
These results show that an impaired role of epoxyeicosatrienoic acids contributes, together with an alteration in NO/reactive oxygen species balance and endothelin-1 pathway, to conduit artery endothelial dysfunction in essential hypertension.
Clinical Trial Registration—
https://www.eudract.ema.europa.eu
. Unique identifier: RCB2007-A001–10-53.
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Affiliation(s)
- Jeremy Bellien
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Michele Iacob
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Isabelle Remy-Jouet
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Daniele Lucas
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Christelle Monteil
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Laurence Gutierrez
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Cathy Vendeville
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Yvonne Dreano
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Alain Mercier
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Christian Thuillez
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
| | - Robinson Joannides
- From the Department of Pharmacology, Rouen University Hospital, Rouen (J.B., M.I., C.T., R.J.); Institut National de la Sante et de la Recherche Medicale (INSERM) U1096, Rouen Medical School, University of Rouen, Rouen (J.B., M.I., I.R.-J., C.M., C.V., C.T., R.J.); Centre d'Investigation Clinique–INSERM 0204, Rouen University Hospital, Rouen (L.G.); Department of General Medicine, Rouen Medical School, University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen (A.M.); and
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5
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Pellicelli AM, Barbaro G, Puoti C, Guarascio P, Lusi EA, Bellis L, D'Ambrosio C, Villani R, Vennarecci G, Liotta G, Ettore G, Andreoli A. Plasma Cytokines and Portopulmonary Hypertension in Patients With Cirrhosis Waiting for Orthotopic Liver Transplantation. Angiology 2010; 61:802-806. [DOI: 10.1177/0003319710369101] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Portopulmonary hypertension (PPHTN) is a rare complication in patients with portal hypertension. A role of endothelin 1 (ET-1) and other cytokines was demonstrated in primary pulmonary hypertension but not in PPHTN. We evaluated the possible role of ET-1, interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α) in the pathogenesis of PPHTN. Plasmatic concentrations of ET-1, IL-6, IL-1β, and TNF-α were measured in patients with pulmonary systolic arterial pressure (PAPs) >30 mm Hg and in patients with cirrhosis. In all, Six out of 11 patients with PAPs >30 mm Hg had PPHTN on right heart catheterization. The remaining 10 patients had an hyperdynamic circulation (HC). In PPHTN patients, ET-1 and IL-6 were significantly higher compared with HC and patients with cirrhosis. Endothelin 1 and IL-6 could be implicated in the pathogenesis of PPHTN. On the basis of these results, ET-1 receptor antagonists or anti-IL-6 could have a rationale in the treatment of PPHTN.
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Affiliation(s)
| | - Giuseppe Barbaro
- Cardiology Unit, Department of Medical Pathophysiology, University La Sapienza, Rome, Italy
| | | | - Paolo Guarascio
- Liver Unit, Azienda Ospedaliera San Camillo, Forlanini, Rome, Italy
| | | | - Lia Bellis
- Liver Unit, Marino General Hospital, Rome, Italy
| | | | - Roberto Villani
- Liver Unit, Azienda Ospedaliera San Camillo, Forlanini, Rome, Italy
| | - Giovanni Vennarecci
- Department of General Surgery and Transplantation, Azienda San Camillo Forlanini, Rome, Italy
| | - Gianluca Liotta
- Department of General Surgery and Transplantation, Azienda San Camillo Forlanini, Rome, Italy
| | - Giuseppe Ettore
- Department of General Surgery and Transplantation, Azienda San Camillo Forlanini, Rome, Italy
| | - Arnaldo Andreoli
- Liver Unit, Azienda Ospedaliera San Camillo, Forlanini, Rome, Italy
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11
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Yao DM, Yao XX, Yang CJ, Feng ZJ, Fang HM, Gao JP. Effects of ET-1 and NO on hepatic hemodynamics at various stages of isolated perfused cirrhotic liver in rats. Shijie Huaren Xiaohua Zazhi 2003; 11:726-729. [DOI: 10.11569/wcjd.v11.i6.726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of ET-1, NO on hepatic hemodynamics in isolated perfused rat liver at various stages of liver cirrhosis (LC).
METHODS LC was induced by an intraperitoneal injection of CCL4 combined with ethanol as drinking water. According to time points of CCL4 injection, and combined with histopathological changes of liver and ascites, the isolated perfusion of liver was performed at a constant flow rate to determine the modulating effects of ET-1 and NO in the ends of 9th week (E-LC) and 14th week (L-LC) after injected CCL4.
RESULTS After perfusion of L-NAME into the portal vein, there were no significant changes in the perfused pressure of portal vein (PP) and the hepatic venous pressure (Phv) of the L-LC group, the E-LC group and control group (P>0.05). After perfusion of ET-1, the PP of each group increased significantly (P<0.01). The elevated ranges of PP of the L-LC group was more than that of the E-LC group (P<0.01), both of which were higher than that of the control group (P<0.01). Compared with the ET-1 groups, the PP of the control group, the E-LC group and the L-LC group increased significantly (P<0.05) after perfusion of ET-1+L-NAME. There were no significant differences between the elevated ranges of PP of the L-LC and that of the E-LC group (P>0.05), both of which were more than that of the control group (P<0.01).
CONCLUSION ET-1 plays a key role in elevating intra-hepatic resistance, facilitating synthesis of NO, which grow stronger in LC. With the development of LC, the compensation of NO decreases further. It is considered that antagonist of ET receptor and NO provider can increase synthesis of NO and be thus used in treatment of the high pressure of portal vein.
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Affiliation(s)
- Dong-Mei Yao
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
| | - Xi-Xian Yao
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
| | - Chuan-Jie Yang
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
| | - Zhi-Jie Feng
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
| | - Hong-Mei Fang
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
| | - Jun-Ping Gao
- Department of Gastroenterology, The Second Affiliated Hospital, Hebei Medical Univercity, Shijiazhuang 050000, Hebei Province, China
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