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

Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl4)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl4-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl4 (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl4 treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl4 administration, and progressively thereafter during the development of cirrhosis. The acute CCl4-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7+/-1.8 to 17.6+/-3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62+/-8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6+/-2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.
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PMID:An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats. 954 66

Many different diseases and toxins can cause liver damage, which is difficult to treat and often leads to the development of liver fibrosis or even cirrhosis. The key event in this process is the activation of hepatic stellate cells (HSCs). During such activation, HSCs undergo a dramatic transformation in morphology and behavior, changing from a neuronal-like to a fibroblast-like morphology. After activation, HSCs increase their proliferation rate and extracellular matrix (ECM)production. Overproduction of ECM, which contains mainly collagen type I, is a direct cause of liver disruption. HSCs also produce substances which inhibit protease activities, such as TIMPs,which enhance ECM deposition in the liver. On the molecular level, HSCs are activated by cytokines,growth factors, and oxidative stress, which are abundant in afflicted liver. These factors induce intracellular signals transmitted by many kinases, the most important of which are JNK,ERK1/2, p38, TAK-1, PKC, FAK, and P3IK. Signals transmitted via these pathways change the activities of transcription factors such as Smad, AP-1, and NF-kB. This in turn causes changes in gene transcription and ultimately alters the whole cell's behavior and morphology. The cell begins the production collagen type I, TIMP-1, and alphaSMA. Activated HSCs can sustain their own activation by producing growth factors such as PDGF and TGF-beta. Despite the vast knowledge about the mechanisms causing liver fibrosis and cirrhosis, there is still no effective cure. Further studies are therefore needed to solve this problem.
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PMID:[Role of stellate cells in alcoholic liver fibrosis]. 1959 40