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Frankova S, Lunova M, Gottfriedova H, Senkerikova R, Neroldova M, Kovac J, Kieslichova E, Lanska V, Urbanek P, Spicak J, Jirsa M, Sperl J. Liver stiffness measured by two-dimensional shear-wave elastography predicts hepatic vein pressure gradient at high values in liver transplant candidates with advanced liver cirrhosis. PLoS One 2021; 16:e0244934. [PMID: 33411729 PMCID: PMC7790429 DOI: 10.1371/journal.pone.0244934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/20/2020] [Indexed: 12/15/2022] Open
Abstract
Liver stiffness is a reliable non-invasive predictor of Hepatic Venous Pressure Gradient (HVPG) above 10 mm Hg. However, it failed to predict higher thresholds of HVPG. Our aim was to investigate whether liver stiffness and selected previously published non-invasive blood biomarkers could predict higher HVPG thresholds in liver transplant candidates without ongoing alcohol use. One hundred and nine liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG measurement, liver stiffness measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France) and assessment of blood HVPG biomarkers (osteopontin, VCAM-1, IL-6, TNF-α, IL-1ra/IL-1F3 and ELF score). The correlation between liver stiffness and HVPG was linear up to 30 mm Hg of HVPG (r = 0.765, p < 0.0001). The regression lines had similar slopes for HVPG values below and above 16 mm Hg (p > 0.05) and the correlation in patients with HVPG <16 mm Hg (r = 0.456, p = 0.01) was similar to patients with HVPG ≥ 16 mm Hg (r = 0.499, p < 0.0001). The correlation was similar in the subgroup patients with alcoholic (r = 0.718, p < 0.0001), NASH (r = 0.740, p = 0.008), cryptogenic (r = 0.648, p = 0,0377), cholestatic and autoimmune (r = 0.706, p < 0.0001) and viral cirrhosis (r = 0.756, p < 0.0001). Liver stiffness distinguished patients with HVPG above 16, and 20 mm Hg with AUROCs 0.90243, and 0.86824, sensitivity 0.7656, and 0.7027, and specificity 0.9333, and 0.8750. All studied blood biomarkers correlated better with liver stiffness than with HVPG and their AUROCs did not exceed 0.8 at both HVPG thresholds. Therefore, a composite predictor superior to liver stiffness could not be established. We conclude that liver stiffness is a clinically reliable predictor of higher HVPG thresholds in non-drinking subjects with advanced liver cirrhosis.
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Affiliation(s)
- Sona Frankova
- Department of Hepatogastroenterology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Mariia Lunova
- Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Halima Gottfriedova
- Department of Hepatogastroenterology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Renata Senkerikova
- Department of Hepatogastroenterology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Charles University, First Faculty of Medicine, Prague, Czech Republic
| | - Magdalena Neroldova
- Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jozef Kovac
- Department of Diagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Kieslichova
- Anaesthesiology, Resuscitation and Intensive Care Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vera Lanska
- Department of Biostatistics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petr Urbanek
- Charles University, First Faculty of Medicine, Prague, Czech Republic
- Department of Internal Medicine, Central Military Hospital, Prague, Czech Republic
| | - Julius Spicak
- Department of Hepatogastroenterology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Milan Jirsa
- Laboratory of Experimental Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Charles University, First Faculty of Medicine, Prague, Czech Republic
| | - Jan Sperl
- Department of Hepatogastroenterology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Charles University, First Faculty of Medicine, Prague, Czech Republic
- * E-mail:
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Baker PR, Friedman JE. Mitochondrial role in the neonatal predisposition to developing nonalcoholic fatty liver disease. J Clin Invest 2018; 128:3692-3703. [PMID: 30168806 DOI: 10.1172/jci120846] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global epidemic in obese children and adults, and the onset might have fetal origins. A growing body of evidence supports the role of developmental programming, whereby the maternal environment affects fetal and infant development, altering the risk profile for disease later in life. Human and nonhuman primate studies of maternal obesity demonstrate that risk factors for pediatric obesity and NAFLD begin in utero. The pathologic mechanisms for NAFLD are multifactorial but have centered on altered mitochondrial function/dysfunction that might precede insulin resistance. Compared with the adult liver, the fetal liver has fewer mitochondria, low activity of the fatty acid metabolic enzyme carnitine palmitoyl-CoA transferase-1, and little or no gluconeogenesis. Exposure to excess maternal fuels during fetal life uniquely alters hepatic fatty acid oxidation, tricarboxylic acid cycle activity, de novo lipogenesis, and mitochondrial health. These events promote increased oxidative stress and excess triglyceride storage, and, together with altered immune function and epigenetic changes, they prime the fetal liver for NAFLD and might drive the risk for nonalcoholic steatohepatitis in the next generation.
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Affiliation(s)
- Peter R Baker
- Section of Clinical Genetics and Metabolism, Department of Pediatrics
| | - Jacob E Friedman
- Section of Neonatology, Department of Pediatrics.,Department of Biochemistry and Molecular Genetics, and.,Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Aller MA, Arias N, Peral I, García-Higarza S, Arias JL, Arias J. Embrionary way to create a fatty liver in portal hypertension. World J Gastrointest Pathophysiol 2017; 8:39-50. [PMID: 28573066 PMCID: PMC5437501 DOI: 10.4291/wjgp.v8.i2.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/18/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension in the rat by triple partial portal vein ligation produces an array of splanchnic and systemic disorders, including hepatic steatosis. In the current review these alterations are considered components of a systemic inflammatory response that would develop through three overlapping phenotypes: The neurogenic, the immune and the endocrine. These three inflammatory phenotypes could resemble the functions expressed during embryonic development of mammals. In turn, the inflammatory phenotypes would be represented in the embryo by two functional axes, that is, a coelomic-amniotic axis and a trophoblastic yolk-sac or vitelline axis. In this sense, the inflammatory response developed after triple partial portal vein ligation in the rat would integrate both functional embryonic axes on the liver interstitial space of Disse. If so, this fact would favor the successive development of steatosis, steatohepatitis and fibrosis. Firstly, these recapitulated embryonic functions would produce the evolution of liver steatosis. In this way, this fat liver could represent a yolk-sac-like in portal hypertensive rats. After that, the systemic recapitulation of these embryonic functions in experimental prehepatic portal hypertension would consequently induce a gastrulation-like response in which a hepatic wound healing reaction or fibrosis occur. In conclusion, studying the mechanisms involved in embryonic development could provide key results for a better understanding of the nonalcoholic fatty liver disease etiopathogeny.
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Golic I, Velickovic K, Markelic M, Stancic A, Jankovic A, Vucetic M, Otasevic V, Buzadzic B, Korac B, Korac A. Calcium-induced alteration of mitochondrial morphology and mitochondrial-endoplasmic reticulum contacts in rat brown adipocytes. Eur J Histochem 2014; 58:2377. [PMID: 25308841 PMCID: PMC4194389 DOI: 10.4081/ejh.2014.2377] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 07/18/2014] [Indexed: 12/18/2022] Open
Abstract
Mitochondria are key organelles maintaining cellular bioenergetics and integrity, and their regulation of [Ca2+]i homeostasis has been investigated in many cell types. We investigated the short-term Ca-SANDOZ® treatment on brown adipocyte mitochondria, using imaging and molecular biology techniques. Two-month-old male Wistar rats were divided into two groups: Ca-SANDOZ® drinking or tap water (control) drinking for three days. Alizarin Red S staining showed increased Ca2+ level in the brown adipocytes of treated rats, and potassium pyroantimonate staining localized electron-dense regions in the cytoplasm, mitochondria and around lipid droplets. Ca-SANDOZ® decreased mitochondrial number, but increased their size and mitochondrial cristae volume. Transmission electron microscopy revealed numerous enlarged and fusioned-like mitochondria in the Ca-SANDOZ® treated group compared to the control, and megamitochondria in some brown adipocytes. The Ca2+ diet affected mitochondrial fusion as mitofusin 1 (MFN1) and mitofusin 2 (MFN2) were increased, and mitochondrial fission as dynamin related protein 1 (DRP1) was decreased. Confocal microscopy showed a higher colocalization rate between functional mitochondria and endoplasmic reticulum (ER). The level of uncoupling protein-1 (UCP1) was elevated, which was confirmed by immunohistochemistry and Western blot analysis. These results suggest that Ca-SANDOZ® stimulates mitochondrial fusion, increases mitochondrial-ER contacts and the thermogenic capacity of brown adipocytes.
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Manti S, Marseglia L, D'Angelo G, Filippelli M, Cuppari C, Gitto E, Romano C, Arrigo T, Salpietro C. Portal hypertension as immune mediate disease. HEPATITIS MONTHLY 2014; 14:e18625. [PMID: 24976841 PMCID: PMC4071352 DOI: 10.5812/hepatmon.18625] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 04/13/2014] [Indexed: 12/11/2022]
Abstract
CONTEXT Portal Hypertension (PH) is a progressive complication due to chronic liver disease. In addition to pathophysiologic changes in the micro-circulation, in PH are established fibrous tissue (periportal fibrous septal) and regenerative hyperplastic nodules (from micro- to macro-nodules) promoting hepatic architectural distortion. EVIDENCE ACQUISITION A literature search of electronic databases was undertaken for the major studies published from 1981 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the keywords: "portal hypertension, children, immune system, endocrine system, liver fibrosis". RESULTS It is believed that PH results from three "phenotype": ischemia-reperfusion, involving nervous system (NS); edema and oxidative damage, involving immune system; inflammation and angiogenesis, involving endocrine system. However, its exact cause still underdiagnosed and unknown. CONCLUSIONS PH is a dynamic and potentially reversible process. Researchers have tried to demonstrate mechanisms underlying PH and its related-complications. This review focuses on the current knowledge regarding the pathogenesis, and immune, endocrine-metabolic factors of disease. The strong positive association between immune system and development of PH could be efficient to identify non-invasive markers of disease, to modify prognosis of PH, and to development and application of specific and individual anti-inflammatory therapy.
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Affiliation(s)
- Sara Manti
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Lucia Marseglia
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Gabriella D'Angelo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Martina Filippelli
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Caterina Cuppari
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Eloisa Gitto
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Claudio Romano
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Teresa Arrigo
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
| | - Carmelo Salpietro
- Department of Pediatric Sciences, Genetics and Pediatric Immunology Unit, University of Messina, Messina, Italy
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Aller MA, Heras N, Blanco-Rivero J, Arias JI, Lahera V, Balfagón G, Arias J. Portal hypertensive cardiovascular pathology: the rescue of ancestral survival mechanisms? Clin Res Hepatol Gastroenterol 2012; 36:35-46. [PMID: 22264837 DOI: 10.1016/j.clinre.2011.07.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 07/26/2011] [Indexed: 02/04/2023]
Abstract
The portal system derives from the vitelline system, which is an extra-embryonic venous system. It could be suggested that this extraembryonic origin determines some of the characteristics attributed to portal hypertension, both compensated, i.e. prehepatic, and decompensated, i.e. fibrotic or cirrhotic. The experimental models most frequently used for studying both types of portal hypertension are portal vein ligation and common bile duct ligation in rats, respectively. We propose that in partial portal vein ligated rats, a low-grade inflammatory response, formed by the successive expression of three overlapping phenotypes - ischemia-reperfusion, vitellogenic-like and remodeling or gastrulation-like - is produced. The names of these inflammatory phenotypes developed in compensated portal hypertension are based on some metabolic similarities that can be established with the abovementioned phases of embryonic development. In bile-duct ligated rats, decompensation related to hepatic insufficiency would induce a high-grade inflammatory response. In this experimental model, the splanchnic interstitium, the mesenteric lymph and the peritoneal mesothelium seem to create an inflammatory axis that produces ascites. The functional comparison between the ascitic and the amniotic fluids would imply that, in the decompensated portal hypertensive syndrome, the abdominal mesothelium acquires properties of the amniotic membranes or amnion. In conclusion, the hypothetical comparison between the inflammatory portal hypertensive evolutive types and the evolutive phases of embryonic development could allow for translational research.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery I, School of Medicine, Complutense University of Madrid, Plaza de Ramon y Cajal s.n., 28040 Madrid, Spain
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Aller MA, Prieto I, Argudo S, de Vicente F, Santamaría L, de Miguel MP, Arias JL, Arias J. The interstitial lymphatic peritoneal mesothelium axis in portal hypertensive ascites: when in danger, go back to the sea. Int J Inflam 2010; 2010:148689. [PMID: 21152120 PMCID: PMC2990101 DOI: 10.4061/2010/148689] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Revised: 06/10/2010] [Accepted: 07/26/2010] [Indexed: 12/19/2022] Open
Abstract
Portal hypertension induces a splanchnic and systemic low-grade inflammatory response that could induce the expression of three phenotypes, named ischemia-reperfusion, leukocytic, and angiogenic phenotypes.During the splanchnic expression of these phenotypes, interstitial edema, increased lymph flow, and lymphangiogenesis are produced in the gastrointestinal tract. Associated liver disease increases intestinal bacterial translocation, splanchnic lymph flow, and induces ascites and hepatorenal syndrome. Extrahepatic cholestasis in the rat allows to study the worsening of the portal hypertensive syndrome when associated with chronic liver disease. The splanchnic interstitium, the mesenteric lymphatics, and the peritoneal mesothelium seem to create an inflammatory pathway that could have a key pathophysiological relevance in the production of the portal hypertension syndrome complications. The hypothetical comparison between the ascitic and the amniotic fluids allows for translational investigation. From a phylogenetic point of view, the ancestral mechanisms for amniotic fluid production were essential for animal survival out of the aquatic environment. However, their hypothetical appearance in the cirrhotic patient is considered pathological since ultimately they lead to ascites development. But, the adult human being would take advantage of the potential beneficial effects of this “amniotic-like fluid” to manage the interstitial fluids without adverse effects when chronic liver disease aggravates.
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Affiliation(s)
- M A Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
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Abstract
The use of an operating microscope in rat liver surgery makes it possible to obtain new experimental models and improve the already existing macrosurgical models. Thus, microsurgery could be a very valuable technique to improve experimental models of hepatic insufficiency. In the current review, we present the microsurgical techniques most frequently used in the rat, such as the portacaval shunt, the extrahepatic biliary tract resection, partial and total hepatectomies and heterotopic and orthotopic liver transplantation. Hence, reducing surgical complications allows for perfecting the resulting experimental models. Thus, liver atrophy related to portacaval shunt, prehepatic portal hypertension secondary to partial portal vein ligation, cholestasis by resection of the extrahepatic biliary tract, hepatic regeneration after partial hepatectomies, acute liver failure associated with subtotal or total hepatectomy and finally complications derived from preservation or rejection in orthotopic and heterotopic liver transplantation can be studied in more standardized experimental models. The results obtained are therefore more reliable and facilitates the flow of knowledge from the bench to the bedside. Some of these microsurgical techniques, because of their simplicity, can be performed by researchers without any prior surgical training. Other more complex microsurgical techniques require in-depth surgical training. These techniques are ideal for achieving a complete surgical training and more select microsurgical models for hepatology research.
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Affiliation(s)
- Maria-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University, Madrid, Spain.
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Rosmaninho-Salgado J, Araújo IM, Alvaro AR, Mendes AF, Ferreira L, Grouzmann E, Mota A, Duarte EP, Cavadas C. Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin-1beta: role of neuropeptide Y and nitric oxide. J Neurochem 2009; 109:911-22. [PMID: 19309436 DOI: 10.1111/j.1471-4159.2009.06023.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Adrenal chromaffin cells synthesize and secrete catecholamines and neuropeptides that may regulate hormonal and paracrine signaling in stress and also during inflammation. The aim of our work was to study the role of the cytokine interleukin-1beta (IL-1beta) on catecholamine release and synthesis from primary cell cultures of human adrenal chromaffin cells. The effect of IL-1beta on neuropeptide Y (NPY) release and the intracellular pathways involved in catecholamine release evoked by IL-1beta and NPY were also investigated. We observed that IL-1beta increases the release of NPY, norepinephrine (NE), and epinephrine (EP) from human chromaffin cells. Moreover, the immunoneutralization of released NPY inhibits catecholamine release evoked by IL-1beta. Moreover, IL-1beta regulates catecholamine synthesis as the inhibition of tyrosine hydroxylase decreases IL-1beta-evoked catecholamine release and the cytokine induces tyrosine hydroxylase Ser40 phosphorylation. Moreover, IL-1beta induces catecholamine release by a mitogen-activated protein kinase (MAPK)-dependent mechanism, and by nitric oxide synthase activation. Furthermore, MAPK, protein kinase C (PKC), protein kinase A (PKA), and nitric oxide (NO) production are involved in catecholamine release evoked by NPY. Using human chromaffin cells, our data suggest that IL-1beta, NPY, and nitric oxide (NO) may contribute to a regulatory loop between the immune and the adrenal systems, and this is relevant in pathological conditions such as infection, trauma, stress, or in hypertension.
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Aller M, Vara E, García C, Méndez M, Méndez-López M, Mejía I, López L, Arias J, Arias J. Prehepatic portal hypertension worsens the enterohepatic redox balance in thioacetamide-cirrhotic rats. PATHOPHYSIOLOGY 2008; 15:233-42. [DOI: 10.1016/j.pathophys.2008.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 09/19/2008] [Indexed: 02/07/2023] Open
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Sánchez-Patán F, Anchuelo R, Aller MA, Vara E, García C, Nava MP, Arias J. Chronic prehepatic portal hypertension in the rat: is it a type of metabolic inflammatory syndrome? Lipids Health Dis 2008; 7:4. [PMID: 18271959 PMCID: PMC2262079 DOI: 10.1186/1476-511x-7-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2007] [Accepted: 02/13/2008] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A progressive development of hepatic steatosis with an increase in the lipid hepatocyte content and the formation of megamitochondria have been demonstrated in rats with prehepatic portal hypertension. The aim of this study is to verify the existence of liver and serum lipid metabolism impairments in rats with long-term (2 years) portal hypertension. METHODS Male Wistar rats: Control (n = 10) and with prehepatic portal hypertension by triple partial portal vein ligation (n = 9) were used. Liver content of Triglycerides (TG), phospholipids (PL) and cholesterol and serum cholesterol, lipoproteins (HDL and LDL), TG, glucose and Lipid Binding Protein (LBP) were assayed with specific colorimetric commercial kits. Serum levels of insulin and somatostatin were assayed by RIA. RESULTS The liver content of TG (6.30 +/- 1.95 vs. 4.17 +/- 0.59 microg/ml; p < 0.01) and cholesterol (1.48 +/- 0.15 vs. 1.10 +/- 0.13 microg/ml; p < 0.001) increased in rats with portal hypertension. The serum levels of cholesterol (97.00+26.02 vs. 114.78 +/- 37.72 mg/dl), TG (153.41 +/- 80.39 vs. 324.39 +/- 134.9 mg/dl; p < 0.01), HDL (20.45 +/- 5.14 vs. 55.15 +/- 17.47 mg/dl; p < 0.001) and somatostatin (1.32 +/- 0.31 vs. 1.59 +0.37 mg/dl) decreased, whereas LDL (37.83 +/- 15.39 vs. 16.77 +/- 6.81 mg/dl; p < 0.001) and LBP (308.47 +/- 194.53 vs. 60.27 +/- 42.96 ng/ml; p < 0.001) increased. CONCLUSION Portal hypertension in the rat presents changes in the lipid and carbohydrate metabolisms similar to those produced in chronic inflammatory conditions and sepsis in humans. These underlying alterations could be involved in the development of hepatic steatosis and, therefore, in those described in the metabolic syndrome in humans.
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Affiliation(s)
| | - Raquel Anchuelo
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
| | - Maria-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
| | - Elena Vara
- Biochemistry and Molecular Biology III Department, School of Medicine, Complutense University of Madrid, Spain
| | - Cruz García
- Biochemistry and Molecular Biology III Department, School of Medicine, Complutense University of Madrid, Spain
| | - Maria-Paz Nava
- Department of Physiology (Animal Physiology II), School of Biology, Complutense University of Madrid, Spain
| | - Jaime Arias
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
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Aller MA, Arias JL, Cruz A, Arias J. Inflammation: a way to understanding the evolution of portal hypertension. Theor Biol Med Model 2007; 4:44. [PMID: 17999758 PMCID: PMC2206015 DOI: 10.1186/1742-4682-4-44] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Accepted: 11/13/2007] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Portal hypertension is a clinical syndrome that manifests as ascites, portosystemic encephalopathy and variceal hemorrhage, and these alterations often lead to death. HYPOTHESIS Splanchnic and/or systemic responses to portal hypertension could have pathophysiological mechanisms similar to those involved in the post-traumatic inflammatory response.The splanchnic and systemic impairments produced throughout the evolution of experimental prehepatic portal hypertension could be considered to have an inflammatory origin. In portal vein ligated rats, portal hypertensive enteropathy, hepatic steatosis and portal hypertensive encephalopathy show phenotypes during their development that can be considered inflammatory, such as: ischemia-reperfusion (vasodilatory response), infiltration by inflammatory cells (mast cells) and bacteria (intestinal translocation of endotoxins and bacteria) and lastly, angiogenesis. Similar inflammatory phenotypes, worsened by chronic liver disease (with anti-oxidant and anti-enzymatic ability reduction) characterize the evolution of portal hypertension and its complications (hepatorenal syndrome, ascites and esophageal variceal hemorrhage) in humans. CONCLUSION Low-grade inflammation, related to prehepatic portal hypertension, switches to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease.
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Affiliation(s)
- María-Angeles Aller
- Surgery I Department. Medical School, Complutense University, 28040 Madrid, Spain
| | - Jorge-Luis Arias
- Psychobiology Laboratory, School of Psychology, University of Oviedo, Asturias, Spain
| | - Arturo Cruz
- Surgery I Department. Medical School, Complutense University, 28040 Madrid, Spain
- General Surgery Department, Virgen de la Luz General Hospital, 16002 Cuenca, Spain
| | - Jaime Arias
- Surgery I Department. Medical School, Complutense University, 28040 Madrid, Spain
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Aller MA, Arias JL, Arias J. The mast cell integrates the splanchnic and systemic inflammatory response in portal hypertension. J Transl Med 2007; 5:44. [PMID: 17892556 PMCID: PMC2034541 DOI: 10.1186/1479-5876-5-44] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2007] [Accepted: 09/24/2007] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension is a clinical syndrome that is difficult to study in an isolated manner since it is always associated with a greater or lesser degree of liver functional impairment. The aim of this review is to integrate the complications related to chronic liver disease by using both, the array of mast cell functions and mediators, since they possibly are involved in the pathophysiological mechanisms of these complications. The portal vein ligated rat is the experimental model most widely used to study this syndrome and it has been considered that a systemic inflammatory response is produced. This response is mediated among other inflammatory cells by mast cells and it evolves in three linked pathological functional systems. The nervous functional system presents ischemia-reperfusion and edema (oxidative stress) and would be responsible for hyperdynamic circulation; the immune functional system causes tissue infiltration by inflammatory cells, particularly mast cells and bacteria (enzymatic stress) and the endocrine functional system presents endothelial proliferation (antioxidative and antienzymatic stress) and angiogenesis. Mast cells could develop a key role in the expression of these three phenotypes because their mediators have the ability to produce all the aforementioned alterations, both at the splanchnic level (portal hypertensive enteropathy, mesenteric adenitis, liver steatosis) and the systemic level (portal hypertensive encephalopathy). This hypothetical splanchnic and systemic inflammatory response would be aggravated during the progression of the chronic liver disease, since the antioxidant ability of the body decreases. Thus, a critical state is produced, in which the appearance of noxious factors would favor the development of a dedifferentiation process protagonized by the nervous functional system. This system rapidly induces an ischemia-reperfusion phenotype with hydration and salinization of the body (hepatorenal syndrome, ascites) which, in turn would reduce the metabolic needs of the body and facilitate its temporary survival.
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Affiliation(s)
- María-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
| | - Jorge-Luis Arias
- Psychobiology Department, School of Psychology, University of Oviedo, Asturias, Spain
| | - Jaime Arias
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain
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Aller MA, Nava MP, Cuellar C, Chivato T, Arias JL, Sanchez-Patan F, de Vicente F, Alvarez E, Arias J. Evolutive phases of experimental prehepatic portal hypertension. J Gastroenterol Hepatol 2007; 22:1127-33. [PMID: 17608859 DOI: 10.1111/j.1440-1746.2007.04876.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Partial portal vein ligation is the experimental model most frequently used to study prehepatic portal hypertension. Different systemic and splanchnic biochemical and histological alterations in short-term (28-45 days) and long-term (12-14 months) evolutive phases which has been described in this experimental model suggest the existence of different pathophysiological mechanisms involved in their production. The enteropathy produced could develop in three phases: an early or acute phase with vasomotor hemodynamic alterations (ischemia-reperfusion associated with intestinal hyperemia, edema and oxidative stress); an intermediate phase with immunological alterations (mesenteric lymphadenopathy, increased mucosal infiltration by mast cells and the hepato-intestinal release of pro- and anti-inflammatory mediators); and a late or chronic phase with intestinal remodeling (vascular and epithelial). The alterations which are produced in these three evolutive phases make it possible to propose an inflammatory etiopathogeny for hypertensive portal enteropathy.
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Affiliation(s)
- Maria-Angeles Aller
- Surgery Department I, Medical School, Complutense University of Madrid, Madrid, Spain
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Rosmaninho-Salgado J, Alvaro AR, Grouzmann E, Duarte EP, Cavadas C. Neuropeptide Y regulates catecholamine release evoked by interleukin-1beta in mouse chromaffin cells. Peptides 2007; 28:310-4. [PMID: 17207896 DOI: 10.1016/j.peptides.2006.11.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Activation of the hypothalamic-pituitary-adrenal gland (HPA) axis can modulate the immune system. Cytokines and neuropeptide Y (NPY) are potent regulators of the HPA axis and are both produced by the adrenal medulla. The cytokine interleukin-1beta (IL-1beta) belongs to the interleukin-1 family along with interleukin-1alpha and the interleukin receptor antagonist (IL-1ra). The aim of the present study was to determine the interaction between NPY and IL-1beta in catecholamine (norepinephrine, NE and epinephrine, EP) release from mouse chromaffin cells in culture. We found that IL-1beta increased the constitutive release of NPY, NE and EP from mouse chromaffin cells. This IL-1beta stimulatory effect was blocked by IL-1ra. The immunoneutralization of NPY and the use of the NPY Y(1) receptor antagonist (BIBP 3226) inhibited the stimulatory effect of IL-1beta on catecholamine release from these cells. The present work shows that IL-1beta induces catecholamine release, and in turn this peptide will induce an additional increase in catecholamine release acting through the Y(1) receptor. This work suggests that NPY is involved in the regulatory loop between the immune and the adrenal system in some pathophysiological conditions where plasmatic IL-1beta increases, like in sepsis, rheumatoid arthritis, stress or hypertension.
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Méndez-López M, Méndez M, Sánchez-Patán F, Casado I, Aller MA, López L, Corcuera MT, Alonso MJ, Nava MP, Arias J, Arias JL. Partial portal vein ligation plus thioacetamide: a method to obtain a new model of cirrhosis and chronic portal hypertension in the rat. J Gastrointest Surg 2007; 11:187-94. [PMID: 17390171 DOI: 10.1007/s11605-006-0063-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n = 10), 2 [triple partial portal vein ligation (TPVL); n = 9], 3 (TAA; n = 11), and 4 (TPVL plus TAA; n = 9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL + TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.
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Affiliation(s)
- Marta Méndez-López
- Psychobiology Department, Psychology School, University of Oviedo, Asturias, Spain
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Aller MA, Vara E, García C, Nava MP, Angulo A, Sánchez-Patán F, Calderón A, Vergara P, Arias J. Hepatic lipid metabolism changes in short- and long-term prehepatic portal hypertensive rats. World J Gastroenterol 2006; 12:6828-34. [PMID: 17106932 PMCID: PMC4087438 DOI: 10.3748/wjg.v12.i42.6828] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To verify the impairment of the hepatic lipid metabolism in prehepatic portal hypertension.
METHODS: The concentrations of free fatty acids, diacylglycerol, triglycerides, and phospholipids were assayed by using D-[U-14C] glucose incorporation in the different lipid fractions and thin-layer chromatography and cholesterol was measured by spectrophotometry, in liver samples of Wistar rats with partial portal vein ligation at short- (1 mo) and long-term (1 year) (i.e. portal hypertensive rats) and the control rats.
RESULTS: In the portal hypertensive rats, liver phospholipid synthesis significantly decreased (7.42 ± 0.50 vs 4.70 ± 0.44 nCi/g protein; P < 0.01) and was associated with an increased synthesis of free fatty acids (2.08 ± 0.14 vs 3.36 ± 0.33 nCi/g protein; P < 0.05), diacylglycerol (1.93 ± 0.2 vs 2.26 ± 0.28 nCi/g protein), triglycerides (2.40 ± 0.30 vs 4.49 ± 0.15 nCi/g protein) and cholesterol (24.28 ± 2.12 vs 57.66 ± 3.26 mg/g protein; P < 0.01).
CONCLUSION: Prehepatic portal hypertension in rats impairs the liver lipid metabolism. This impairment consists in an increase in lipid deposits (triglycerides, diacylglycerol and cholesterol) in the liver, accompanied by a decrease in phospholipid synthesis.
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Affiliation(s)
- Maria-Angeles Aller
- Surgery I Department, School of Medicine, Complutense University of Madrid, Spain.
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López L, Aller MA, Miranda R, Sánchez-Patán F, Nava MP, Arias J, Arias JL. Prehepatic portal hypertension induces alterations in cytochrome oxidase activity in the rat adrenal gland. J INVEST SURG 2006; 19:79-86. [PMID: 16531365 DOI: 10.1080/08941930600567096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
One approach to assess neuroendocrine response to portal hypertension in short-term portal vein-stenosed rats consists in studying metabolic and functional activity patterns in adrenal glands using mitochondrial enzyme cytochrome c oxidase (COX) as a histochemical marker. Male Wistar rats were divided into two groups: a control group (Group I; n = 8), in which the animals did not undergo any operative intervention, and a triple calibrated portal vein stenosis group (TPVS) (Group II; n = 7). The sections of suprarenal glands were histochemically stained for COX and the optical densitometry was measured by a computer image analyzer attached to a microscope. In TPVS rats, COX activity in the adrenal gland cortex is lower than in control rats and affects the fascicular (52.30, 47.16-60.98, vs. 67.12, 60.31-73.89, p = .002), glomerular (49.68, 46.19-53.56 vs. 70.47, 64.64-73.51, p < .001), and reticular (47.35, 35.63-54.39, vs. 55.37, 49.76-58.97; p < .05) layers. In contrast, COX activity in the adrenal gland medulla is similar in TPVS rats and in control rats (29.91, 29.54-31.18, vs. 29.67, 28.95-30.23). The changes in adrenocortical COX activity in short-term-TPVS rats could constitute a pathogenic factor for both splanchnic and systemic hyperdynamic circulations, described in this experimental model of prehepatic portal hypertension.
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Affiliation(s)
- Laudino López
- Psychobiology Laboratory, School of Psychology, University of Oviedo, Principado de Asturias, Spain
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