Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hemolysis caused by ABO antibodies after ABO-compatible, nonidentical solid organ transplantation has been previously reported. The passenger B lymphocytes within the donor organ presumably generate an acute, primarily red cell-directed graft vs. host (GVH) response. Graft survival may also be compromised. GVH Rh antibodies have also been described, primarily in renal transplants. Only three cases, two only in abstract form, have been reported thus far describing GVH Rh antibodies in liver transplant patients, to which we add a fourth. A 62-year-old blood group A Rho(D)-positive woman with cirrhosis underwent orthotopic liver transplantation from a group A Rho(D)-negative, previously Rho(D)-sensitized donor and subsequently developed acute, self-limited hemolysis requiring four units of packed red cells. Anti-Rho(D) was identified in both serum and red cell eluate. An antibody detection test, identification, and assessment of the antibody reactivity score from the pretransplant donor specimen may identify patients at risk for hemolysis due to GVH Rh antibodies.
 ...
PMID:Graft versus host anti-Rho(D) following minor Rh-incompatible orthotopic liver transplantation. 821 65

Today's knowledge on the natural history of hepatitis C virus infection derives mainly from local outbreaks and still limited clinical trials. There is a general consensus now that chronic infection occurs in at least 80% of cases after acute disease. Chronic hepatitis C usually runs a mild course with little or no morbidity. In a 15-yr follow-up evaluation of a cohort of 152 women having been infected with HCV-contaminated Rho (D)-immunoglobulin none had developed chronic active hepatitis or cirrhosis. On the other hand, half of 80 patients who started out with more advanced forms of chronic hepatitis C developed cirrhosis over a mean period of 12 yr. Recent observations indicate that progression to severe chronic hepatitis may even occur in HCV-RNA positive individuals with normal aminotransferase activities in serum for long periods. Overall, chronic HCV infection is a slowly progressive disease which often needs histological evaluation, especially in patients with normal biochemical findings.
 ...
PMID:The natural history of hepatitis C: clinical experiences. 883 89

Portal thrombosis may complicate the clinical course of cirrhosis, but the pathophysiologic mechanism is unclear. Aim of the study was to evaluate the behavior of clotting system and endotoxemia in portal vein and in peripheral circulation of 11 cirrhotic patients undergoing transjugular port-systemic shunt (TIPS). Portal blood showed higher values of F1 + 2 [Median (range): 2.5 (1.1-5.3) vs. 1.1 (0.6-2.1) nM, p < 0.01], D-dimer [765 (184-1713) vs. 192 (64-813) ng/ml, p < 0.01] and endotoxemia [31 (16-47.2) vs. 13.7 (7.5-23.5) pg/ml, p < 0.01] than peripheral circulation. In the portal vein, all but one sample had F1 + 2 > 1.2 nM (upper limit of control values), all but one had D-dimer > 216 mg/dl (mean + 2 SD of controls) and 100% had values of endotoxemia > 9.6 pg/ml (upper limit of control values). Fibrinogen was lower in the portal circulation compared to peripheral circulation but the difference was not significant [85 (58-195) vs. 134 (75-244) mg/dl, p > 0.05]. Endotoxemia was directly correlated with F1 + 2 (Rho = 0.92 p < 0.006) and D-dimer (Rho = 0.93, p < 0.005). This study shows that an ongoing prothrombotic state is present in the portal circulation of cirrhotic patients and may play a pivotal role in the thrombotic episodes occurring in this clinical setting.
 ...
PMID:Ongoing prothrombotic state in the portal circulation of cirrhotic patients. 903 47

Clotting activation may occur in liver cirrhosis, but the pathophysiological mechanism has not been fully elucidated. Because a previous study demonstrated that lipid peroxidation is increased in cirrhosis, we analyzed whether there is a relationship between lipid peroxidation and clotting activation. Thirty cirrhotic patients (19 men and 11 women; age, 34 to 79 years) and 30 controls matched for sex and age were investigated. In all subjects, monocyte expression of tissue factor (TF) antigen and activity; plasma levels of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation; and urinary excretion of Isoprostane-F2alpha-III, a marker of lipid peroxidation, were measured. Furthermore, the above-reported variables were re-evaluated after 30 days of treatment with standard therapy (n = 5) or standard therapy plus 300 mg vitamin E twice daily (n = 9). In addition, we analyzed in vitro if vitamin E (50 micromol/L) influenced monocyte TF expression and F1+2 generation. Cirrhotic patients had higher values of Isoprostane-F2alpha-III (P <. 0001), F1+2 (P <.0001), and monocyte TF antigen (P <.0001) and activity (P <.03) than controls. Isoprostane-F2alpha-III was significantly correlated with F1+2 (Rho = 0.85; P <.0001) and TF antigen (Rho = 0.95; P <.0001) and activity (Rho = 0.94; P <.0001). After vitamin E treatment, Isoprostane-F2alpha-III (P =.008), F1+2 (P <.008), and monocyte TF antigen (P =.012) and activity (P =.008) significantly decreased; no changes of these variables were detected in patients not receiving vitamin E. In vitro, vitamin E significantly reduced the expression of monocyte TF antigen (-52%; P =.001) and activity (-55%; P =.003), as well as F1+2 generation (-51%; P =.025). This study shows that vitamin E reduces both lipid peroxidation and clotting activation and suggests that lipid peroxidation may be an important mediator of clotting activation in liver cirrhosis.
 ...
PMID:Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. 1021 89

By using a selective ROCK inhibitor Y-27632, the role of Rho-ROCK signaling in the function of hepatic stellate cells in culture was studied. Stellate cells maintained the "star-like" configuration of the quiescent stage in the presence of Y-27632, while the expression of smooth muscle alpha-actin and PDGF receptor beta was not affected by the agent. Serum-stimulated migration of the cells was significantly suppressed by Y-27632. The contraction of stellate cells induced by 5 nM endothelin-1 was attenuated by the agent in a dose-dependent manner. Formation of F-actin stress fibers and phosphorylation of myosin light chain was apparently reduced by Y-27632 even under the stimulation with endothelin-1. On the other hand, ex vivo liver perfusion experiment revealed that endothelin-1 (2 nM)-induced increase of portal vein constriction was almost completely inhibited by 20 microM Y-27632 with a concomitant improvement of hepatocyte degeneration. These results suggest that ROCK is one of the key regulators of stellate cell motility and that the clinical application of ROCK inhibitors such as Y-27632 should be considered in the reduction of portal hypertension in liver fibrosis and cirrhosis.
 ...
PMID:ROCK inhibitor Y-27632 attenuates stellate cell contraction and portal pressure increase induced by endothelin-1. 1060 Apr 96

Liver fibrosis and its end-stage disease cirrhosis are major world health problems arising from chronic injury of the liver by a variety of etiological factors including viruses, alcohol and drug abuse, the metabolic syndrome, autoimmune disease and hereditary disorders of metabolism. Fibrosis is a progressive pathological process in which wound-healing myofibroblasts of the liver respond to injury by promoting replacement of the normal hepatic tissue with a scar-like matrix composed of cross-linked collagen. Until recently it was believed that this process was irreversible. However emerging experimental and clinical evidence is starting to show that even cirrhosis is potentially reversible. Key to this is the discovery that reversion of fibrosis is accompanied by clearance of hepatic stellate cells (HSC) by apoptosis. Furthermore, proof-of-concept studies in rodents have demonstrated that experimental augmentation of HSC apoptosis will promote the resolution of fibrosis. Consequently there is now considerable interest in determining the molecular events that regulate HSC apoptosis and the discovery of drugs that will stimulate HSC apoptosis in a selective manner. This review will consider the regulatory role played by growth factors (e.g. NGF, IGF-1, TGFbeta), death receptor ligands (TRAIL, FAS), components and regulators of extracellular matrix (integrins, collagen, matrix metalloproteinases and their tissue inhibitors) and signal transduction proteins and transcription factors (Rho/Rho kinase, Jun N-terminal Kinase (JNK), IkappaKinase (IKK), NF-kappa B). The potential for known pharmacological agents such as gliotoxin, sulfasalazine, benzodiazepine ligands, curcumin and tanshinone I to induce HSC apoptosis and therefore to be used therapeutically will be explored.
 ...
PMID:The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. 1615 28

Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the alpha-smooth muscle actin (alpha-sma) promoter, because alpha-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl(4)) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis-as well as higher mortality-than CCl(4)-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.
 ...
PMID:Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. 1705 65

Hepatic stellate cells (HSCs) play an important role in hepatic fibrogenesis. In response to liver injury, HSCs undergo a process called activation, which involves 2 steps jonit nation from quiescent phenotype to myofibroblast-like phenotype, and perpetuation that maintains the activated phenotype of HSCs. The fate of the activated HSCs depends on the apoptotic and survival signals that they receive. The apoptosis of HSCs results from a series of complex and interrelated signaling events. Apoptotic signals for the activated HSCs include proteins from membrane receptors, such as death receptors, nerve growth factor receptor and peripheral-type benzodiazepine receptor, as well as proteins from cytoplasm such as Bcl-2 family members. The survival signals for the activated HSCs are induced by some kinases and cytokines including tissue inhibitors of metalloproteinase-1, Rho/Rho kinase, platelet-derived growth factor, transforming growth factor beta-1, and insulin-like growth factor-1. Approaches that specifically initiate HSC apoptosis are promising to be direct and effective strategies to treat liver fibrosis. Although it remains unclear whether the activated HSCs could be reversed back to the quiescent phenotype, the different expression and sensitivity of pro-apoptotic and survival molecules between quiescent and activated HSCs provide a prospect to develop therapeutic approaches that specifically targets apoptosis of the activated HSCs. These therapeutic strategies to induce HSC apoptosis are current research hotspot and the future for the patients with liver fibrosis and cirrhosis.
 ...
PMID:Apoptotic and survival signals in hepatic stellate cells. 1800 61

In liver cirrhosis, down-regulation of endothelial nitric oxide synthase (eNOS) has been implicated as a cause of increased intrahepatic resistance. We investigated whether Rho-kinase activation is one of the molecular mechanisms involved in defective eNOS signaling in secondary biliary cirrhosis. Liver cirrhosis was induced by bile duct ligation (BDL). We measured mean arterial pressure (MAP), portal venous pressure (PVP), and hepatic tissue blood flow (HTBF) during intravenous infusion of saline (control), 0.3, 1, or 2 mg/kg/hour fasudil for 60 minutes. In BDL rats, 1 and 2 mg/kg/hour fasudil significantly reduced PVP by 20% compared with controls but had no effect on HTBF. MAP was significantly reduced in response to 2 mg/kg/hour fasudil. In the livers of BDL rats, 1 and 2 mg/kg/hour fasudil significantly suppressed Rho-kinase activity and significantly increased eNOS phosphorylation, compared with controls. Fasudil significantly reduced the binding of serine/threonine Akt/PKB (Akt) to Rho-kinase and increased the binding of Akt to eNOS. These results show in secondary biliary cirrhosis that (1) Rho-kinase activation with resultant eNOS down-regulation is substantially involved in the pathogenesis of portal hypertension and (2) Rho-kinase might interact with Akt and subsequently inhibit the binding of Akt to eNOS.
 ...
PMID:Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis. 1816 63

Activation of hepatic stellate cells (HSCs) plays an important role in the development of cirrhosis through the increased production of collagen and the enhanced contractile response to vasoactive mediators such as endothelin-1 (ET-1). The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidneys, adrenals, and intestine. FXR is also expressed in HSCs and activation of FXR in HSCs is associated with significant decreases in collagen production. However, little is known about the roles of FXR in the regulation of contraction of HSCs. We report in this study that treatment of quiescent HSCs with GW4064, a synthetic FXR agonist, significantly inhibited the HSC transdifferentiation, which was associated with an inhibition of the upregulation of ET-1 expression. These GW4064-treated cells also showed reduced contractile response to ET-1 in comparison to HSCs without GW4064 treatment. We have further shown that GW4064 treatment inhibited the ET-1-mediated contraction in fully activated HSCs. To elucidate the potential mechanism we showed that GW4064 inhibited ET-1-mediated activation of Rho/ROCK pathway in activated HSCs. Our studies unveiled a new mechanism that might contribute to the anti-cirrhotic effects of FXR ligands.
 ...
PMID:Inhibition of endothelin-1-mediated contraction of hepatic stellate cells by FXR ligand. 2108 52


1 2 3 Next >>