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Probert, Philip Michael Evan. "Refining and replacing models of hepatocytes and periportal fibrosis." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2700.
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The liver plays an important role in drug toxicity, in part through its significant expression of drug-metabolising enzymes. For this reason, liver cells are often used in toxicity screening. Chronic liver injury is also a growing health concern, but its study in-vivo is limited by the severity of the bile duct ligation (BDL) animal model. In investigating ways to replace animals as a source of liver cells for toxicity screening and reduce and refine the BDL model, rat AR42J-B-13 (B-13) cells have been examined as an alternative to primary hepatocytes and chemical alternatives to BDL have been examined respectively. B-13 cells were readily converted by glucocorticoid treatment to hepatocyte-like (B-13/H) cells, which expressed functional CYP1A and CYP3A sub-families whose expression could be induced in response to prototypical inducers. CYP2B1 could be induced at mRNA but not protein level. The CYP1A2 gene in B-13 cells was disrupted/non-functional, however stable introduction of human CYP1A2 showed B-13 cells could be humanised and used for assessment of bioactivation-dependent genotoxins. Drug transporter mRNA expression was low in B-13 and B-13/H cells, but HNF4α overexpression enhanced transporter mRNA expression and function in B-13/H cells. The chronic administration of methapyrilene and α-naphthylisothiocyanate in rats and mice respectively, caused liver injury qualitatively equivalent to that seen after BDL but without the associated mortality or severity seen with BDL. These data suggest that B-13/H cells could be used as an alternative to primary hepatocytes for drug toxicity screening. Chronic administration of methapyrilene and α-naphthylisothiocyanate could be used as alternative less severe models of periportal fibrosis in rats and mice respectively. Use of B-13/H cells would reduce the number of animals required for hepatocyte derivation and through refinement of the BDL model of periportal fibrosis, fewer rodents would be subject to the associated complications and high mortality rate of BDL.
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Vyas, Samir Kumar. "Stromelysin-1 and hepatic stellate cells." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242487.
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Kawser, Choudhury Ali. "Regulation of secretion of #alpha#-2 macroglobulin by hepatic lipocytes in relation to hepatic fibrosis." Thesis, University of Southampton, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240644.
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Thompson, Kerry C. "The expression and function of interleukin-10 in liver injury." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285873.
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Ramachandran, Prakash. "Identification and characterisation of the restorative hepatic macrophage." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9555.
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Long thought to be irreversible, it is now clear that liver fibrogenesis is a dynamic process, with scar tissue capable of being remodelled as well as deposited. Macrophages have been shown to have a critical role in both liver fibrogenesis and fibrosis resolution. Whilst previous work has identified a Ly-6Chi hepatic macrophage population, derived from recruitment of inflammatory monocytes, as being the main pro-fibrogenic population, the nature and phenotype of the pro-resolution macrophage subset is unknown. In this thesis, I sought to identify and characterise this restorative hepatic macrophage. I established a reversible murine model of liver fibrosis using CCl4. At the time of initiation of fibrosis regression, Ly-6Clo CD11bhi F4/80int hepatic macrophages represented the most numerous macrophage population and the principal expresser of matrix degrading MMP enzymes. Depletion of this population in CD11b-diphtheria toxin (DTR) mice prevented fibrosis resolution. Subsequent, adoptive transfer and in situ labelling experiments, demonstrated that this restorative macrophage population derives from inflammatory monocytes, a common origin to the pro-fibrotic Ly-6Chi hepatic macrophage subset, indicating a switch in macrophage phenotype in situ to form the restorative phenotype. Characterisation of FACS-sorted restorative and pro-fibrogenic liver macrophage subsets using gene expression profiling demonstrated higher expression of pro-resolution genes and lower expression of pro-fibrotic genes in restorative macrophages, which also upregulated a number of genes involved in phagocytosis. Confocal microscopy confirmed that restorative macrophages showed evidence of prior phagocytosis. This could be replicated in vitro, where feeding macrophages with cellular debris resulted in matrix-degrading properties analogous to those seen in vivo, which was dependent on activation of the ERK signalling cascade. This effect was also demonstrated with the phagocytosis of liposomes in vitro. Finally, the administration of liposomes to CCl4-injured mice in vivo induced phagocytosis, causing an increase in hepatic restorative macrophage number and accelerating fibrosis regression. Hence, I have been able to identify and characterise the restorative hepatic macrophage and have utilised these data to develop a novel method to alter macrophage phenotype in vivo and accelerate the resolution of liver fibrosis and restoration of normal tissue architecture.
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Maltby, Julia. "The T-lymphocyte/hepatic stellate cell axis in liver fibrosis." Thesis, University of Southampton, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418619.
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Chang, Ping. "Quantitative evaluation of hepatic morphological alterations and pharmacokinetic changes of cationic drugs in fibrosis-inducing hepatic diseases /." St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16767.pdf.
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Pickering, Judith Ann. "Function of tissue inhibitor of metalloproteinase-1 in liver fibrosis." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244995.
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Reichenbach, Marinkovic Vedrana. "Hepatic remodeling, serum biomarkers and prevention of fibrosis progression in liver disease." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/107757.
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Hepatic fibrosis is characterized by intense tissue remodeling. In this study, we assessed whether CO3-610, a new identified neoepitope, could be used as a surrogate biomarker of liver fibrosis and portal hypertension in CCl4-induced experimental fibrosis. Serum CO3-610 was measured by ELISA. Liver fibrosis was quantified by Sirius red staining. Serum hyaluronic acid (HA) was measured with a binding-protein assay. Gene expression of collagens I and III, MMP2 and MMP9, and tissue inhibitors of matrix metalloproteinase 1 and 2 was quantified by PCR. Hemodynamic measurements were taken in a subgroup of animals. A close direct relationship was found between serum CO3-610 and hepatic collagen content (r= 0.78; P<0.001), superior to that found for serum HA (r= 0.49; P<0.05). CO3-610 levels in rats with severe fibrosis (43.5±3.3 ng/mL, P<0.001) and cirrhosis (60.6±4.3 ng/mL, P<0.001) were significantly higher than those in control animals (26.6±1.3 ng/mL). Importantly, a highly significant relationship was found between serum CO3-610 and portal hypertension (r= 0.84; P<0.001). Liver MMP9 expression increased significantly in fibrotic animals but decreased to control levels in cirrhotic ones. Circulating CO3-610 behaves as a reliable indicator of hepatic remodeling and portal hypertension in experimental fibrosis. Therefore, this peptide could ultimately be a useful marker for the management of liver disease in patients.
Endocannabinoids behave as antifibrogenic agents by interacting with cannabinoid CB2 receptors, whereas the apelin (AP) system acts as a proangiogenic and profibrogenic mediator in the liver. This study assessed the effect of long-term stimulation of CB2 receptors or AP receptor (APJ) blockade on fibrosis progression in rats under a non-discontinued fibrosis induction program. The study was performed in control and CCl4-treated rats for 13 weeks. Fibrosis-induced rats received a CB2 receptor agonist (AM1241) (1 mg/kg), an APJ antagonist (F13A) (75 μg/kg), or vehicle daily during the last 5 weeks of the CCl4 inhalation program. Mean arterial pressure (MAP), portal pressure (PP), hepatic collagen content, angiogenesis, cell infiltrate, and mRNA expression of a panel of fibrosis-related genes were measured in all animals. Fibrosis-induced rats showed increased hepatic collagen content, reduced MAP, PP, and increased expression of the assessed messengers in comparison with control rats. However, fibrotic rats treated with either AM1241 or F13A had reduced hepatic collagen content, improved MAP and PP, ameliorated cell viability, and reduced angiogenesis and cell infiltrate compared with untreated fibrotic rats. These results were associated with attenuated induction of PDGFRβ, α-SMA, MMPs, and TIMPs. CB2 receptor stimulation or APJ blockade prevents fibrosis progression in CCl4-treated rats. The mechanisms underlying these phenomena are coincident despite the marked dissimilarities between the CB2 and APJ signaling pathways, thus opening new avenues for preventing fibrosis progression in liver diseases.
PDGF is the most potent stimulus for proliferation and migration of stellate cells. PDGF receptor β expression is an important phenotypic change in myofibroblastic cells that mediates proliferation and chemotaxis. Here we analyzed the relationship between PDGFRβ expression, hemodynamic deterioration, and fibrosis. Thereafter, we investigated the effects produced by an adenovirus encoding a dominant-negative soluble PDGFRβ (sPDGFRβ) on hemodynamic parameters, PDGFRβ signaling pathway, and fibrosis. Hemodynamics, PDGFRβ mRNA expression, and hepatic collagen were assessed in controls and fibrosic/cirrhotic rats. Next, 30 fibrotic rats were randomized into three groups receiving iv saline and an adenovirus encoding for sPDGFRβ or β-galactosidase. After 7days, hemodynamics, serum sPDGFRβ, and hepatic collagen were measured. CCl4-treated animals for 18weeks showed a significantly higher increase in PDGFRβ mRNA compared to those treated for 13weeks and control rats. In CCl4-treated rats, the fibrous tissue area ranged from moderate to severe fibrosis. A direct relationship between the degree of fibrosis, hemodynamic changes, and PDGFRβ expression was observed. Fibrotic rats transduced with the adenovirus encoding sPDGFRβ showed increased MAP, decreased PP, lower activation of the PDGFRβ signaling pathway, and reduced hepatic collagen than fibrotic rats receiving β-gal or saline. PDGFRβ activation closely correlates with hemodynamic disorders and increased fibrosis in CCl4-treated rats. Adenoviral dominant negative soluble PDGFRβ improved fibrosis. As a result, the hemodynamic abnormalities were ameliorated.
Cirrhotic patients have altered host-defense response mechanisms. Here we assessed whether impaired expression of CB2 receptor in monocytic cells of cirrhotic patients could be involved in the pathogenesis of this phenomenon. CB2 mRNA and protein expression was assessed in a differentiated human monocytic cell line (U937) stimulated with endotoxin (LPS). A PCR array of 86 different genes was assessed in U937 cells treated with LPS. A migration assay towards endocannabinoids or the CB2 antagonist, SR144528, was performed in U937 cells exposed to LPS. Finally, CB1 and CB2 mRNA expression were measured in monocytes and macrophages of cirrhotic patients with or without spontaneous bacterial peritonitis. LPS reduced CB2 expression in human monocytes. Endocannabinoids increased the migratory activity of U937 cells, which was reverted when the experiments were performed in the presence of LPS. Transcriptional profiling showed marked upregulation of 9 genes related to proinflammatory signaling. However, only two genes encoding for CB1 and CB2 were reduced in LPS-treated cells. Circulating monocytes of cirrhotic patients showed a significantly diminished mRNA expression of CB1 and CB2. Markedly low CB1 and CB2 mRNA levels were found in peritoneal macrophages of cirrhotic patients with ascites, being almost suppressed when analyzed in patients with peritonitis. LPS reduces CB2 expression in human monocytes resulting in depressed chemotactic activity and therefore impaired host defense response of these cells.La característica más destacable de la fibrosis es la desregulación de la ME. El equilibrio que existe entre la síntesis y la degradación de la ME en un hígado normal se pierde, y como consecuencia se favorece la síntesis y acumulación de fibras de colágeno, el cual provoca la distorsión de la arquitectura del parénquima y de la red vascular hepática. El CO3-610 es un producto de degradación del colágeno III que ha mostrado estar correlacionado significativamente con el aumento de la cantidad de colágeno y progresión de la fibrosis. Los valores máximos de CO3-610 se han encontrado ratas cirróticas. El resultado más importante es que el CO3-610 ha mostrado tener una estrecha correlación con los valores de presión portal. Existe un gran interés en investigar y desarrollar terapias dirigidas a la prevención de la progresión de la fibrosis. Los endocannabinoides son moléculas lipídicas que participan en un amplio rango de procesos fisiológicos. Los efectos son mediados por dos tipos de receptores, el CB1 y el CB2. El sistema de la apelina es otro sistema endógeno que ha despertado mucho interés en los últimos años. La apelina es el único ligando conocido para el receptor APJ. El tratamiento con AM1241, un agonista selectivo de CB2 y F13A, un antagonista de APJ mejoró la función hepática, la hemodinámica sistémica y portal, y provocó una reducción significativa del grado de fibrosis hepática. Ambos tratamientos produjeron una disminución del infiltrado inflamatorio, angiogénesis y del grado de apoptosis en el parénquima hepático. El análisis de la expresión del mRNA de varios genes importantes implicados en el proceso fibrogénico, reveló que el tratamiento tanto con AM1241 como con F13A, producían una disminución de la expresión del PDGFRβ, del αSMA y de genes de remodelado tisular. La inhibición parcial de la vía de PDGF mediante la administración de un dominante negativo para la fracción soluble del receptor β de PDGF, ha demostrado que mejora la hemodinámica sistémica y la presión portal además de mejorar el grado de fibrosis. Por último, los pacientes cirróticos con ascitis tienen una mayor probabilidad de sufrir infecciones (peritonitis bacteriana espontánea, PBE). Se ha observado que estos pacientes tienen una menor expresión de CB2. In vitro se han realizado experimentos con células monocíticas (U937) y se ha observado que el LPS disminuye drásticamente la expresión de CB2 al igual que afecta a la capacidad de migración de estas células. En conjunto, se puede concluir que la evaluación de la fibrosis hepática es una herramienta muy importante para el diagnostico de la enfermedad hepática y que éste puede mejorarse a través del uso de biomarcadores no invasivos que correlacionen con la hemodinámica y el grado de fibrosis hepática. La prevención de la progresión de la fibrosis a través de fármacos o bien actuando sobre genes clave involucrados en la fibrogénesis son posibles dianas terapéuticas. Finalmente, es posible mejorar la calidad de vida de los pacientes cirróticos con ascitis con infección por PBE mediante terapias que involucren los receptores de cannabinoides CB2.
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MacFarlane, David Peter. "Factors determining the progression of nonalcoholic fatty liver disease : the role of abnormal fatty acid and glucocorticoid metabolism." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5914.
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Obesity and insulin resistance are associated with a constellation of features including hypertension, dyslipidaemia, type 2 diabetes, and premature cardiovascular disease, collectively termed the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic component of this syndrome, incorporating a spectrum of liver disease with increasing morbidity and mortality, from simple steatosis, to non-alcoholic steatohepatitis (or NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. However, factors influencing this progression are incompletely understood. In this thesis I sought to investigate pathways which promote hepatic inflammation and fibrosis by studying two contrasting dietary models of NAFLD in mice in which the risk of hepatic inflammation, insulin resistance and fibrosis differ; namely the methionine and choline deficient diet (MCDD) which induces steatohepatitis, hepatic insulin resistance, and weight loss, and the choline deficient diet (CDD) which may be protected from insulin resistance, and leads to steatosis without inflammation or weight loss. I investigated the possible molecular mechanisms underlying these differences, and whether they influenced progression to hepatic fibrosis induced by carbon tetrachloride (CCl4).
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Brand, Jonathan Frieman. "Staging Liver Fibrosis with Statistical Observers." Diss., The University of Arizona, 2016. http://hdl.handle.net/10150/612941.
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Chronic liver disease is a worldwide health problem, and hepatic fibrosis (HF) is one of the hallmarks of the disease. Pathology diagnosis of HF is based on textural change in the liver as a lobular collagen network that develops within portal triads. The scale of collagen lobules is characteristically on order of 1mm, which close to the resolution limit of in vivo Gd-enhanced MRI. In this work the methods to collect training and testing images for a Hotelling observer are covered. An observer based on local texture analysis is trained and tested using wet-tissue phantoms. The technique is used to optimize the MRI sequence based on task performance. The final method developed is a two stage model observer to classify fibrotic and healthy tissue in both phantoms and in vivo MRI images. The first stage observer tests for the presence of local texture. Test statistics from the first observer are used to train the second stage observer to globally sample the local observer results. A decision of the disease class is made for an entire MRI image slice using test statistics collected from the second observer. The techniques are tested on wet-tissue phantoms and in vivo clinical patient data.
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Reeves, Helen Louise. "Signal transduction cascades involved in the activation and proliferation of hepatic stellate cells." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324796.
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Dorn, Christoph Michael. "Analysis of the effects of xanthohumol on hepatic homeostasis, inflammation, fibrosis and cancerogenesis." kostenfrei, 2009. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1361/.
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Becares, Salles Natalia. "Effects of LXRα phosphorylation on the regulation of lipid metabolism and hepatic fibrosis." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10024625/.
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Liver X Receptors (LXRα and β) are members of the nuclear receptor superfamily of ligand-activated transcription factors. LXRs are activated by oxidised metabolites of cholesterol and several synthetic ligands, play a crucial role in the regulation of cholesterol and fatty acid homeostasis, and act as strong modulators of inflammation and immunity. This has positioned them as targets for the treatment of several pathologies, including atherosclerosis and obesity. Besides ligand binding, LXR activity can be modulated by post-translational modifications, and previous work has shown that phosphorylation of LXRα alters its transcriptional activity in a gene-specific manner in a macrophage cell line. This thesis has focused on better understanding the regulation of LXRα phosphorylation and investigating how changes in the receptor’s phosphorylation status modulate its activity in vivo; more specifically, in relation to its effects on hepatic lipid metabolism, and the development of inflammation and fibrosis. To do so, I have used a novel mouse model that expresses a whole-body non-phosphorylatable mutant version of LXRα (S196A) and have assessed its responses to a High Fat and High Cholesterol diet, as a dietary model of Non-Alcoholic Fatty Liver Disease (NAFLD). Furthermore, I have studied how the transcriptional capacity of the mutant receptor is modulated, assessing its differential binding to DNA and to other proteins. In order to evaluate the relevance of my findings in the context of human disease, I have also examined LXR activity on the activation of human hepatic stellate cells, key players in the development of liver fibrosis. Lastly, I have sought to examine new stimulants capable of inducing LXRα phosphorylation in vitro, and how this phenomenon can be pharmacologically impaired by using already-available kinase inhibitors. Overall, the work described in this thesis shows that LXRα phosphorylation critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome and modulates metabolic, inflammatory and fibrotic responses that are key in NAFLD progression This novel work significantly contributes to our understanding of LXRα activity in liver disease in a pre-clinical setup, and places the modulation of LXRα phosphorylation as a potential anti-inflammatory/anti-fibrotic therapeutic target.
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Iwaisako, Keiko. "Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells." Kyoto University, 2008. http://hdl.handle.net/2433/124246.
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Benitez-Rajal, Joaquin. "Phospholipase D1 : a possible role in nucleotide-mediated hepatic stellate cell contraction." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366643.
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Zhou, Xiaoying. "Regulation of hepatic stellate cells by extracellular matrix : role of integrin α[subscript v]β₃." Thesis, University of Southampton, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270667.
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Vincent, Karen Jane. "Studies on the expression and regulation of transcription factors in hepatic stellate cells." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323790.
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Gaça, Marianna Danuta Aleksandria. "The bi-directional relationship between mast cells and hepatic stellate cells in liver fibrosis." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323958.
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Martin, Katherine. "Investigating the role of beta1 integrin in hepatic stellate cell activation and liver fibrosis." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/investigating-the-role-of-beta1-integrin-in-hepatic-stellate-cell-activation-and-liver-fibrosis(6be2c604-7be1-40d2-80da-95380ce90da2).html.
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Liver fibrosis is characterised by progressive deposition of type 1 collagen-rich extracellular matrix in response to iterative liver injury. The progressive accumulation of scar tissue within the liver predisposes to the development of hepatocellular carcinoma, and ultimately leads to organ failure. Liver fibrosis is an increasing cause of morbidity and mortality. However, current treatment options are limited, and the only curative option for end stage liver disease is transplantation. Anti-fibrotic agents are urgently needed to halt, or reverse, the fibrotic process; however, to date, they have remained frustratingly elusive. The primary cell type responsible for laying down the pathological fibrotic matrix is the hepatic stellate cell (HSCs). In the healthy liver, HSCs are quiescent vitamin A storing cells, however, in response to liver injury they are activated into proliferative, migratory and contractile myofibroblasts. A number of cytokines and transcription factors are implicated in this activation process; in addition, biomechanical forces have emerged as an important regulator. The integrins are a family of cell surface receptors, which are predominately involved in mediating cellular interactions with the microenvironment. The work presented in this thesis demonstrates that beta1 integrin (Itgb1) plays an important role in HSC activation through regulation of the actin myosin cytoskeleton, and thereby, the cell’s ability to sense and respond to changes in the biomechanical microenvironment. By identifying and investigating downstream effectors of Itgb1 in HSC activation, the group I p21-activated kinases (Paks) were discovered as potential therapeutic targets in liver fibrosis. In addition, alpha11 integrin was identified as a fibroblast-specific partner of Itgb1 in HSCs, which crucially, may allow HSC-specific targeting of Itgb1. Taken together, the data presented in this thesis suggest that disrupting Itgb1 signalling in HSC activation may be a novel therapeutic avenue for liver fibrosis. In particular, pharmacological inhibition of the downstream effectors, the group I Paks, has shown promise as an anti-fibrotic both in vitro and in vivo.
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Molokanova, Olena [Verfasser]. "Suppression of hepatic fibrosis by efficient Col1a1 silencing using shRNA inducible mouse models / Olena Molokanova." Mainz : Universitätsbibliothek Mainz, 2018. http://d-nb.info/1162658800/34.
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Hovell, Christopher John. "Membrane-type 1 matrix metalloproteinase expression by hepatic stellate cells : its role in liver fibrosis." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322017.
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George, David Keith. "The role of liver matrix degradation in the development of hepatic fibrosis in genetic haemochromatosis." Thesis, University of Bristol, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299332.
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Saito, Shunichi. "Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis." Kyoto University, 2013. http://hdl.handle.net/2433/180349.
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Patel, Keyur. "The influence of host factors on hepatic fibrosis and virolologic response in chronic hepatitis C infection." Thesis, University of Southampton, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485034.
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Chronic hepatitis C (CHC) infection affects an estimated 170 million people worldwide, and is characterized by varying degrees of inflammation and progressive hepatic fibrosis leading to . cirrhosis and complications of end-stage liver disease in a proportion of patients over 20 to 40 years. CHC infection is now the leading indication for liver transplantation in developed nations. Several host and viral factors have been implicated disease progression and predicting response to therapy. The aims of this thesis were to characterize host determinants of progressive fibrosis and assess virologic responses in a large cohort ofCHC patients linked to an extensive and pedigreed biorepository. Our studies indicate that HLA class 1 allelic diversity has a relatively weak influence on disease severity and fibrosis progression compared to standard host factors such as age, gender and alcohol intake. However, steatosis is an important host variable that is associated with fibrosis, and also reduces both early and sustained virologic responses to therapy in genotype-l infected patients. Myeloperoxidase gene polymorphisms also appear to be associated with fibrosis severity, thus implicating oxidative stress in this regard. Non-invasive alternatives to a needle liver biopsy to stage and follow disease progression in CHC patients would be a useful clinical tool. We have developed and validated a serodiagnostic panel of matrix proteins to differentiate mild from moderate-to-severe stages of fibrosis that could provide an alternative to liver biopsy for binary disease staging in a proportion ofCHC patients. At present, there are no reliable host, or viral, predictors of relapse following an end-of-treatment viral response. Our studies indicate that hepatic HCV RNA measurement has minimal clinical utility in following virologic responses to therapy, although residual intrahepatic virus may be present in a minority of patients that relapse following an apparent sustained virologic response. Whole blood extraction methods for viral detection also do not appear to provide any clinical benefit over conventional serum based assays during therapy, or in predicting relapse after an end-of-treatment response. Our ongoing studies will plan to better define the role of host immune response in hepatic injury, and develop accurate and reliable non-invasive markers of fibrosis.
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Williams, Elizabeth Jean. "Secretion and activation of TGF-ß1 by hepatic stellate cells and its contribution to liver fibrosis." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423221.
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Al, Sharif Roaa. "The effect of hepatic fibrosis on T2 value in a mouse model at 3T MRI scanner." Thesis, Boston University, 2012. https://hdl.handle.net/2144/31497.
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Thesis (M.A.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
PURPOSE: To correlate spin- spin relaxation time (T2) measurements with degree of hepatic fibrosis of ex vivo murine liver specimens at 3T MRI scanner. MATERIALS AND METHODS: The protocol and procedures were approved by The Institutional Animal Care and Use Committee (IACUC). Sixteen male, six week old C578L/6 mice were divided into two groups, a control group (n=1), which was provided normal food, and for liver fibrosis induction an experimental group (n=15), were provided a 0.1% 3,5-diethoxycarbonyl-1 ,4-dihydrocollidine (DOC) to induce liver fibrosis. Exvivo liver specimens were scanned using 3 T MRI scanner. Multi- echo spin-echo sequence was used to perform T2 map. Hematoxylin-eosin with Masson's trichrome staining was performed in liver specimens. Repeated t-test paired sample was used. RESULTS: Increasing the degree of hepatic fibrosis was seen to decrease liver T2 values. CONCLUSION: In this model, liver fibrosis was detected with T2 MR Imaging; the degree of hepatic fibrosis was correlated with the degree of decrease in T2 measurements.
2031-01-01
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Sundaram, Balamurugan [Verfasser]. "Inactive Rhomboid Protease 2 Reduces Liver Fibrosis by Inhibiting Proliferation of Hepatic Stellate Cells / Balamurugan Sundaram." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1208209671/34.
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Eulenberg, Vera [Verfasser]. "RNA sequencing, gene expression analysis, and immunohistochemical studies indogs with chronic hepatitis and hepatic fibrosis / Vera Eulenberg." Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1222974967/34.
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Bragg, Sarah A. "Impaired Hepatic Fatty Acid Synthesis: A Potential Mechanism of the Reduced Growth Phenotype of Cystic Fibrosis Knockout Mice." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1272503069.
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Nakamura, Toshio. "Expression of the Na+/Ca2+ exchanger emerges in hepatic stellate cells after activation in association with liver fibrosis." Kyoto University, 1998. http://hdl.handle.net/2433/182267.
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Brand, Jonathan F., Lars R. Furenlid, Maria I. Altbach, Jean-Philippe Galons, Achyut Bhattacharyya, Puneet Sharma, Tulshi Bhattacharyya, Ali Bilgin, and Diego R. Martin. "Task-based optimization of flip angle for fibrosis detection in T1-weighted MRI of liver." SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS, 2016. http://hdl.handle.net/10150/622346.
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Chronic liver disease is a worldwide health problem, and hepatic fibrosis (HF) is one of the hallmarks of the disease. The current reference standard for diagnosing HF is biopsy followed by pathologist examination; however, this is limited by sampling error and carries a risk of complications. Pathology diagnosis of HF is based on textural change in the liver as a lobular collagen network that develops within portal triads. The scale of collagen lobules is characteristically in the order of 1 to 5 mm, which approximates the resolution limit of in vivo gadolinium-enhanced magnetic resonance imaging in the delayed phase. We use MRI of formalin-fixed human ex vivo liver samples as phantoms that mimic the textural contrast of in vivo Gd-MRI. We have developed a local texture analysis that is applied to phantom images, and the results are used to train model observers to detect HF. The performance of the observer is assessed with the area-under-the-receiver-operator-characteristic curve (AUROC) as the figure-of-merit. To optimize the MRI pulse sequence, phantoms were scanned with multiple times at a range of flip angles. The flip angle that was associated with the highest AUROC was chosen as optimal for the task of detecting HF. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
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Rodríguez, Navarro Sarai. "New and combined treatments for cirrhosis and portal hypertension: effects on hemodynamics and hepatic fibrosis in experimental animal models." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/390964.
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La cirrosi, la causa més freqüent d’hipertensió portal (HTP) en els països occidentals, és considerada una malaltia amb múltiples fases, que evoluciona des d'etapes inicials asimptomàtiques a un estat de cirrosi descompensada amb diverses manifestacions clíniques, les quals representen la principal causa de mort i de trasplantament hepàtic a tot el món. Per tant, caldria adaptar les diferents teràpies per a la cirrosi a cadascuna de les fases de la malaltia. Malgrat els avenços realitzats en les últimes dècades per entendre millor la fisiopatologia de la HTP i poder desenvolupar noves estratègies farmacològiques, fins al moment, els beta-bloquejants no selectius (BBNS) continuen sent la base del tractament dels pacients cirròtics amb HTP per a reduir la pressió portal (PP) i prevenir l'hemorràgia per varius.
Aquesta tesi doctoral se centra en l'estudi de noves estratègies terapèutiques per al tractament de la cirrosi hepàtica en diferents etapes de la malaltia. Concretament, hem provat dos nous potencials fàrmacs orals, sols o en combinació amb d’altres fàrmacs convencionals, per veure la seva eficàcia en diversos models d’experimentació animal d’HTP: el model de lligadura de la vena porta (LVP), el de lligadura del conducte biliar (LCB), i el model d’intoxicació per tetraclorur de carboni (CCl4).
Tres estudis conformen aquesta tesi. En el primer estudi, es va avaluar la utilitat de la droxidopa, un fàrmac pro-adrenèrgic que ja s'utilitza en humans per a altres indicacions, en el tractament de les alteracions hemodinàmiques i renals associades a la cirrosi hepàtica; en el segon estudi, es van testar combinacions de droxidopa amb d’altres fàrmacs que disminueixen la PP (BBNS o estatines), per tal d'intentar aconseguir un efecte sinèrgic i, en el tercer estudi, es va dur a terme una comparació, pel que fa a la reducció de la PP i la toxicitat, de l’efecte de les estatines convencionals (simvastatina, atorvastatina) amb el NCX 6560, una atorvastatina alliberadora d'òxid nítric (ON). La droxidopa va produir un efecte diürètic i natriürètic destacat, i va millorar les alteracions sistèmiques i hemodinàmiques de les rates amb HTP mitjançant l'augment de la pressió arterial mitjana i la resistència de l’artèria mesentèrica superior conjuntament amb una reducció del flux sanguini en l'artèria mesentèrica superior. El tractament crònic amb propranolol més droxidopa va reduir la PP, tot mantenint l'increment en la diüresi i la natriüresi de la droxidopa. Ni la combinació aguda de carvedilol més droxidopa, ni la combinació amb atorvastatina, van aconseguir un efecte sinèrgic. La comparació entre les diferents estatines va mostrar un major efecte tòxic d'aquests fàrmacs en un model que reprodueix una funció hepàtica deteriorada i colèstasi (especialment amb el tractament amb simvastatina), i el NCX 6560 va millorar la HTP de manera similar a l'atorvastatina en dos models cirròtics (LCB i CCl4), però amb menor toxicitat i un millor perfil vasoprotector intrahepàtic.
En conjunt, els resultats d’aquesta tesi apunten a un potencial ús terapèutic de la droxidopa per al tractament dels pacients cirròtics amb ascites refractària i síndrome hepatorenal tipus 2, fins i tot en aquells pacients que estan en tractament amb propranolol, i a un ús més segur del NCX 6560 en el potencial tractament a llarg termini de la HTP amb estatines.Cirrhosis, the most frequent cause of portal hypertension (PHT) in Western countries, is considered a multistage disease progressing from asymptomatic initial stages to decompensated cirrhosis with multiple clinical manifestations, which are a leading cause of death and liver transplantation worldwide. Therefore, therapies in liver cirrhosis should be adapted to each stage of the disease. Although many advances has been made in the last decades to understand the pathophysiology of PHT and develop new pharmacological approaches, up to now, non-selective beta-blockers (NSBB) still remain the mainstay of treatment in cirrhotic patient with PHT in order to reduce portal pressure (PP) and prevent variceal bleeding. The present doctoral thesis focuses on the study of new therapeutic strategies for the management of liver cirrhosis at different stages of the disease. In particular, two potential oral new drugs were tested, alone or in combination with other conventional drugs, to see their efficacy in several experimental animal models of PHT: the portal vein ligation (PVL), the bile duct ligation (BDL), and the carbon tetrachloride (CCl4) models. Three studies constitute this thesis. In the first study, the pro-adrenergic drug droxidopa, already used in humans for other indications, was evaluated for the management of the hemodynamic and renal alterations associated with liver cirrhosis; in the second study, combinations of droxidopa with other PP-lowering drugs (NSBB or statins) were performed in order to achieve a synergistic effect and, in the third study, a comparison of conventional statins (simvastatin, atorvastatin) with the nitric oxide (NO)-donating atorvastatin NCX 6560, in terms of PP lowering effect and toxicity, was also carried out. Droxidopa produced a marked diuretic and natriuretic effect, and improved the systemic and hemodynamic alterations of portal hypertensive rats by increasing mean arterial pressure and superior mesenteric artery resistance and by reducing superior mesenteric artery blood flow. A chronic treatment with propranolol plus droxidopa reduced PP, maintaining the increase in diuresis and natriuresis caused by droxidopa. Neither the acute combination of carvedilol plus droxidopa nor the combination with atorvastatin achieved a synergistic effect. The comparison among statins showed a magnified toxic effect of these drugs in a model that mimics a deteriorated liver function and cholestasis (especially with simvastatin treatment), and NCX 6560 improved PHT similarly to atorvastatin in two cirrhotic models (BDL and CCl4), but with less toxicity and a better intrahepatic vasoprotective profile. Altogether, the results presented in this thesis point to a potential therapeutic use of droxidopa in the management of cirrhotic patients with refractory ascites and type-2 hepatorenal syndrome, even in those patients on propranolol therapy, and to a safer use of NCX 6560 in the potential long-term statin treatment of PHT.
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Ghosh, Sumona. "A Novel Role for CEACAM1 in Hepatic Stellate Cell Activation in the Progression of Non-Alcoholic Steatohepatitis." University of Toledo Health Science Campus / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=mco1333740758.
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Karlas, Thomas, and Johannes Wiegand. "Non-Invasive Assessment of Hepatic Steatosis in Patients with NAFLD Using Controlled Attenuation Parameter and 1H-MR Spectroscopy." Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-142654.
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Introduction: Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease
(NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP)
correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a headto-
head comparison between both methods.
Methods: Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient
elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2
34–66%, S3 $67%.
Results: Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated
with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiveroperating
characteristics curves were 0.93 vs. 0.88 for steatosis $S1 and 0.94 vs. 0.88 for $S2, respectively. Boot-strapping
analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for
the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total
cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity
of 100% and 98.1% at a cut-off value of 8.85 kPa.
Conclusion: Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification.
Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive
characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects,
anthropometry, and presence of advanced liver fibrosis.
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Rodrigues, Alexandro dos Santos. "Expressão e distribuição da conexina 32 em fígados com fibrose experimentalmente induzida." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-12042007-182154/.
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A conexina 32 (Cx32) é uma estrutura protéica que constitui os canais que promovem as comunicações intercelulares via junções comunicantes (GJIC), permitindo difusão de pequenas moléculas citoplasmáticas de uma célula à outra. Este trabalho objetivou os estudos destas estruturas devido a sua importância em processos hepáticos, mais especificamente, a fibrose hepática. O presente estudo foi realizado através da administração oral da droga hepatotoxica dimetilnitrosamina (DMN) em ratas Wistar duas vezes por semana em dias consecutivos no prazo de cinco semanas. A necropsia destes animais foi realizada após cinco semanas da última administração da droga e revelou um quadro de fibrose hepática, em contra partida aos resultados obtidos em um grupo controle com a mesma quantidade de animais. O material fibrótico foi submetido à análise imunohistoquímica que revelou uma presença preferencial de Cx32 dispersa no citoplasma, o que pode levar à hipótese de problemas no mecanismo de transporte citoplasmático destas estruturas, em contrapartida ao material pertencente ao grupo controle que evidenciou a presença das Cx32 na membrana plasmática formando placas juncionais. Quando submetido à análises moleculares o fígado fibrótico revelou uma diminuição da expressão gênica embora o produto protéico deste material quando comparado ao grupo controle não tenha se mostrado diminuído.The connexin 32 (Cx32) is a proteic structure that constitute the channels that promote the cell communication by means of the gap junction (GJIC), allowing the diffusion of short cytoplasmic molecules from a cell to another. This work aimed to study these structures due to their importance in the hepatic metabolic processes. The hepatic fibrosis was triggered by the oral administration of dimethylnitrosamine (DMN) in the female rat Wistars twice a week in consecutive days during five weeks. The necropsy of these animals was carried out after the last drug administration. They presented a hepatic fibrosis state. The fibrotic material was submitted to the imunohistochemical analysis, which showed a preferencial presence of Cx32 in the cytoplasm, whereas in the control group the Cx32 was located at the membranes, in the junctional plaques. The molecular analysis showed a decrease of the genic expresson of the fibrotic material, however the proteic product wasn? t reduced in comparison with the control group as it was shown by western blot. We concluded that the fibrotic state introduced a disturbance in the intracellular distribution and genic expression of the connexin 32.
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Silva, Cristiane Nonato da. "Avaliação da Variabilidade de uma Biblioteca de Anticorpos construída a partir de sangue de pacientes com Hepatite C Crônica com diferentes Graus de Fibrose." Botucatu, 2019. http://hdl.handle.net/11449/183345.
Full textAbstract:
Orientador: Rejane Maria Tommasini GrottoResumo: A progressão da fibrose hepática somada à infecção pelo vírus da hepatite C (VHC) tem sido associada à resposta imunológica permanente. O estudo no repertório de anticorpos Anti-VHC na progressão da fibrose hepática foi explorado através de ferramentas de sequenciamento em larga escala (NGS) possibilitando uma análise de repertórios altamente variáveis como as porções variáveis VH (cadeia pesada) e Vk (cadeia leve) das imunoglobulinas, e a determinação de famílias e subfamílias dos genes V-D-J associadas à resposta humoral encontrada nas diferentes fases da doença proporcionam uma ferramenta importante no entendimento da resposta imune frente à infecção viral pelo VHC. As porções VH e Vk das imunoglobulinas foram obtidas a partir da amplificação de RNA de sangue de paciente VHC positivos e com diferentes graus de fibrose, e sequenciadas na plataforma Illumina® Miseq, fornecendo uma grande variabilidade de sequências que foram pré-processadas por ferramentas de bioinformática e analisadas em dois bancos de anticorpos diferentes: IgBlast (NCBI) e IMGT® quanto às famílias e subfamílias mais expressas. A expressão restrita de algumas famílias e subfamílias: IGHV1, IGHV3, IGHV4 e subfamílias já descritas em vários estudos associados ao VHC corrobora com nossos achados de que existe uma tendência do uso de algumas subfamílias como: IGHV1-2, IGHV1-8, IGVH1-69, IGHV3-11, IGHV3-21, IGHV3-23, IGVH3-30, IGHV4-4, IGHV4-34 IGHV4-39 na cadeia pesada; assim como IGkV3-15 e IGkV3-20 na cadei... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The progression of hepatic fibrosis in the hepatitis C virus (HCV) infection has been linked with permanent immune response. The study in the repertoire of Anti-HCV antibodies in the progression of hepatic fibrosis was analysed for large-scale sequencing (NGS) tools enabling a highly variable analysis such as the VH (heavy chain) and Vk (light chain) portions of immunoglobulins and the determination of families and subfamilies of the V-D-J genes in the humoral response found in the different phases of the disease, a great tool in the understanding of the immune response to HCV viral infection. The VH and V portions of the immunoglobulins were obtained from the amplification of HCV positive HCV patient blood with different degrees of fibrosis and sequenced on the Illumina® Miseq platform, providing a large sequence variability that was preprocessed by tools of bioinformatics and analyzed in two different antibody banks: IgBlast (NCBI) and IMGT® for the most expressed families and subfamilies. The restricted expression of some families: IGHV1, IGHV3, IGHV4 and subfamilies already described in several HCV-related studies confirm our findings that there is a tendency to use some subfamilies, such as: IGHV1-2, IGHV1-8, IGVH1- 69, IGHV3-11, IGHV3-21, IGHV3-23, IGVH3-30, IGHV4-4, IGHV4-34 IGHV4-39 in the heavy chain; as well as IGkV3-15 and IGkV3-20 in the light chain, but the subfamilies: IGHV1-8, IGHV3-11, IGHV4-39, IGkV1-5, IGkV1-12, IGkV1-39 were also among the most expressed, i... (Complete abstract click electronic access below)
Mestre
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Elsharkawy, Ahmed M. "The opposing roles of the p50 and c-Rel subunits of NF-κB in the hepatic inflammation-fibrosis cancer axis." Thesis, University of Newcastle Upon Tyne, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.545789.
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Gibelli, Nelson Elias Mendes. ""Fibrose portal e periportal na obstrução extra-hepática experimental em ratos jovens e adultos: contribuição para o estudo da atresia das vias biliares"." Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-11112005-112052/.
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A atresia das vias biliares é afecção hepática da infância. A etiologia é desconhecida, e o diagnóstico baseia-se na biópsia hepática, cujo achado é a proliferação ductular. A ligadura do ducto biliar comum em ratos é modelo utilizado para estudo das doenças colestáticas. A proposta do trabalho foi estudar, em modelo experimental de obstrução biliar, as alterações histológicas hepáticas em ratos jovens e compará-las com o animal adulto. Avaliou-se a semiquantificação da proliferação ductular e inflamação pelo HE; quantificação da fibrose portal e periportal pelo picrosírius; semiquantificação da expressão de desmina e a-actina de músculo liso pelas células estreladas e miofibroblastos. Apesar das respostas de proliferação ductular e inflamação mais lentas no rato jovem, a fibrose e a expressão de desmina foram mais intensas neste grupoBiliary atresia is an hepatic disease of infancy. Etiology is unknown, and diagnosis is made by liver biopsy, with ductular proliferation being the main histological feature. Bile duct ligation in rats is an useful experimental model of biliary obstruction. The aim of this study of extra-hepatic cholestasis was analyse hepatic histological alterations in young rats compared to adult animals. The responses were studied by semiquantification of ductular proliferation and inflammatory infiltrated by HE stain; quantification of portal and periportal fibrosis with the sirius-red stain; semiquantification of the expression of desmin and a-smooth muscle actin by the hepatic stellated cells and myofibroblasts. In young animals, despite the very slow response of ductular proliferation and inflammation observed with HE, there were significantly more fibrosis and expression of desmin than in adult group
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Murata, Toru. "Inhibitory effect of Y-27632,a ROCK inhibitor,on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells." Kyoto University, 2002. http://hdl.handle.net/2433/149343.
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CARMO, Rodrigo Feliciano do. "Avaliação de polimorfismos de único nucleotídeo (SNPs) envolvidos com a gravidade da doença hepática crônica causada pelo vírus da hepatite C (HCV)." Universidade Federal Rural de Pernambuco, 2016. http://www.tede2.ufrpe.br:8080/tede2/handle/tede2/4863.
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Submitted by Mario BC (mario@bc.ufrpe.br) on 2016-06-28T12:52:01Z
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Rodrigo Feliciano do Carmo.pdf: 3731491 bytes, checksum: 86d8eb6b218e10bf0ba32ef83c2d9050 (MD5)Made available in DSpace on 2016-06-28T12:52:01Z (GMT). No. of bitstreams: 1 Rodrigo Feliciano do Carmo.pdf: 3731491 bytes, checksum: 86d8eb6b218e10bf0ba32ef83c2d9050 (MD5) Previous issue date: 2016-05-23
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
The hepatitis C virus (HCV) represents a worldwide health problem, with over 170 million people infected all over the world, corresponding to almost 3% of the world’s population. Approximately 70% of the individuals will develop the chronic form of the disease; 25% will develop cirrhosis and about 5% among the cirrhotic will develop hepatocellular carcinoma (HCC). The reason why some individuals evolve more rapidly to the severe forms is still unknown, however, several studies have pointed the influence of genetic factors of the host which are involved with the disease progression in the liver. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in humans, and they might alter serum levels or even the function of important proteins. Pentraxin 3 (PTX3) is an acute phase protein that is able to bind the surface of microorganisms and to regulate the complement system. Studies have demonstrated that PTX3 may influence positively the progression of various types of cancer. Additionally, some studies have demonstrated an important influence of a chromosomic region (6q23), associated with the progression of liver fibrosis in schistosomiasis. The IL22RA2 gene is located in this region e may be associated with the severity of fibrosis in HCV, once this gene codifies an inhibitor of an important cytokine correlated with the repair of liver damage, the interleukin-22 (IL-22). Thus, the aim of the present study was to associate the severity of the liver disease caused by HCV with SNPs in the PTX3 and IL22RA2 genes, as well as to identify new SNPs through exome sequencing approach. Patients with chronic hepatitis C were recruited and attended at the service of Gastrohepatology of the Oswaldo Cruz University Hospital/Liver Institute of Pernambuco (Recife, Pernambuco, Brazil) between August 2010 and December 2014. The detection of SNPs was performed by real time PCR using TaqMan probes (Thermo Fisher Scientific). Regarding the exome sequencing, it was used the IonTorrent platform (Thermo Fisher Scientific). A total of three studies were performed, the first study identified two polymorphisms (rs6570136 and rs2064501) on the IL22RA2 gene, associated with the severity of hepatic fibrosis, in a total of 532 patients. It was observed a higher frequency of genotypes GG/GA of rs6570136 and TT/TC of rs2064501 in the group of individuals with severe fibrosis (p=0,007 OR 1,7 and p=0,004 OR 2,4). On the second study, with a total of 524 patients, it was possible to notice a significant association of the genotype AA in the PTX3 gene (rs2305619) with risk of HCC (p=0.024 OR 1,94). Finally, the exome sequencing was carried in 9 HCC cases and 10 cirrhotic controls, where it was possible to identify two genes (PRSS58 and SOCS5), which are possibly associated with the development of HCC. Therefore, through this study we have demonstrated, for the first time, the association of SNPs in IL22RA2, PTX3, PRSS58 and SOCS5 with the progression of the hepatic disease caused by HCV. Other studies are needed in order to evaluate the use of these SNPs as progression markers of hepatitis C; as well as to evaluate the possible use of these molecules as therapeutic targets.
O vírus da hepatite C (HCV) representa um problema de saúde mundial, acometendo mais de 170 milhões de pessoas em todo o mundo, o que corresponde a cerca de 3% da população mundial. Aproximadamente 70% dos indivíduos irão desenvolver a forma crônica da doença, 25% desenvolverão cirrose e cerca de 5% dos cirróticos desenvolverão carcinoma hepatocelular (HCC). O motivo pelo qual alguns indivíduos evoluem mais rapidamente para formas mais graves ainda é desconhecido, entretanto diversos estudos têm apontado a influência de fatores genéticos do hospedeiro envolvidos com a progressão da doença no fígado. Polimorfismos de único nucleotídeo (SNPs) são o tipo de variação genética mais comum em humanos, e podem influenciar os níveis séricos ou até mesmo a função de proteínas importantes. A pentraxina 3 (PTX3) é uma proteína de fase aguda capaz de se ligar a microrganismos e de regular o sistema complemento. Estudos têm demonstrado que a PTX3 pode influenciar positivamente a progressão de vários tipos de câncer. Além disso, alguns estudos têm demonstrado uma grande influência de uma região cromossômica (6q23) associada com a progressão da fibrose hepática na esquistossomose. O gene IL22RA2 está localizado nesta região e poderia estar associado com a gravidade da fibrose no HCV, uma vez que este gene codifica um inibidor de uma importante citocina envolvida com a reparação de danos hepáticos, a interleucina-22 (IL-22). Portanto, o objetivo do presente trabalho foi associar a gravidade da doença hepática causada pelo HCV, com SNPs nos genes PTX3 e IL22RA2, assim como identificar novos SNPs através da técnica de sequenciamento de exoma. Foram recrutados pacientes com hepatite C crônica, atendidos no serviço de Gastrohepatologia do Hospital Universitário Oswaldo Cruz/Instituto do Fígado de Pernambuco (Recife-PE, Brasil) entre agosto de 2010 e dezembro de 2014. A detecção dos SNPs foi realizada por PCR em tempo real através de sondas TaqMan®. Para o sequenciamento do exoma, foi utilizada a plataforma IonTorrent®. Um total de três estudos foram realizados, o primeiro estudo identificou dois polimorfismos (rs6570136 e rs2064501) no gene IL22RA2, associados com a gravidade da fibrose hepática, em um total de 532 pacientes. Foi observada uma maior frequência dos genótipos GG/GA do rs6570136 e TT/TC do rs2064501 no grupo de indivíduos com fibrose grave (p=0,007 OR 1,7 e p=0,004 OR 2,4). No segundo estudo, com um total de 524 pacientes, foi possível observar uma associação significativa do genótipo AA no gene PTX3 (rs2305619) com o risco de HCC (p=0.024 OR 1,94). Por fim, foi realizado o sequenciamento do exoma de 9 casos com HCC e 10 controles cirróticos, onde foi possível identificar dois genes (PRSS58 e SOCS5) possivelmente associados com o desenvolvimento de HCC. Portanto, através do presente estudo, foi demonstrado pela primeira vez a associação de SNPs no IL22RA2, PTX3, PRSS58 e SOCS5 com a progressão da doença hepática causada pelo HCV. Outros estudos são necessários para avaliar o uso desses SNPs como marcadores de progressão da hepatite C, bem como avaliar o possível uso dessas moléculas como alvos terapêuticos.
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Hammerich, Linda [Verfasser]. "Chemokine receptor CCR6-dependent accumulation of IL-17 producing gamma/delta T cells in injured liver restricts hepatic inflammation and fibrosis / Linda Hammerich." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2013. http://d-nb.info/1038603005/34.
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Yamamoto, Gen. "Pancreatic Stellate Cells Have Distinct Characteristics from Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-Producing Cells in the Pancreas." Kyoto University, 2018. http://hdl.handle.net/2433/230997.
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Santos, Elisângela Trindade. "Schistosoma mansoni: avaliação da fibrose hepática em camundongos submetidos à quimioterapia e reinfectados." reponame:Repositório Institucional da FIOCRUZ, 2011. https://www.arca.fiocruz.br/handle/icict/5833.
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Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil
A esquistossomose mansônica é uma doença parasitária tropical. Causadas por helmintos do gênero Schistosoma. Com a intenção de conter a doença, diversos institutos e organizações vêm desenvolvendo medidas de controle para tratar indivíduos infectados e evitar a ocorrência de novas infecções. Estratégias de administração de medicamentos em massa são eficazes na cura da doença, entretanto o tratamento com drogas anti-helmínticas não previnem a possibilidade da ocorrência de reinfecções. Diante desta questão, neste trabalho propusemo-nos a analisar a cinética da fibrose hepática em camundongos esquistossomóticos tratados e submetidos à reinfecção. Para alcançar este objetivo, 70 camundongos Swiss foram infectados com 50 cercárias de S.mansoni, posteriormente tratados com Oxamniquine ou Praziquantel e reinfectados quatro meses após tratamento. Os fígados destes animais foram submetidos a técnicas de imunohistoquímica e imunofluorescência e microscopia eletrônica de transmissão para avaliação da expressão e participação de componentes envolvidos no processo fibrogênico. Para verificar os índices de colágeno entre os grupos utilizou-se a análise morfométrica. A análise histológica revelou que camundongos esquistossomóticos submetidos à quimioterapia específica desenvolveram altos índices de fibrose durante a reinfecção. A imunomarcação para alfa actina de músculo liso (α-SMA) revelou que grande parte do parênquima hepático dos animais tratados e reinfectados exibiam células com perfil miofibloblástico. A imunofluorescência demonstrou que o padrão de marcação para laminina estava alterado em animais com esquistossomose. A análise morfométrica revelou que reinfecção destes animais ocasionou uma intensa deposição de fibras colágenas no parênquima hepático. Os dados obtidos demonstraram que a reinfecção em animais previamente tratados, foi capaz de induzir uma resposta fibrótica semelhante a encontrada nos animais com infecção primária.
Schistosomiasismansoni is a tropical parasitic disease. Caused by helminths of the genus Schistosoma. In an attempt to contain the disease, various institutes and organizations are developing control measures to treat infected individuals and prevent new infections. Strategies of mass drug administration are effective in curing the disease, whereas treatment with anthelmintic drugs do not prevent the possibility of the occurrence of reinfection. Faced with this question, in this work we decided to analyze the kinetics of hepatic fibrosis in schistosomiasis treated mice and subjected to reinfection. To achieve this goal, 70 Swiss mice were infected with 50 cercariaeS.mansoni subsequently treated with oxamniquine or praziquantel and reinfected four months after treatment. The livers of these animals were subjected to immunohistochemistry and immunofluorescence techniques and transmission electron microscopy to evaluate the expression and participation of constituents involved in the fibrogenic process. To check the rates of collagen between the groups used the morphometric analysis. Histological analysis revealed that mice submitted to specific chemotherapy schistosomiasis developed fibrosis during high rates of reinfection. Immunostaining for alpha smooth muscle actin (α-SMA) revealed that much of the liver parenchyma of animals treated and reinfected cells exhibited myofibloblastic profile. Immunofluorescence showed that the labeling pattern for laminin was abnormal in animals with schistosomiasis. Morphometric analysis revealed that reinfection of animals caused an intense collagen deposition in the liver parenchyma. The data obtained showed that reinfection in animals previously treated, was able to induce a fibrotic response similar to that found in animals with primary infection
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Lei, Lin. "Identification of portal mesenchymal stem cells and derived myofibroblasts in liver fibrosis." Thesis, Sorbonne université, 2020. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2020SORUS099.pdf.
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Les travaux antérieurs ont montré que les myofibroblastes portaux (PMFs) contribuaient de manière significative à la fibrogenèse et à l'angiogénèse dans la fibrose hépatique. L'objectif principal de cette thèse était de cartographier les cellules mésenchymateuses portales, et plus particulièrement la niche des cellules souches mésenchymateuses portales. Nous avons caractérisé la variété des cellules mésenchymateuses portales du foie de souris. Résultat important, nous avons identifié une population de cellules mésenchymateuses portales ayant les caractéristiques de cellules souches mésenchymateuses, désignées cellules souches mésenchymateuses portales (PMSCs), qui ont la capacité de se transformer en PMFs in vitro. Nous avons identifié Slit2 comme un marqueur des PMSCs par scRNA-seq et bulk RNA-seq. In vivo, nous avons mis en évidence l'expansion de PMSCs dans le foie de modèles murins de fibrose hépatique et de patients ayant une maladie chronique du foie. Nous avons identifié des signatures transcriptomiques spécifiques des PMSCs d’une part et des cellules étoilées du foie (CEF), de l’autre. Les résultats obtenus par l’utilisation de ces marqueurs, renforcent nos conclusions selon lesquelles les PMSCs s’accumulent de façon corrélée avec la fibrogenèse et l'angiogenèse, tandis que la signature des CEFs ne varie pas. En conclusion, nos travaux apportent des éléments à la connaissance des populations de cellules mésenchymateuses portales du foie. Ils ont permis d’identifier et caractériser les PMSCs ainsi que les myofibroblastes qui en dérivent, ouvrant de nouvelles perspectives dans le domaine des thérapies ciblées et des biomarqueurs pour la pratique cliniquePrevious work has demonstrated that portal myofibroblasts (PMFs) significantly contributed to liver fibrogenesis and modulated angiogenesis in liver fibrosis. The main aim of this thesis was to elucidate the landscape of portal mesenchymal cells, with a particular focus on a portal mesenchymal stem cell niche. We characterized the murine normal liver portal mesenchymal cell landscape. Importantly, we revealed a portal mesenchymal cell population with the features of mesenchymal stem cells (MSCs), designated portal mesenchymal stem cells (PMSCs) that possessed the ability to give rise to PMFs in vitro. Furthermore, we identified Slit2 as a new marker of PMSCs based on scRNA-seq and bulk RNA-seq analysis. In vivo, we observed PMSC expansion (measured by the expression of Slit2) in liver from both animal fibrosis models (DDC and CDAA) and patients with chronic liver disease (NASH, PSC and other liver disease). Notably, we defined the specific gene signatures for PMSCs and hepatic stellate cells (HSCs), respectively. By using these markers, we provide further evidence indicating that PMSCs expand in correlation with fibrogenesis and angiogenesis in different murine and human liver diseases, whereas the HSCs gene signatures did not vary. In conclusion, our work collectively offers insights into the components and functions of the mammalian liver portal mesenchymal cell populations, and in particular, identify and characterize PMSCs and their derived myofibroblasts, opening up the possibility for the development of novel targeted drugs or biomarkers of clinical significance with increased precision
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Pereira, Marcio Aparecido. "Tratamento com células derivadas do fígado embrionário retarda a progressão da fibrose hepática em ratos." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-21032017-154002/.
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As células derivadas de fígado embrionário tanto de animais quanto de humanos tem sido cada vez mais estudas devido ao seu potencial antiinflamatório, imunomodulador e regenerativo, demonstrado as mesmas bipotencial de diferenciação em hepatócitos e colangiocitos. Na presente pesquisa utilizou-se células derivadas de fígados embrionários de ratos com 14,5 dias de gestação. As células apresentaram marcadores de células progenitoras hepáticas, bem como marcadores de células hepáticas e biliares diferenciadas confirmando, seu bipotencial. A terapia celular utilizando as células supracitadas, reduziu significativamente a progressão da fibrose hepática, diminuindo a inflamação e ainda estimulando a regeneração hepática de ratos submetidos à cirrose por ligadura do ducto biliar. As análises realizadas mediante avaliação quantitativa pela técnica de morfometria, demonstraram redução da deposição de fibras de colágeno, bem como menor proliferação de ductos biliares nos animais tratados. Os resultados foram ainda complementados por analise semiquantitativa, a qual avaliou a intensidade da necroinflamação dos tecidos hepáticos analisados, apontando menor escore de inflamação dos animais tratados. As células poderão ter efeito benéfico para o tratamento de doenças hepáticas crônicas, que estimulam a formação de fibrose. A cirrose é o estágio final comum à doenças hepáticas crônicas por causadas por fatores de diversas etiologias. Esta ocupa a decima quarta causa mundial de mortalidade em humanos, sendo que o único tratamento definitivo atualmente é transplante do órgão. Entretanto o número de transplantes está longe de suprir a demanda atual, visto que há um déficit de doadores do órgão. Terapias que possam oferecer uma alternativa de tratamento confiável, segura e acessível são bastante oportunas. Nossos resultados sugerem que as células utilizadas neste trabalho podem modular a fibrogênese, e consequentemente retardar o estabelecimento da cirrose em doenças hepáticas crônicas.Studies on human and animal embryonic liver stem cells have been growing due to its anti-inflammatory, immunomodulatory and regenerative potential. These cells show also a bipotential do differentiate into hepatocytes and cholangiocytes. In the present study, it was used rodent embryonic liver with 14.5 of gestation. The cells presented hepatic progenitor, as well adult hepatic and biliary cells markers, confirming their bipotential. Previous studies with these cells in therapy decreased hepatic fibrosis progression in rat models submitted to cirrhosis by biliary duct ligation. Quantitative analysis was performed by morphometry showed decreased collagen fibers deposition and lower proliferation of biliary ducts in treated animals. Results were complemented with semiquantitative analysis with evaluation of necroinflammation of the analyzed hepatic tissues, in which a decreased inflammation score was observed. Cirrhosis is a common final stage for chronic hepatic diseases caused by different factors in several etiologies. It occupies the 14th world cause of mortality in human. However, the number of liver transplants is insufficient for current demand, caused by deficit in organs donors. Therapies that could offer an alternative for a reliable, safe and accessible treatment is opportune. Our results suggest that cells used in this study can modulate fibrogenesis and consequently delay the establishment of cirrhosis in chronic liver diseases.
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Fernandes, Flávia Ferreira. "ELF (Enhanced Liver Fibrosis) como marcador não invasivo de fibrose hepáticana hepatite C crônica." Universidade do Estado do Rio de Janeiro, 2014. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=8773.
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A fibrose hepática é o aspecto mais relevante e o mais importante determinante de morbimortalidade na hepatite C crônica (HCC). Historicamente, a biópsia hepática é o método de referência para avaliação da fibrose causada pela HCC, apesar de apresentar limitações. O estudo de marcadores não invasivos, que possam obviar a necessidade da biópsia, é uma área de constante interesse na hepatologia. Idealmente, a avaliação da fibrose hepática deveria ser acurada, simples, prontamente disponível, de baixo custo e informar sobre o prognóstico da patologia. Os marcadores não invasivos mais estudados são a elastografia hepática transitória (EHT) e os laboratoriais. A EHT já foi extensamente validada na HCC e está inserida na rotina de avaliação destes pacientes. Dentre os laboratoriais, existem diversos testes em continua experimentação e, até o momento, nenhum foi integrado à prática clínica no Brasil, embora já aplicados rotineiramente em outros países. O Enhanced Liver Fibrosis (ELF), um teste que dosa no soro ácido hialurônico, pró-peptídeo amino-terminal do colágeno tipo III e inibidor tissular da metaloproteinase 1, tem se mostrado bastante eficaz na detecção de fibrose hepática significativa e de cirrose na HCC. Neste estudo o ELF teve o seu desempenho avaliado em relação a biópsia hepática e demonstrou apresentar boa acurácia na detecção tanto de fibrose significativa quanto de cirrose. Na comparação com a EHT apresentou acurácia semelhante para estes mesmos desfechos, com significância estatística. No entanto, foi observada uma superestimação da fibrose com a utilização dos pontos de corte propostos pelo fabricante. Este achado está em acordo com a literatura, onde não há consenso sobre o melhor ponto de corte a ser empregado na prática clínica. Com a ampliação da casuística foi possível propor novos pontos de corte, através da análise clássica, com a biópsia hepática como padrão ouro. O resultado obtido vai ao encontro do observado por outros autores. Em seguida, os novos pontos de corte do ELF foram reavaliados sem que a biópsia hepática fosse a referência, através da análise de classes latentes. Mais uma vez o ELF apresentou bom desempenho, inclusive com melhora de suas sensibilidade e especificidade em comparação com a análise clássica, onde a biópsia hepática é a referência. Assim sendo, é possível concluir que o ELF é um bom marcador não invasivo de fibrose hepática. No entanto, para detecção de fibrose significativa e cirrose, deve ser considerada a aplicação na prática clínica dos novos pontos de corte aqui propostos.Liver fibrosis is the most relevant issue concerning chronic hepatitis C (CHC) and determines its prognosis. Historically, liver biopsy has been the reference method for evaluating fibrosis related to CHC, though it presents many drawbacks. There is a continuing interest in the development of non invasive markers capable of replacing liver biopsy. The ideal surrogate for fibrosis evaluation should be accurate, simple, low cost and yield prognostic information. So far, the most well known non invasive methods are transient hepatic elastography (TE) and laboratory panels. TE has already been extensively validated and is integrated in patients routine. There is plenty of laboratory panels in continuing evaluation and some are already integrated in daily practice abroad. In Brasil, until the present moment, it is not a reality. Enhanced Liver Fibrosis (ELF) panel comprises the serum concentration of hyaluronic acid, tissue inhibitor of matrix metalloproteinases-1, and aminoterminal propeptide of type III procollagen and has demonstrated good performance in detecting significant fibrosis and cirrhosis in CHC patients. In the present study ELF had its performance evaluated against liver biopsy and obtained satisfactory accuracy in detecting significant fibrosis and cirrhosis. In comparison to TE no statistically significant diference was observed, for the same endpoints mentioned before. However, the application of manufacturers cutoff points produced overestimation of fibrosis stages. These findings are in accordance with other authors results, in that there is no consensus so far on the most adequate cutoff points for main clinical end points. Enlarging the data permited calculating new cutoff points, through the classical statistical approach, using liver biopsy as the gold standard. The results once more matched those published in literature. Following this, the ELF new cutoff points were evaluated in a statistical modeling where there are no gold standards, the latent classes analysis. Besides showing a satisfactory performance, in this new approach, ELF experimented an improvement in sensitivity and specificity, if compared with the classical analisys, with liver biopsy as reference. ELF panel has a good performance as a noninvasive fibrosis marker. However, new cutoff points need to be applied to improve its performance for the discrimination of different stages of fibrosis in CHC patients.
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He, Hongbin. "Studies on the genetic control of infection and hepatic disease in schistosoma haematobium and schistosoma japonicum infections in human." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20720.
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La bilharziose reste un problème de santé majeur. L'équipe du Pr Dessein a montré que les infections élevées étaient déterminées par un locus majeur en 5q31 et que des polymorphismes dans un gène à ce locus,IL13, aggravent l'infection. Notre premier objectif était d'évaluer si des variants d'autres gènes de la voie de l'IL13 intervenaient dans le contrôle de l'infection. Nous avons observé une association entre le SNP rs324013, dans le promoteur de STAT6,et les niveaux d'infection à S. haematobium. Ce polymorphisme a un effet additif avec le polymorphisme IL13rs1800925. Ce SN modifie la fixation de facteurs nucléaires au niveau du promoteur de STAT6. L'équipe du Pr Dessein avait également montré que les fibres hépatiques avancées et sévères étaient déterminées par un autre locus majeur localisé en 6q23. Notre deuxième objectif fut d'évaluer dans le laboratoire du Pr Dessein et en étroite collaboration avec le laboratoire du Pr Li(Yueyang Institute of Parasitic disease)deux gènes candidats(IFNGR1 et CTGF) situés dans cette région chromosomique. Nous avons observé une association entre les deux polyporphismes(rs17066192 er rs673156)localisés dans le promoteur du gène. Nous avons observé une association entre les deux polymorphismes(rs17066192 et rs673156)localisés dans le promoteur du gène IFNGR1 et la fibrose hépatique: le génotype rs673156A/A et rs17066192C/C sont associés à un risque 7.3 fois et 1.5 fois plus élevé, respectivement, de fibrose avancée. Nous avons également montré que les variants rs9402373 et rs12526196 du gène CTGF sont indépendamment associés à la fibrose chez les fermiers et pêcheurs chinois infectés par S.japonicum. Sur la population chinoise d'étude, les risques relatifs associés aux polymorphismes rs9402373 et rs12526196 sont de 2.8 et 3Schistosomiasis remains one of the world’s most prevalent diseases. It comprises a group of chronic diseases caused by helminths of the Schistosoma genus. Schistosoma haematobium causes obstructive nephropathy that can be aggravated by urinary bacterial infections. S.japonicum and S.mansoni cause hepatic fibrosis associated with portal blood hypertension, which can be lethal. In previous studies, our laboratory had shown that worm burden in S.haematobium infections were aggravated by IL13 variants and that severe hepatic fibrosis (HF) was controlled by gene(s) located on 6q23. The present study is to further evaluate other IL-13 pathway genes (STAT6) in the control of infection in Malian farmers and to test candidate genes in the 6q23 region in hepatic fibrosis (HF) in S.japonicum infected Chinese fishermen and farmers. First we have developped an improved FTA® technology technique to perform SNP genotyping. This technique allows us to use saliva samples for genotyping SNPs. Subsequently, this improved FTA® technology was used in our study on HF.Our work on a Malian sample infected with S. haematobium indicated that a polymorphism (rs324013) in the promoter of STAT6 gene was associated with the control of S. haematobium infection levels and has an additive effect with IL13rs1800925, a polymorphism previously associated with infection in this same population. Both SNPs modify the binding of nuclear factors to the promoter regions of their respective genes. Thus, both SNPs may play a crucial role in controlling S. haematobium infection levels. In order to study HF in S.japonicum infections, we have participated actively in the study that recruited of a large sample of Chinese fishermen and farmers who had been exposed to the infection for most of their life. HF was evaluated by ultrasound and covariates that could affect HF were evaluated by interviews. Then, we tested two genes (IFNGR1, CTGF) of the 6q23 region that were good candidates for the control of HF on these samples. Both genes encode molecules that were shown in animal and human studies to have strong effect on extracellular matrix proteins deposition and turnover. We found that two polymorphisms (rs17066192 and rs673156) in IFNGR1 promoter were associated with HF: the rs673156A/A genotype was associated with a 7.3-fold increased risk of advanced HF; and rs17066192C/C genotype with a 1.5-fold increased risk of HF. These results must now be confirmed in another population sample. We also found that variants of CTGF rs9402373 and rs12526196 were independently associated with HF in Chinese fishermen and farmers, in Sudanese, and in Brazilians infected with either S. japonicum or S. mansoni. Our results provide additional evidence for a protective role of IL-13 in schistosome infections, and they also demonstrate that TGFβ / CTGF pathway plays a key role in HF and should be targeted by chemotherapy. Ongoing studies evaluate whether CTGF variants could be used in the prognosis of the HF caused by schistosomes and also by other infectious agents
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Schaffner, Denise [Verfasser], and Irmgard [Akademischer Betreuer] Merfort. "Investigations of hepatic hemodynamics and alterations in the NO-cGMP pathway in an animal model of liver fibrosis / cirrhosis suggest PDE5 inhibitors as promising adjunct in portal hypertension therapy." Freiburg : Universität, 2018. http://d-nb.info/1189583216/34.
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Figueiredo, Sergio Souza. "Inter-relações entre o Antígeno Leucocitário Humano-G, o pseudorreceptor inibidor de proteína morfogênica de osso e ativina ligado à membrana, e os processos inflamatórios/fibrogênicos hepáticos na hepatite autoimune." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17143/tde-26042018-113541/.
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A Hepatite Autoimune (HAI) é uma doença inflamatória crônica oriunda de autoimunidade, ocasionando fibrose hepática. O objetivo desse estudo foi verificar possíveis inter-relações entre HLA-G, BAMBI e processos inflamatórios/fibrogênicos hepáticos na Hepatite Autoimune, tanto em biópsias de pacientes pré quanto póstratamento com imunossupressores. Foram selecionadas noventa e cinco biópsias de pacientes do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto diagnosticados com HAI, associados ou não a depósitos de ferro no fígado. As biópsias foram submetidas à imuno-histoquímica para marcação das proteínas HLAG e BAMBI. As estatísticas foram determinadas pelos testes Mann-Whitney e correlação de Spearman. A expressão de HLA-G e de BAMBI se apresentou aumentados conforme o agravamento da inflamação e fibrose em pacientes pré- tratamento com boa ou má resposta ao tratamento. No entanto, a expressão de HLAG e de BAMBI foi reduzida nas biópsias pós-tratamento apenas nos pacientes bom respondedores (diminuição da fibrose). Não houve quaisquer relações entre as quantificações de HLA-G e BAMBI com o número de plasmócitos ou com depósitos de ferro no fígado tanto em pacientes pré quanto pós-tratamento. Os resultados sugerem que tanto HLA-G quanto BAMBI são imunorreguladores sensíveis à intensidade do processo inflamatório no fígado, tendo suas expressões aumentadas ou diminuídas de acordo com a demanda por substâncias que regulem compostos e células imunológicas na HAI. Sugerem também que o infiltrado plasmocitário não é regulado diretamente pelo HLA-G ou BAMBI, e que os depósitos de ferro no fígado não são capazes de influenciar nem o grau inflamatório, nem as expressões de HLAG e BAMBI.Autoimmune Hepatitis (HAI) is a chronic inflammatory disease originating from autoimmunity, causing liver fibrosis. The objective of this study was to verify possible interrelations between HLA-G, BAMBI and inflammatory / fibrogenic hepatic processes in Autoimmune Hepatitis, both in pre and post-treatment immunosuppressive biopsies. Ninety-five biopsies of patients from the Clinical Hospital of the Medical School of Ribeirão Preto diagnosed with HAI, associated or not with iron deposits in the liver, were selected. Biopsies were submitted to immunohistochemistry for the labeling of HLA-G and BAMBI proteins. The statistics were determined by the Mann-Whitney tests and Spearman\'s correlation. The expression of HLA-G and BAMBI was increased as worsening of inflammation and fibrosis in pre-treatment patients with good or poor response to treatment. However, the expression of HLA-G and BAMBI was reduced in post-treatment biopsies only in patients with good responders (decreased fibrosis). There were no relationships between the quantifications of HLA-G and BAMBI with the number of plasma cells or with liver iron deposits in both pre and post-treatment patients. The results suggest that both HLA-G and BAMBI are immunoregulators sensitive to the intensity of the inflammatory process in the liver, their expressions being increased or decreased according to the demand for substances that regulate immune cells and compounds in HAI. They also suggest that plasmacytic infiltrate is not directly regulated by HLA-G or BAMBI, and that the liver iron deposits are not capable of influencing either the inflammatory grade or the expressions of HLA-G and BAMBI.