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Mast cell-mediated splanchnic cholestatic inflammation. Clin Res Hepatol Gastroenterol 2019; 43:561-574. [PMID: 30853494 DOI: 10.1016/j.clinre.2019.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 01/21/2019] [Accepted: 02/04/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Splanchnic mast cells increase in chronic liver and in acute-on-chronic liver diseases. We administered Ketotifen, a mast cell stabilizer, and measured the mast cells in the splanchnic organs of cholestatic rats. MATERIAL AND METHODS These groups were studied: sham-operated rats (S; n = 15), untreated microsurgical cholestasic rats (C; n = 20) and rats treated with Ketotifen: early (SK-e; n = 20 and CKe; n = 18), and late (SK-l; n = 15 and CK-l; n = 14). RESULTS The cholestatic rats showed systemic and splanchnic impairments, such as ascites, portal hypertension, and biliary proliferation and fibrosis. The rats also showed a splanchnic increase of TNF-α, IL-1β and MCP-1, and a reduction of IL-4, IL-10 and antioxidants. An increase of VEGF in the ileum and mesenteric lymphatic complex was associated with a liver reduction of TGF-β1. Ketotifen reduces the degree of hepatic insufficiency and the splanchnic inflammatory mediators, as well as VEGF and TGF-ß1 levels. Ketotifen also reduces the connective tissue mast cells in the mesenteric lymphatic complex of cholestatic rats, while increases the hepatic mucosal mast cells. CONCLUSIONS In cholestatic rats, Ketotifen improves liver function and ascites, and also reduces pro-inflammatory mediators in the splanchnic area. The decrease in connective tissue mast cells in the mesenteric lymphatic complex due to the administration of Ketotifen would lead to the improvement of the inflammatory splanchnic response, and consequently the abovementioned complications.
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Aller MA, Blanco-Rivero J, Arias N, Santamaria L, Arias J. The Lymphatic Headmaster of the Mast Cell-Related Splanchnic Inflammation in Portal Hypertension. Cells 2019; 8:cells8070658. [PMID: 31261968 PMCID: PMC6678304 DOI: 10.3390/cells8070658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/24/2019] [Accepted: 06/25/2019] [Indexed: 11/16/2022] Open
Abstract
Portal hypertension is a common complication of liver disease, either acute or chronic. Consequently, in chronic liver disease, such as the hypertensive mesenteric venous pathology, the coexisting inflammatory response is classically characterized by the splanchnic blood circulation. However, a vascular lymphatic pathology is produced simultaneously with the splanchnic arterio-venous impairments. The pathological increase of the mesenteric venous pressure, by mechanotransduction of the venous endothelium hyperpressure, causes an inflammatory response involving the subendothelial mast cells and the lymphatic endothelium of the intestinal villi lacteal. In portal hypertension, the intestinal lymphatic inflammatory response through the development of mesenteric-systemic lymphatic collateral vessels favors the systemic diffusion of substances with a molecular pattern associated with damage and pathogens of intestinal origin. When the chronic hepatic insufficiency worsens the portal hypertensive inflammatory response, the splanchnic lymphatic system transports the hyperplasied intestinal mast cells to the mesenteric lymphatic complex. Then, an acquired immune response regulating a new hepato-intestinal metabolic scenario is activated. Therefore, reduction of the hepatic metabolism would reduce its key centralized functions, such as the metabolic, detoxifying and antioxidant functions which would try to be substituted by their peroxisome activity, among other functions of the mast cells.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
| | - Javier Blanco-Rivero
- Department of Physiology, School of Medicine, Autonomous University of Madrid, 28049 Madrid, Spain
- Instituto de Investigación Biomédica La Paz (IdIPAZ), 28046 Madrid, Spain
- Centro de Investigación Biomédica en Red (Ciber) de Enfermedades Cardiovasculares, 28029 Madrid, Spain
| | - Natalia Arias
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London WC2R 2LS, UK
- INEUROPA (Instituto de Neurociencias del Principado de Asturias), 33003 Oviedo, Spain
| | - Luis Santamaria
- Department of Anatomy, Histology and Neuroscience, School of Medicine, Autonoma University of Madrid, 28029 Madrid, Spain
| | - Jaime Arias
- Department of Surgery, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
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Aller MA, Arias N, Blanco-Rivero J, Arias JL, Arias J. Hepatic encephalopathy: Sometimes more portal than hepatic. J Gastroenterol Hepatol 2019; 34:490-494. [PMID: 30345537 DOI: 10.1111/jgh.14514] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 10/08/2018] [Indexed: 12/29/2022]
Abstract
Hepatic encephalopathy is a severe complication of both chronic and acute liver diseases. The term hepatic encephalopathy stems from the belief that hepatic insufficiency is its fundamental etiopathogenic factor. However, most clinical cases show liver failure along with mesenteric venous portal hypertension. This portal hypertension would explain the abnormal mechanical forces suffered by the digestive tract in the early stages of the disorder. These forces could regulate some gut biochemical pathological pathways in a process known as mechanotransduction. Thus, portal hypertension would begin with the establishment of a mechanotransduced afferent or sensory inflammatory gut-brain pathway, resulting in functional and structural changes in the central nervous system. In this review, we will revisit the term "hepatic encephalopathy" in light of new results where portal hypertension occurs before liver failure and is accompanied by brain changes. Moreover, we will point out cellular links that can explain the microbiota, immune, gut, and brain axis disturbances found in this disorder.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
| | - Natalia Arias
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.,INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Javier Blanco-Rivero
- Department of Physiology, School of Medicine, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (Idi PAZ), Autonoma University of Madrid, Madrid, Spain
| | - Jorge L Arias
- INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain.,Laboratory of Neuroscience, Department of Psychology, University of Oviedo, Asturias, Spain
| | - Jaime Arias
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
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Arias N, Méndez M, Alcalde I, Íñigo-Portugués A, Merayo-Lloves J, Arias J, Arias JL. Assessing the brain through the eye: New ways to explore hepatic encephalopathy. Physiol Behav 2017; 173:263-271. [PMID: 28238775 DOI: 10.1016/j.physbeh.2017.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/21/2017] [Accepted: 02/21/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Minimal hepatic encephalopathy (mHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments in mHE. We studied one of its precipitating factors, portal hypertension which is driving the inflammatory process behind mHE. The purpose was to describe an indirect diagnostic method able to detect the pathology at early stages based on the study of the vascularization and mast cells conjunctival hyperplasia as secondary inflammatory response associated to portal hypertension. Finally, we correlated the presence of histological changes in the eye in mHE with deficits in behavioral task acquisition. METHODS Rats were trained on a stimulus-response task and a spatial working memory task using the Morris water maze. Two groups of animals were used: a SHAM (sham-operated) group (n=10) and a portal hypertension (HT) group (n=10). The triple portal vein ligation method was used to create an animal model of mHE. Latencies to reach the platform, number of glial fibrillary acidic protein-immunoreactive astrocytes (GFAP-IR), mast cell expression and presence/absence of blood and lymphatic vessels were examined. RESULTS There were differences in stimulus-response behavioral performance, with a deficit in the acquisition in the HT group. However, no differences between groups were found on the spatial working memory task. At the same time, differences between groups were found in the GFAP-IR density, which was lower in the HT group, and in the number of mast cells and the presence of vessels, which were higher in the HT group. CONCLUSIONS In this study, we provide the first preliminary insight into the validity of exploring the eye as a possible tool to assess the diagnosis of mHE conditions.
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Affiliation(s)
- Natalia Arias
- Institute for Liver and Digestive Health, University College of London, Department of Medicine, Rowland Hill Street, London, UK; INEUROPA, Instituto de Neurociencias del Principado de Asturias, Spain.
| | - Marta Méndez
- INEUROPA, Instituto de Neurociencias del Principado de Asturias, Spain; Laboratorio de Neurociencias, Departamento de Psicología, Universidad de Oviedo, Plaza Feijoo s/n, 33003 Oviedo, Spain
| | - Ignacio Alcalde
- Fundación de Investigación Oftalmológica (FIO), Instituto Oftalmológico Fernández-Vega, Avda. Dres Fernández-Vega, 34, 33012 Oviedo, Spain
| | - Almudena Íñigo-Portugués
- Fundación de Investigación Oftalmológica (FIO), Instituto Oftalmológico Fernández-Vega, Avda. Dres Fernández-Vega, 34, 33012 Oviedo, Spain
| | - Jesús Merayo-Lloves
- Fundación de Investigación Oftalmológica (FIO), Instituto Oftalmológico Fernández-Vega, Avda. Dres Fernández-Vega, 34, 33012 Oviedo, Spain
| | - Jaime Arias
- Surgery Department, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
| | - Jorge L Arias
- INEUROPA, Instituto de Neurociencias del Principado de Asturias, Spain; Laboratorio de Neurociencias, Departamento de Psicología, Universidad de Oviedo, Plaza Feijoo s/n, 33003 Oviedo, Spain
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Aller MA, Martinez V, Corcuera MT, Benito J, Traver E, Gómez-Aguado F, Vergara P, Arias J. Liver impairment after portacaval shunt in the rat: the loss of protective role of mast cells? Acta Histochem 2012; 114:301-10. [PMID: 21937094 DOI: 10.1016/j.acthis.2011.06.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Revised: 06/03/2011] [Accepted: 06/19/2011] [Indexed: 01/05/2023]
Abstract
Mast cells are involved in various liver diseases and appear to play a broader pathogenic role than originally thought. They may participate in the splanchnic alterations related to a porto-systemic shunt. To verify this hypothesis we studied the serum and hepatic histological changes in rats four weeks after an end-to-side portacaval shunt. In this experimental model of chronic liver insufficiency we also assessed the mucosal mast cells (MMC) and connective tissue mast cells (CTMC) in the liver, mesenteric lymph nodes and small intestine, as well as the serum levels of rat mast cell protease-II (RMCP-II). The results show liver and testes atrophy, with hypoalbuminemia (p=0.0001), hyperbilirubinemia (p=0.0001) and increase in aspartate aminotransferase (p=0.004) and alanine aminotransferase (p=0.0001). Hepatic histopathology demonstrates hepatocytic necrosis and apoptosis, portal inflammation, biliary proliferation, steatosis and fibrosis. There is a decrease of MMCs and CTMCs in the liver, while in the ileum CTMCs increase and MMCs decrease. These results suggest the involvement of mast cells in the pathophysiological splanchnic impairments in this experimental model. In particular, the decreased number of liver mast cells may be associated with the hepatic atrophy. If this is the case, we propose that the disruption of the hepato-intestinal axis after a portocaval shunt in the rat could inhibit the ability of the liver to developing an appropriate repair response mediated by mast cells.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery I, School of Medicine, Complutense University of Madrid, Spain.
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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, Arias N, Prieto I, Santamaria L, Miguel MPD, Arias JL, Arias J. Portal hypertension-related inflammatory phenotypes: From a vitelline and amniotic point of view. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/abb.2012.37110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Abstract
BACKGROUND Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat. AIM We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis. METHODS One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-α) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes. RESULTS The significant increase of fractalkine in mesenteric lymph nodes (P<0.05) and its receptor (CX3CR1) in the small bowel (P<0.05) and hippocampus (P<0.01), associated with the increased expression of SDF1-α in the hippocampus (P<0.01) and the cerebellum (P<0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis. CONCLUSION The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines.
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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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Bacterial translocation to mesenteric lymph nodes increases in chronic portal hypertensive rats. Dig Dis Sci 2010; 55:2244-54. [PMID: 19834810 DOI: 10.1007/s10620-009-1001-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2008] [Accepted: 09/21/2009] [Indexed: 12/12/2022]
Abstract
PURPOSE Bacterial translocation is a frequent complication in portal hypertension related to cirrhosis in the human clinical area. The aim of this study was to verify the existence of intestinal bacterial translocation to mesenteric lymph nodes in male Wistar rats with triple partial portal vein ligation during short- (48 h) and long-term (1 month) postoperative evolution. RESULTS At 48 h, ileal total aerobes bacteria (p < 0.001) and Lactobacillus decrease in sham-operated (SO) and portal hypertensive (PH) rats. At 1 month, ileal Enterococci and Streptococcus sp. show a statistically significant decrease in SO- and PH-rats. Lactobacillus decreases in the colon in SO- (p < 0.01) and in PH-rats (p < 0.001). At 1 month, colonic Enterococci decreases compared to control (p < 0.001) and SO-rats (p < 0.01). These intestinal microfloral changes are associated with bacterial translocation to mesenteric lymph nodes at 48 h (50%; p = 0.004) and 1 month (100%; p < 0.001) of postoperative evolution in PH-rats. CONCLUSIONS The enlargement of the stenosed portal tract related to triple partial portal vein ligation in the rat, since it increases the resistance to the portal blood flow, may be a key factor involved in one of the pathological consequences of portal hypertension, as is bacterial translocation to mesenteric lymph nodes.
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Moquillaza LM, Aller MA, Nava MP, Santamaría L, Vergara P, Arias J. Partial hepatectomy, partial portal vein stenosis and mesenteric lymphadenectomy increase splanchnic mast cell infiltration in the rat. Acta Histochem 2010; 112:372-82. [PMID: 19446312 DOI: 10.1016/j.acthis.2009.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2008] [Revised: 03/03/2009] [Accepted: 03/13/2009] [Indexed: 12/11/2022]
Abstract
It is currently believed that portal hypertension induces an inflammatory response in which mast cells may be involved. The aim of this study was to verify the involvement of the intestinal submucosal and mesenteric lymph node mast cells in the splanchnic inflammatory response related to portal hypertension. Mast cell infiltration in the intestine (duodenum, jejunum, ileum, caecum and distal colon) and in the mesenteric lymph node complex (MLC) was measured using a stereological method in sham-operated rats (SO; n = 12), in two experimental models of portal hypertension, chronic (triple partial portal vein ligation, TPVL; n = 12) and transient (microsurgical partial hepatectomy; n = 12) and in rats in which the MLC was resected (n = 12). The small and large bowel submucosal infiltration increases in MLC-resected rats (p = 0.0001), in TPVL rats (p = 0.0001) and in rats with partial hepatectomy (p = 0.0001). An extensive mast cell infiltration in the MLC (p = 0.0001) was found in TPVL rats and in rats with partial hepatectomy (347.40+/-45.25 and 351.92+/-99.28/mm(3), respectively) in relation to sham-operated rats (135.27+/-30.28/mm(3)). We conclude that mast cells could be involved in the splanchnic alterations developed in the surgical experimental models of portal hypertension studied.
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Aller MA, García-Domínguez J, Vergara P, Arias J. Mast cells in wound-healing cholestatic liver response. Burns 2009; 36:292-4; author reply 294. [PMID: 19932566 DOI: 10.1016/j.burns.2008.12.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2008] [Accepted: 12/12/2008] [Indexed: 12/23/2022]
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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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Guerrero S, Muñíz E, Teijón C, Olmo R, Teijón JM, Blanco MD. Ketotifen-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers: characterization and in vivo evaluation. J Pharm Sci 2008; 97:3153-69. [PMID: 18023014 DOI: 10.1002/jps.21241] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Ketotifen (KT) was encapsulated into poly(D,L-lactide) (PLA) and poly(D,L-lactide-co-glycolide) (PLGA 50/50) by spray-drying to investigate the use of biodegradable drug-loaded microspheres as delivery systems in the intraperitoneal cavity. Ketotifen stability was evaluated by HPLC, and degradation was not observed. Drug entrapment efficiency was 74 +/- 7% (82 +/- 8 microg KT/mg for PLA) and 81 +/- 6% (90 +/- 7 microg KT/mg for PLGA 50/50). PLA microspheres released ketotifen (57% of encapsulated KT) in 350 h at two release rates (221 microg/h, 15 min to 2 h; 1.13 microg/h, 5-350 h). A quicker release of ketotifen took place from PLGA 50/50 microspheres (67.4% of encapsulated KT) in 50 h (322 microg/h, 15 min to 2 h; 16.18 microg/h, 5-50 h). After intraperitoneal administration (10 mg KT/kg b.w.), microsphere aggregations were detected in adipose tissue. Ketotifen concentration was determined in plasma by HPLC. The drug released from PLA and PLGA 50/50 microspheres was detected at 384 and 336 h, respectively. Noncompartmental analysis was performed to determine pharmacokinetic parameters. The inclusion of ketotifen in PLGA and PLA microspheres resulted in significant changes in the plasma disposition of the drug. Overall, these ketotifen-loaded microspheres yielded an intraperitoneal drug release that may be suitable for use as delivery systems in the treatment of inflammatory response in portal hypertension.
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Affiliation(s)
- Sandra Guerrero
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
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Abstract
PURPOSE OF REVIEW This article gives an overview of the several morphological and functional alterations in the gastrointestinal tract that occur in liver disease and their systemic impact. RECENT FINDINGS Recent endoscopic studies have revealed similar mucosal alterations in the upper gastrointestinal as well as the colon that include inflammatory-like changes and vascular lesions. Gut-barrier integrity is consequently impaired. There is an evidence that bacterial translocation with subsequent endotoxaemia provokes an inflammatory response that might trigger the cachexia syndrome in liver disease. Novel therapeutic approaches that address gut-barrier function such as supplementation with insulin-like growth factor or synbiotics have shown promising results. SUMMARY There are various alterations of the gastrointestinal tract in liver disease and portal hypertension, which might be less clinically overt than the cardinal potentially life-threatening features, ascites and oesophageal varices. However, these alterations, for example gut-barrier dysfunction and alterations of gut flora (microbiota) have immense impact on the portal enteropathy, as they both contribute to the systemic inflammation in liver cirrhosis, which is considered a risk factor for infections as well as the development of cachexia.
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Affiliation(s)
- Kristina Norman
- Medizinische Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Charité Universitätsmedizin Berlin, CCM, Charitéplatz 1, Berlin, Germany
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Sánchez-Patán F, Aller MA, Cuellar C, Rodero M, Corcuera MT, Nava MP, Gómez F, Blanco MD, Guerrero S, Anchuelo R, Muñiz E, Alonso MJ, Teijón JM, Arias J. Mast cell inhibition by ketotifen reduces splanchnic inflammatory response in a portal hypertension model in rats. ACTA ACUST UNITED AC 2008; 60:347-55. [DOI: 10.1016/j.etp.2008.03.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2006] [Accepted: 03/20/2008] [Indexed: 01/10/2023]
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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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21
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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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22
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Sánchez-Patán F, Aller MA, Corcuera MT, Vara E, Casado I, Gómez F, García C, Alonso MJ, Arias J. [Chronic inflammatory portal hypertensive enteropathy in the rat]. Cir Esp 2006; 80:162-7. [PMID: 16956552 DOI: 10.1016/s0009-739x(06)70945-9] [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: 01/13/2023]
Abstract
INTRODUCTION Experimental portal hypertensive enteropathy could have an inflammatory etiopathogenesis and, if so, it would produce intestinal remodeling. The aim of this study was to test this hypothesis. MATERIAL AND METHOD Male Wistar rats with portal hypertension (PHT) produced by partial portal vein ligation were divided into four groups: group I (control; n = 9), group II (PHT; n = 8) at 3 months after surgery, group III (control; n = 8), and group IV (PHT; n = 10) at 1 year after surgery. The density of duodenal goblet cells and ileal levels of tumor necrosis factor (TNF)alpha, interleukin (IL)-1beta, and IL-10 were studied using an ELISA method. RESULTS At 3 months after surgery, rats with PHT showed an increase in the number of goblet cells in the small bowel (103.63 +/- 14.37 vs 99.42 +/- 19.19/1,000 microm2). This change was associated with an increase (p < 0.05) in ileal levels of TNFalpha (0.20 +/- 0.09 vs 0.08 +/- 0.02 pmol/mg protein), and IL-1beta (0.40 +/- 0.21 vs 0.19 +/- 0.09 pmol/mg protein), as well as with a decrease (p < 0.05) in ileal IL-10 levels (0.06 +/- 0.02 vs 0.12 +/- 0.03 pmol/mg protein). At 1 year after surgery, rats with PHT showed hyperplasia of goblet cells in the small bowel (172.79 +/- 40.46 vs 121.76 +/- 20.74 /1,000 microm2) (p < 0.01), associated with an increase in ileal levels of TNFalpha (0.37 +/- 0.18 vs 0.17 +/- 0.08 pmol/mg protein) (p < 0.05), IL-1beta (0.28 +/- 0.14 vs 0.205 +/- 0.05 pmol/mg protein), and IL-10 (0.25 +/- 0.14 vs 0.20 +/- 0.11 pmol/mg protein). CONCLUSIONS The increase in TNFalpha and IL-1beta levels and the decrease in IL-10 level in the small bowel in rats with chronic prehepatic PHT suggest the existence of an inflammatory process related to goblet cell hyperplasia. This inflammation could be responsible for the intestinal epithelial remodeling that occurs in the long term in this experimental model.
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Affiliation(s)
- Fernando Sánchez-Patán
- Cátedra de Cirugía, Departamento de Cirugía I, Facultad de Medicina, Universidad Complutense, Madrid, España
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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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24
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Aller MA, Arias J. Portal systemic collateral development: is it a trophic adaptation mechanism to hepatic deprivation? J Gastroenterol Hepatol 2006; 21:1643-5. [PMID: 16984582 DOI: 10.1111/j.1440-1746.2006.04508.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Palma MD, Aller MA, Vara E, Nava MP, Garcia C, Arias-Diaz J, Balibrea JL, Arias J. Portal hypertension produces an evolutive hepato-intestinal pro- and anti-inflammatory response in the rat. Cytokine 2006; 31:213-26. [PMID: 15950486 DOI: 10.1016/j.cyto.2005.04.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2004] [Revised: 12/12/2004] [Accepted: 04/27/2005] [Indexed: 01/29/2023]
Abstract
An inflammatory etiopathogeny can be suggested in portal hypertensive enteropathy since infiltration of the intestinal wall by mononuclear cells has been described in this condition. This work was carried out with the intention of shedding light on this matter. Male Wistar rats were divided into 4 control groups and 4 groups with partial portal vein ligation at 1, 2, 3 and 15 months. TNF-alpha, IL-1beta and IL-10 were quantified in liver and ileum by ELISA. CO and NO were measured in splanchnic and systemic vein by spectrophotometry and Griess reaction, respectively. Expression of constitutive and inducible isoforms of NO and HO were assayed by Western blot in liver and ileum. An increased hepatic release of proinflammatory mediators (TNF-alpha, IL-1beta and NO) associated with intestinal release of anti-inflammatory mediators (IL-10, CO) occurs in an early evolutive phase (1 month) of experimental portal hypertension. On the contrary, in the long-term (15 months), the increase in the intestinal release of proinflammatory mediators (TNF-alpha, IL-1beta) is associated with an increase in the hepatic release of anti-inflammatory mediators (IL-10, CO). These results suggest that experimental prehepatic portal hypertension presents changes in the serum and tissular (liver and small bowel) concentrations of mediators which are considered as pro- and anti-inflammatory.
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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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Prieto I, Aller MA, Santamaría L, Nava MP, Madero R, Pérez-Robledo JP, Arias J. Prehepatic portal hypertension produces increased mast cell density in the small bowel and in mesenteric lymph nodes in the rat. J Gastroenterol Hepatol 2005; 20:1025-31. [PMID: 15955210 DOI: 10.1111/j.1440-1746.2005.03831.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Because most of the characteristics of the portal hypertensive enteropathy can be explained on the basis of increased levels of mast cell mediators, the purpose of the present paper was to study mast cell splanchnic infiltration. METHODS Duodenum, jejunum, ileum and mesenteric lymph node complex infiltration by mast cells was assayed by a stereological technique in control rats (group I; n = 5) and in an experimental model of portal hypertension (the portal vein-stenosed rat, group II; n = 5) at 6 weeks after operation. RESULTS Intestinal and mesenteric lymph node complex infiltration by mast cells increased in the animals with partial portal vein ligation. The mast cell density progressively increased distally along the small bowel. The mast cell increase in the mesenteric lymph node complex in portal vein-stenosed rats was greater than in the duodenum (P = 0.001), jejunum (P = 0.006) and ileum. CONCLUSION The rise of mast cells density in the small bowel and mesenteric lymph node complex in rats with partial portal vein ligation suggests that these cells are involved in the etiopathogenesis of experimental portal prehepatic hypertensive enteropathy.
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Affiliation(s)
- Isabel Prieto
- Surgery I Department, School of Medicine, Complutense University of Madrid, Madrid, Spain
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Aller MA, Vara E, Garcia C, Palma MD, Arias JL, Nava MP, Arias J. Proinflammatory liver and antiinflammatory intestinal mediators involved in portal hypertensive rats. Mediators Inflamm 2005; 2005:101-11. [PMID: 16030393 PMCID: PMC1533904 DOI: 10.1155/mi.2005.101] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2004] [Accepted: 12/17/2004] [Indexed: 02/07/2023] Open
Abstract
Proinflammatory (TNF-alpha , IL-1beta, and NO) and antiinflammatory (IL-10, CO) levels were assayed in serum, liver, and small bowel in order to verify a hypothetic inflammatory etiopathogeny of portal hypertension that could be the cause of its evolutive heterogeneity. Male Wistar rats were divided into one control group (n=11) and one group with a triple stenosing ligation of the portal vein (n=23) after 28 days of evolution. In one subgroup of portal hypertensive rats, portal pressure, collateral venous circulation, mesenteric vasculopathy, and liver and spleen weights were determined. In the remaining rats with portal hypertension TNF-alpha, IL-1beta, and IL-10 were quantified in liver and ileum by enzyme-linked immunosorbent assay. NO synthase activity was studied in liver and ileum. CO and NO were measured in portal and systemic blood by spectrophotometry and Griess reaction, respectively. Portal hypertensive rats with mayor spleen weight show hepatomegaly and mayor development of collateral circulation. Ileum release of IL-10 (0.30 +/- 0.12 versus 0.14 +/- 0.02 pmol/mg protein; P< .01) is associated with a liver production of both proinflammatory mediators (TNF-alpha: 2 +/- 0.21 versus 1.32 +/- 0.60 pmol/mg protein; P< .05, IL-1beta: 19.17 +/- 2.87 versus 5.96 +/- 1.84 pmol/mg protein; P=.005, and NO: 132.10 +/- 34.72 versus 61.05 +/- 8.30 nmol/mL; P=.005) and an antiinflammatory mediator (CO: 6.49 +/- 2.99 versus 3.03 +/- 1.59 pmol/mL; P=.005). In short-term prehepatic portal hypertension a gut-liver inflammatory loop, which could be fundamental in the regulation both of the portal pressure and of its complications, could be proposed.
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Aller MA, López L, Nava MP, Arias JL, Durán HJ, Arias J. Portal hypertension: return to fetal life to re-attempt differentiation? Med Hypotheses 2004; 62:79-81. [PMID: 14729008 DOI: 10.1016/s0306-9877(03)00275-5] [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: 11/16/2022]
Abstract
We speculate on the final meaning of the alterations that characterize portal hypertensive enteropathy. The similarity of these alterations with certain morphofunctional characteristics of prenatal splanchnic development makes it possible to hypothesize that the dedifferentiation with return to early stages of development could constitute a portal hypertension induced pathogenic mechanism.
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Affiliation(s)
- M A Aller
- Surgery Department I, School of Medicine, Complutense University of Madrid, Spain
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Aller MA, Arias JL, Lorente L, Nava MP, Durán HJ, Arias J. Neuro-immune-endocrine functional system and vascular pathology. Med Hypotheses 2001; 57:561-9. [PMID: 11735311 DOI: 10.1054/mehy.2001.1408] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
A new interpretation of the response to injury by the nervous, immune and endocrine system is proposed, in order to integrate biochemical knowledge into the respective clinical areas. The discovery that the signaling molecules of the classical nervous, immune and endocrine systems, that is, the neurotransmitters, cytokines and hormones, respectively, are expressed and perceived by the three systems, has enabled us to establish a functional concept of these systems. The hypothetical integration of different pathological processes in a functional response made up by three phases, the immediate or nervous, intermediate or immune and late or endocrine ones, makes it possible to consider that all of them represent different forms of expression of a functional response whose meaning is always the same, that is, inflammation. If the functions that characterize each one of these three phases represent the activity of the nervous, immune and endocrine systems, the biochemical knowledge could be integrated into the functional meaning of each system.
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Affiliation(s)
- M A Aller
- Surgery I Department, Faculty of Medicine, Complutense University of Madrid, Plaza de Ramón y Cajal s.n., 28040 Madrid, Spain
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Aller Reyero M, Nava Hidalgo M, Palma Mezquida M, López Álvarez L, Arias Pérez J, Vara Ameigeiras E, Arias Pérez J. Redistribución del peso lobular hepático en ratas con hipertensión portal prehepática crónica. Cir Esp 2001. [DOI: 10.1016/s0009-739x(01)71889-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
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