Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The causes and pathologic changes leading to fibrosis and cirrhosis after orthotopic liver transplantation (OLT) are not fully defined. The computerized pathology files were searched for cases of fibrosis/cirrhosis after OLT. Of 493 grafts from 435 patients, 35 grafts from 32 patients of posttransplantation liver fibrosis/cirrhosis were identified and retrieved (7%). Detailed histopathologic examinations of all post-OLT liver biopsy specimens were performed in conjunction with clinical, virologic, serologic, and molecular diagnostics information. Two cases with subcapsular septa and fibrous tissue close to hilum were excluded as false positives. Fibrosis/cirrhosis was confirmed in the remaining 33 grafts. In 20, the underlying cause was recurrent viral hepatitis, including eight with hepatitis C, 10 with hepatitis B, and two with combined hepatitis C and B. Another two with pretransplantation chronic hepatitis B developed cirrhosis without detectable virologic markers after OLT; these were biliary type secondary to obstruction in one, and chronic changes due to severe graft ischemia in one. Three patients acquired hepatitis C after OLT, with molecular confirmation available in two. In five patients, the underlying causes were Budd-Chiari syndrome and autoimmune hepatitis, recurrent autoimmune hepatitis, recurrent primary biliary cirrhosis, alcohol-induced liver disease, and recurrent bile duct carcinoma. Three cases had centrilobular fibrosis but without bridging septa or cirrhosis as a result of chronic rejection. It was concluded that (1) Cirrhosis after OLT is uncommon (7%). (2) Chronic rejection does not lead to cirrhosis, but it may result in centrilobular fibrosis. (3) In most (70%) cases, cirrhosis after OLT is attributed to recurrent or acquired viral hepatitis.
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PMID:Fibrosis/cirrhosis after orthotopic liver transplantation. 992 25

Hepatic fibrosis is a wound healing response, involving pathways of inflammation and fibrogenesis. In response to various insults, such as alcohol, ischemia, viral agents, and medications or hepatotoxins, hepatocyte damage will cause the release of cytokines and other soluble factors by Kupffer cells and other cell types in the liver. These factors lead to activation of hepatic stellate cells, which synthesize large amounts of extracellular matrix components. With chronic injury and fibrosis, liver architecture and metabolism are disrupted, eventually manifesting as cirrhosis and its complications. In addition to eliminating etiology, such as antiviral therapy and pharmacological intervention, it is encouraging that novel strategies are being developed to directly address hepatic injury and fibrosis at the subcellular and molecular levels. With improvement in understanding these mechanisms and pathways, key steps in injury, signaling, activation, and gene expression are being targeted by molecular modalities and other molecular or gene therapy approaches. This article intends to provide an update in terms of the current status of molecular therapy for hepatic injury and fibrosis and how far we are from clinical utilization of these new therapeutic modalities.
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PMID:Molecular therapy for hepatic injury and fibrosis: where are we? 1648 61

Liver fibrosis is produced by myofibroblasts of different origins. In culture models, rat myofibroblasts derived from hepatic stellate cells (HSCs) and from periductal portal mesenchymal cells, show distinct proliferative and immunophenotypic evolutive profiles, in particular regarding desmin microfilament (overexpressed vs shut-down, respectively). Here, we examined the contributions of both cell types, in two rat models of cholestatic injury, arterial liver ischemia and bile duct ligation (BDL). Serum and (immuno)histochemical hepatic analyses were performed at different time points (2 days, 1, 2 and 6 weeks) after injury induction. Cholestatic liver injury, as attested by serum biochemical tests, was moderate/resolutive in ischemia vs severe and sustained in BDL. Spatio-temporal and morphometric analyses of cytokeratin-19 and Sirius red stainings showed that in both models, fibrosis accumulated around reactive bile ductules, with a significant correlation between the progression rates of fibrosis and of the ductular reaction (both higher in BDL). After 6 weeks, fibrosis was stabilized and did not exceed F2 (METAVIR) in arterial ischemia, whereas micronodular cirrhosis (F4) was established in BDL. Immuno-analyses of alpha-smooth muscle actin and desmin expression profiles showed that intralobular HSCs underwent early phenotypic changes marked by desmin overexpression in both models and that the accumulation of fibrosis coincided with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures. With the exception of desmin-positive myofibroblasts located at the portal/septal-lobular interface at early stages, and of myofibroblastic HSCs detected together with fine lobular septa in BDL cirrhotic liver, the vast majority of myofibroblasts were desmin-negative. These findings suggest that both in resolutive and sustained cholestatic injury, fibrosis is produced by myofibroblasts that derive predominantly from portal/periportal mesenchymal cells. While HSCs massively undergo phenotypic changes marked by desmin overexpression, a minority fully converts into matrix-producing myofibroblasts, at sites, which however may be important in the healing process that circumscribes wounded hepatocytes.
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PMID:Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. 1726 5

A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride (CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute CCl4 intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by CCl4 with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by CCl4, suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by CCl4 in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro.
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PMID:Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats. 1776 35

Cannabinoid receptors (CB1 and CB2) and their endogenous ligands (endocannabinoids) have recently emerged as novel mediators of liver diseases. Endogenous activation of CB1 receptors promotes nonalcoholic fatty liver disease (NAFLD) and progression of liver fibrosis associated with chronic liver injury; in addition, CB1 receptors contribute to the pathogenesis of portal hypertension and cirrhotic cardiomyopathy. CB2 receptor-dependent effects are also increasingly characterized, including antifibrogenic effects and regulation of liver inflammation during ischemia-reperfusion and NAFLD. It is likely that the next few years will allow us to delineate whether molecules targeting CB1 and CB2 receptors are useful therapeutic agents for the treatment of chronic liver diseases.
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PMID:Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver. 1797 29

The liver is a unique organ with respect to its anatomical location, allowing continuous blood flow from the gastrointestinal tract through the sinusoids, and its cellular composition, comprising metabolically active hepatocytes, nonhepatocytic parenchymal cells, and various immune cell populations. Cytokines are key mediators within the complex interplay of intrahepatic immune cells and hepatocytes, as they can activate effector functions of immune cells, as well as hepatocytic intracellular signaling pathways controlling cellular homeostasis. Kupffer cells and liver-infiltrating monocyte-derived macrophages are primary sources of cytokines such as tumor-necrosis factor-alpha (TNF-alpha) and interleukin-6. The liver is also enriched in natural killer (NK) and NK T cells, which fulfill functions in pathogen defense, T cell recruitment, and modulation of liver injury. TNF-alpha can activate specific intracellular pathways in hepatocytes that influence cell fate in different manners, e.g., proapoptotic signals via the caspase cascade, but also survival pathways, namely the nuclear factor (NF)-kappaB pathway. NF-kappaB regulates important functions in liver physiology and pathology. Recent experiments with genetically modified mice demonstrated important and partly controversial functions of this pathway, e.g., in cytokine-mediated hepatocyte apoptosis or ischemia-reperfusion injury. The exact dissection of the contribution of recruited and resident immune cells, their soluble cytokine and chemokine mediators, and the intracellular hepatocytic response in liver homeostasis and injury could potentially identify novel targets for the treatment of acute and chronic liver disease, liver fibrosis, or cirrhosis.
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PMID:Inflammatory pathways in liver homeostasis and liver injury. 1860 Apr 81

Cholestasis is frequently encountered in the ICU and is associated with a poor outcome. Ischaemia should be considered among the numerous aetiologic factors that may trigger cholestasis in the ICU. Blood supply to biliary tract is mainly provided by the hepatic artery, throughout a peribiliary vascular plexus. Interruption of the hepatic artery blood supply leads to cholestasis with a concomitant proliferative biliary reaction. Bile duct proliferation persists, while bile flow restores and biologic cholestasis syndrome spontaneously resolves in several weeks. Liver fibrosis related to the activation of periportal mesenchymental cells is observed in the close vicinity of proliferative bile ducts. Ischaemic cholestasis can be ascribed, at least partly, to hypoxia-induced disorders in the expression of hepatocytes biliary salts membrane transporters.
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PMID:[Ischaemic cholestasis in intensive care unit]. 1876 Aug 91

The factors that influence the long-term histological outcome of transplanted liver allografts in children are not yet fully understood, and the role of surveillance biopsies in patients with normal graft function remains controversial. The aims of this study were to describe the long-term graft histology of pediatric liver transplant recipients surviving at least 3 years and to analyze factors correlating with long-term histological outcome. Histological slides of 63 long-term liver transplant recipients were assessed for inflammation and fibrosis. The histological findings were correlated with clinical, biochemical, serological, and radiological findings. A significant proportion of biopsies from these patients showed some type of histological abnormalities, with fibrosis being observed in 61 (97%) patients. Duration of transplantation of >6 years and > or =grade 2 inflammation were significantly associated with advanced fibrosis. We could not identify any correlation between > or =stage 3 fibrosis and donor age, cold and warm ischemia time, history of de novo autoimmune hepatitis, hepatic artery thrombosis, chronic rejection, or alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase values. In conclusion, liver fibrosis appears to be a common finding in long-term pediatric liver transplant survivors. The cause of this fibrosis is uncertain, and normal alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels do not exclude the presence of significant fibrosis.
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PMID:Graft histology characteristics in long-term survivors of pediatric liver transplantation. 1897 86

The complement system, an essential part of the innate immune system, defends the host against invading pathogens, prevents immune complex disease and aids the acquired immune response. Under normal conditions the host is protected from complement attack by an array of complement regulatory proteins. However, in certain contexts inappropriate complement activation can occur associating the C system with a variety of disease pathologies. This review focuses upon the role complement plays in a number of renal pathologies as well as the role of complement in three examples of extrarenal diseases: paroxysmal nocturnal hemoglobinuria, age-related macular degeneration and liver fibrosis. From the evidence discussed it is clear that mutations or polymorphisms in the complement regulators resulting in reduced levels or inefficient action dramatically enhance susceptibility to certain diseases and in particular render the kidney more vulnerable to complement attack. Additionally, deficiency in the complement components can predispose to disease through reduced clearance of apoptotic cells and subsequent generation of complement activating autoantibodies or enhanced formation of convertases resulting in heightened complement activation. As complement has devastating effects, in such disease contexts it has become a therapeutic target. Therapeutic intervention strategies discussed here focus upon the use of recombinant agents, the most promising of which are the anti-C5 antibody-derived reagents. These agents have proved effective in the treatment of paroxysmal nocturnal hemoglobinuria, nephritis and ischemia-reperfusion injuries and will no doubt, along with other reagents currently being developed, prove invaluable in the treatment of renal pathologies.
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PMID:Complement, roles in renal disease and modulation for therapy. 1900 May 36

Taurine effectively prevents ischemia-induced apoptosis in the cardiomyocytes and hypothalamic nuclei. The present study explores the influence of taurine on mitochondrial damage, oxidative stress and apoptosis in experimental liver fibrosis. Male albino Wistar rats were divided into six groups and maintained for a period of 60 days as follows: Group I, control; Group II, ethanol treatment [6 g/(kg/day)]; Group III, fibrosis induced by ethanol and iron (0.5% w/w); Group IV, ethanol + iron + taurine (2% w/v); Group V, ethanol + taurine treatment and Group VI, control + taurine treatment. Hepatocytes isolated from ethanol plus iron-treated rats showed decreased cell viability and redox ratio, increased reactive oxygen species formation, lipid peroxidation, DNA fragmentation, and formation of apoptotic bodies. Liver mitochondria showed increased susceptibility to swell, diminished activities of mitochondrial respiratory chain complexes and antioxidants. Taurine administration to fibrotic rats restored mitochondrial function, reduced reactive oxygen species formation, prevented DNA damage, and apoptosis. Thus taurine might contribute to the amelioration of the disease process.
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PMID:Mitochondrial damage, cytotoxicity and apoptosis in iron-potentiated alcoholic liver fibrosis: amelioration by taurine. 1938 77


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