RESUMO
Human relaxin-2 reduces hepatic fibrosis in mice. However, the effects of relaxin-2 on hepatic steatosis and fibrosis in animals with non-alcoholic fatty liver disease (NAFLD) remain to be elucidated. C57BL/6 mice fed a high-fat diet (HFD) or methionine-choline-deficient (MCD) diet were randomly assigned to receive recombinant human relaxin-2 (25 or 75 µg/kg/day) or vehicle for 4 weeks. In HFD-fed mice, relaxin-2 decreased systemic insulin resistance and reduced body weight, epididymal fat mass and serum leptin and insulin concentrations. In livers of HFD-fed mice, relaxin-2 attenuated steatosis and increased phosphorylation of insulin receptor substrate-1, Akt and endothelial nitric oxide synthase (eNOS), and activated genes that regulate fatty acid oxidation and suppressed acetyl-CoA carboxylase. Relaxin-2 had no direct anti-steatotic effect on primary mouse hepatocytes, but S-nitroso-N-acetylpenicillamine attenuated palmitic acid-induced steatosis and activated genes regulating fatty acid oxidation in hepatocytes. In mice fed an MCD diet, relaxin-2 attenuated steatosis, inflammation and fibrosis. Relaxin-2 increased eNOS and Akt phosphorylation and transcript levels of cytochrome P450-4a10 and decreased acetyl-CoA carboxylase in MCD-fed mouse livers. Moreover, expression levels of Kupffer cell activation, hepatic stellate cell activation and hepatocyte apoptosis were decreased in MCD diet-fed mice receiving relaxin-2. In conclusion, relaxin-2 reduces hepatic steatosis by activating intrahepatic eNOS in HFD-fed mice and further attenuates liver fibrosis in MCD diet-fed mice. Therefore, human relaxin-2 is a potential therapeutic treatment for NAFLD.
Assuntos
Cirrose Hepática/metabolismo , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Relaxina/farmacologia , Animais , Dieta Hiperlipídica , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Liver fibrosis can progress to cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the antifibrotic agents are limited. Thrombin activates hepatic stellate cells (HSCs). Therefore, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. METHODS: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 or 12 weeks to induce liver fibrosis. The injured rats were assigned an oral gavage of dabigatran etexilate (30 mg/kg/day) or vehicle in the last 4 weeks of TAA administration. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran etexilate or vehicle served as controls. RESULTS: In the 8-week TAA-injured rats, dabigatran ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering the transcript expression of thrombin receptor protease-activated receptor-1. In vitro, dabigatran inhibited thrombin-induced HSC activation. Furthermore, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAA-injured rats. Similarly, in the 12-week TAA-injured rats, a 4-week treatment with dabigatran reduced liver fibrosis and portal hypertension. CONCLUSIONS: By inhibiting thrombin action, dabigatran reduced liver fibrosis and intrahepatic angiogenesis. Dabigatran may be a promising therapeutic agent for treatment of liver fibrosis.
Assuntos
Antitrombinas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Dabigatrana/farmacologia , Cirrose Hepática Experimental/prevenção & controle , Fígado/efeitos dos fármacos , Tioacetamida , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/metabolismo , Citoproteção , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrina/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hipertensão Portal/induzido quimicamente , Hipertensão Portal/fisiopatologia , Hipertensão Portal/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Neovascularização Patológica , Fosforilação , Pressão na Veia Porta/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
BACKGROUND & AIMS: Intestinal hyperpermeability, impaired peritoneal macrophages (PMs) phagocytosis, and bacterial translocation (BT), resulting in increased systemic and local infection/inflammation such as spontaneous bacterial peritonitis (SBP) together with increased tumor necrosis factor-α (TNFα) levels, are all implicated in the pathogenesis of cirrhosis-related complications. Manipulation of the cannabinoid receptors (CB1R and CB2R), which are expressed on the gut mucosa and PMs, has been reported to modulate intestinal inflammation and systemic inflammatory cytokine release. Our study aims to explore the effects of chronic CB1R/CB2R agonist/antagonist treatments on relevant abnormalities in cirrhotic ascitic rats. METHODS: Vehicle, archidonyl-2-chloroethylamide (ACEA, CB1R agonist), JWH133 (CB2R agonist), and AM630 (CB2R antagonist) were given to thioacetamide (TAA) and common bile duct ligation (BDL) cirrhotic rats with ascites for two weeks and various measurement were performed. RESULTS: Compared to sham rats, CB2Rs were downregulated in cirrhotic rat intestines and PMs. The two-week JWH133 treatment significantly decreased systemic/intestinal oxidative stress, TNFα and inflammatory mediators, infection, intestinal mucosal damage and hyperpermeability; the JWH133 treatment also decreased bacterial overgrowth/adhesion, BT and SBP, upregulated intestinal tight junctions and downregulated the PM TNFα receptor/NFκBp65 protein expression in cirrhotic rats. Acute and chronic JWH133 treatment corrected the TNFα-induced suppression of phagocytosis of cirrhotic rat PMs, which then could be reversed by concomitant AM630 treatment. CONCLUSIONS: Our study suggests that CB2R agonists have the potential to treat BT and various relevant abnormalities through inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα release in cirrhosis. Overall, the chronic CB2R agonist treatment affects multiple approach mechanisms, and its direct effect on the hyperdynamic circulation is only minor.
Assuntos
Ascite/tratamento farmacológico , Translocação Bacteriana/efeitos dos fármacos , Canabinoides/administração & dosagem , Cirrose Hepática Experimental/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Animais , Ácidos Araquidônicos/administração & dosagem , Ascite/complicações , Ascite/microbiologia , Infecções Bacterianas/etiologia , Infecções Bacterianas/prevenção & controle , Citocinas/metabolismo , Células Hep G2 , Humanos , Indóis/administração & dosagem , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Circulação Hepática/efeitos dos fármacos , Cirrose Hepática Experimental/complicações , Cirrose Hepática Experimental/microbiologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Peritonite/etiologia , Peritonite/prevenção & controle , Fagocitose/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismoRESUMO
BACKGROUND AND AIM: Acute liver injury is manifested by different degree of hepatocyte necrosis and may recover via the process of hepatocyte regeneration once the injury is discontinued. Most of the liver injury is associating with inflammatory cytokines. Resveratrol (RSV) is a natural phytoalexin with powerful anti-inflammatory effects. AIM: The effects of RSV on cellular factors mediating liver damage and regeneration in acute carbon tetrachloride (CCl4 ) liver injury were investigated. RESULTS: RSV decreased alanine aminotransferase, aspartate aminotransferase, necrosis, and 4-hydroxynonenal in the CCl4 -injured liver. RSV decreased hepatocyte apoptosis by reducing caspase 8 and caspase 3 but not Bax and Bcl-xL. RSV reduced Kupffer cells recruitment, the expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-10. RSV lowered the numbers of anti-5-bromon-2'-deoxyuridine and anti-Ki67-positive hepatocytes. Hepatic hepatocyte growth factor, c-Met and transforming growth factor-α expressions were reduced by RSV, while transforming growth factor-ß1 and hepatic stellate cells activation were not changed. RSV reduced the injury-induced CXCL10 elevations in serum and liver in vivo. Besides, RSV inhibited CXCL10 release from CCl4 -injured hepatocytes in vitro. In contrast, recombinant CXCL10 improved the viability of CCl4 -injured hepatocytes. CONCLUSIONS: RSV therapy can be beneficial for acute toxic liver injury. RSV reduced hepatocyte apoptosis but limited hepatocyte regeneration possibly through reducing the hepatomitogenic signaling and the release of CXCL10.
Assuntos
Anti-Inflamatórios , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Quimiocina CXCL10/metabolismo , Hepatócitos/metabolismo , Regeneração Hepática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Fitoterapia , Estilbenos/farmacologia , Estilbenos/uso terapêutico , Alanina Transaminase/metabolismo , Aldeídos/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Tetracloreto de Carbono , Caspase 3/metabolismo , Caspase 8/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Mediadores da Inflamação/metabolismo , Fígado/patologia , Regeneração Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose/tratamento farmacológico , Resveratrol , Sesquiterpenos , FitoalexinasRESUMO
UNLABELLED: Leptin, the ob gene product, is a protein released from adipocytes and has been detected in fibrotic and cirrhotic livers. Leptin in brain has an inhibitory effect on food intake. Nonalcoholic steatohepatitis (NASH) is characterized by hyperleptinemia. This study explores the possible mechanisms of hyperleptinemia in relation to increased intrahepatic resistance (IHR) and portal hypertension in NASH cirrhotic rats. NASH cirrhotic rats with hyperleptinemia were induced in Zucker (fa/fa) and lean rats by feeding the animals a high fat/methionine-choline-deficient (HF/MCD) diet with and without exogenous administration of recombinant leptin. Portal venous pressure (PVP), IHR, plasma and hepatic levels of various substances, histopathology of the liver, the hepatic hydroxyproline content, and the expression of various hepatic protein and messenger RNA (mRNA) were measured. Hepatic microcirculatory dysfunction and the vasoconstrictive response to endothelin-1 were also observed using a liver perfusion system and intravital microscopy. Finally, the effect of leptin on hepatic stellate cells (HSCs) was evaluated. Both in HF/MCD-Zucker and HF/MCD+leptin lean rats, significant hepatic fibrogenesis and cirrhosis, marked portal hypertension, microcirculatory dysfunction, an enhanced vasoconstrictive response to endothelin-1, and an increased IHR were found to be associated with higher levels of hepatic endothelin-1 and endocannabinoids, expression levels of the cannabinoid type 1 receptor, endothelin-1 type A receptor (ET(A) R), activator protein-1, transforming growth factor beta (TGF-ß)(1), osteopontin, tumor necrosis factor alpha (TNF-α), leptin, and the leptin receptor (OBRb). Interestingly, acute incubation of leptin directly increases the expression of ET(A) R, OBRb and activator protein-1 in HSCs. CONCLUSION: An HF/MCD diet and hyperleptinemia increase hepatic endocannabinoids production, promote hepatic fibrogenesis, enhance the hepatic vasoconstrictive response to endothelin-1, and aggravate hepatic microcirculatory dysfunction; these events subsequently increase IHR and portal hypertension in NASH cirrhotic rats.
Assuntos
Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Endotelina-1/metabolismo , Fígado Gorduroso/fisiopatologia , Hipertensão Portal/fisiopatologia , Leptina/metabolismo , Fígado/metabolismo , Animais , Biópsia por Agulha , Peso Corporal , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Fígado Gorduroso/complicações , Células Estreladas do Fígado/metabolismo , Hipertensão Portal/complicações , Imuno-Histoquímica , Resistência à Insulina/fisiologia , Células de Kupffer/metabolismo , Microcirculação , Hepatopatia Gordurosa não Alcoólica , RNA Mensageiro/análise , Distribuição Aleatória , Ratos , Ratos Zucker , Estatísticas não ParamétricasRESUMO
BACKGROUND & AIMS: Gastric variceal obturation (GVO) therapy is the current treatment of choice for gastric variceal bleeding (GVB). However, the efficacy of non-selective ß-blockers (NSBB) in the secondary prevention of GVB is still debatable. This study aimed at evaluating the efficacy of additional NSBB to repeated GVO in the secondary prevention of GVB. METHODS: From April 2007 to March 2011, 95 patients with GVB after primary hemostasis using GVO were enrolled. Repeated GVO were performed until GV eradication. Forty-eight and 47 patients were randomized into the GVO alone group (Group A) and the GVO+NSBB group (Group B), respectively. Primary outcomes in terms of re-bleeding and overall survival were analyzed by multivariate analysis. RESULTS: After a mean follow-up of 18.10 months in group A, 26 patients bled and 20 died. In group B, 22 patients bled and 22 died after a mean follow-up of 20.29 months. The overall re-bleeding and survival rates analyzed by the Kaplan-Meier method were not different between the two groups (p=0.336 and 0.936, respectively). The model of end-stage liver disease (MELD) score and main portal vein thrombosis (MPT) were independent determinants of re-bleeding while MPT and re-bleeding were independent factors of mortality by time-dependent Cox-regression model. Asthenia was the most common adverse event and was higher in group B (p<0.001). CONCLUSIONS: Adding NSBB therapy to repeated GVO provides no benefit for the secondary prevention of bleeding and mortality in patients with GVB.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Endoscopia Gastrointestinal/métodos , Varizes Esofágicas e Gástricas/complicações , Hemorragia Gastrointestinal/prevenção & controle , Antagonistas Adrenérgicos beta/efeitos adversos , Idoso , Feminino , Seguimentos , Hemorragia Gastrointestinal/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Estudos Retrospectivos , Prevenção Secundária , Taxa de Sobrevida , Resultado do TratamentoRESUMO
During liver transplantation, nonalcoholic steatohepatitis (NASH) aggravates ischemia/reperfusion (IR) injury by activating various kinases and subsequently releasing cytokines and chemokines. Nonetheless, the effect of the multikinase inhibitor sorafenib on IR liver injury in rats with NASH has never been explored. Our study was designed to determine this effect and associated mechanisms in NASH rats. Sorafenib was acutely administered to NASH rats with IR liver injury that were or were not chronically pretreated with the Rho-kinase-specific inhibitor fasudil. Then, the following were evaluated: mean arterial pressure; hepatic blood flow and microcirculatory dysfunction; hepatic inflammation (serum alanine aminotransferase); necrosis; apoptosis; leukocyte infiltration; CD45 staining; caspase levels and DNA fragmentation; various serum and hepatic cytokines; and proteins and genes of the Raf/mitogen-activated protein-extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase, and apoptosis pathways. In NASH rats with IR liver injury, hepatic inflammation, necrosis, apoptosis, leukocyte infiltration, and microcirculatory dysfunction were significantly attenuated by the acute administration of sorafenib through the inhibition of the hepatic release of macrophage inflammatory protein 2, keratinocyte chemoattractant, granulocyte-monocyte colony-stimulating factor, and hepatic caspase-3 and caspase-9 as well as DNA fragmentation. Furthermore, there was decreased expression of p-Raf1 (where p indicates the phosphorylated form), p-MEK1/2, p-ERK1/2, p-Rho-kinase, B cell lymphoma 2-associated death promoter, and B cell lymphoma 2-associated X protein at the protein and messenger RNA levels. Notably, the aforementioned beneficial effects of sorafenib were significantly abolished by chronic pretreatment with the Rho-kinase-specific inhibitor fasudil. This study demonstrated that the multikinase inhibitor sorafenib protects NASH rats from IR injury by interfering with the inflammation, necrotic, and apoptotic responses causing leukocyte-dependent hepatic microcirculatory dysfunction. The hepatoprotective effects of sorafenib seem to work through the inhibition of the Rho-kinase-dependent Raf/MEK/ERK pathway, which is up-regulated during IR injury in the livers of NASH rats.
Assuntos
Fígado Gorduroso/terapia , Fígado/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Quinases Associadas a rho/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Hemodinâmica , Inflamação , Fígado/enzimologia , Fígado/lesões , Sistema de Sinalização das MAP Quinases , Masculino , Necrose , Niacinamida/farmacologia , Hepatopatia Gordurosa não Alcoólica , Inibidores de Proteínas Quinases/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sorafenibe , Transplante HomólogoRESUMO
BACKGROUND: Increased angiotensin II (Ang II) plays an important role in liver inflammation and fibrogenesis. Chronic administration of aliskiren, a newly developed direct renin inhibitor, decreases Ang II in the hypertensive patients and animals. AIMS: Our study aims to evaluate the possible protective effects of chronic administration of aliskiren in a chronic liver injury model. METHODS: C57BL6 mice were injected intraperitoneally with carbon tetrachloride (CCl(4)) to induce chronic liver injury. The injured mice were randomly assigned to aliskiren-treated (25 mg/kg per day for 2 weeks, the CCl(4) + Ali group) or untreated group (the CCl(4) group). Mice without CCl(4) and aliskiren administration served as the normal control. RESULTS: In the CCl(4)-injured mice, aliskiren attenuated liver inflammation and fibrosis. The levels of hepatocyte apoptosis, lipid peroxidation production, the activation of hepatic stellate cells and Kupffer cells, hepatic expression of p47 phox, inflammatory mediators and profibrotic markers were reduced in the CCl(4) + Ali group. Furthermore, aliskiren decreased Ang II, activated the renal expression of renin, but down-regulated the hepatic expression of renin and renin receptor in the CCl(4)-injected mice. CONCLUSIONS: Aliskiren attenuates chronic liver injury in the CCl(4)-treated mice by reducing Ang II. Direct renin inhibition may serve as a potential treatment for chronic liver injury.
Assuntos
Amidas/farmacologia , Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Tetracloreto de Carbono/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Fumaratos/farmacologia , Animais , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Interações Medicamentosas , Fígado/patologia , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Renina/antagonistas & inibidoresRESUMO
BACKGROUND: Hepatic endothelial dysfunction (HED), which is caused by decreased hepatic nitric oxide (NO) bioavailability and increased lipid peroxidation, contributes to portal hypertension, which is a characteristic of cirrhosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is involved in cirrhosis-related HED and portal hypertension. AIMS: We evaluated the effect of vitamin E treatment on the lipid peroxidation, HED and portal hypertension in cirrhotic rats. METHODS: The common bile duct ligation (BDL)-induced cirrhotic rats were treated orally either with vehicle or with vitamin E for 1 month immediately after BDL. Systemic and portal haemodynamics, the magnitude of the increase in portal pressure induced by volume expansion, HED, oxidative stress, levels of ADMA, various proteins and mRNAs were then measured. RESULTS: In the vitamin E-treated BDL rats, a decrease in portal pressure was associated with an attenuation of the increased portal pressure induced by volume expansion. In isolated and perfused BDL rat livers, the vitamin E treatment significantly inhibited the (paradoxical) vasoconstriction response to methoxamine and acetylcholine (HED), and this was abolished by the presence of NOS. Vitamin E decreased ADMA synthesizing enzyme PRMT1 expression and the level of thiobarbituric acid-reactive substances (TBARS) in the liver, while increasing the levels of hepatic ADMA metabolizing enzyme DDAH2, eNOS, phosphor-eNOS, ADMA level and superoxide dismutase activity. CONCLUSIONS: The administration of vitamin E suppressed hepatic ADMA and oxidative stress in the cirrhotic liver circulation, and therefore increases NO bioavailability, which improved HED and portal hypertension.
Assuntos
Antioxidantes/farmacologia , Arginina/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática Experimental/tratamento farmacológico , Vitamina E/farmacologia , Animais , Arginina/farmacologia , Sinergismo Farmacológico , Células Endoteliais/patologia , Hemodinâmica/efeitos dos fármacos , Hipertensão Portal/metabolismo , Hipertensão Portal/patologia , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Perfusão , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND: Portal or bridging fibrosis is an indication for antiviral treatment in patients with chronic hepatitis B (CHB). An early marker predictive of liver fibrosis in hepatitis B e antigen (HBeAg)-negative CHB patients can alert clinicians to plan for treatment before disease progression. GOALS: To predict early and significant liver fibrosis (Ishak score ≥2) in HBeAg-negative CHB by validating several noninvasive markers derived from CHC. STUDY: One hundred seventy-seven consecutive treatment-naive HBeAg-negative CHB patients who underwent liver biopsy were divided into a training group (n=121) and a validation group (n=56). Factors associated with liver fibrosis were analyzed. RESULTS: Multivariate analysis identified Lok's model ≥0.87, cirrhosis discriminant score greater than 4, and positive alanine aminotransferase ratio platelet score as independent factors associated with liver fibrosis in the training group. The area under the receiver operating characteristic curve revealed that Lok's model was better than cirrhosis discriminant score in predicting liver fibrosis in both the training and the validation groups. In patients with hepatitis B virus DNA greater than 2000 IU/mL or greater than 20,000 IU/mL, Lok's model showed equal prediction value (area under the receiver operating characteristic curve 0.709 and 0.704, respectively). Lok's model could also discriminate high and low hepatitis B virus DNA loads. In general, liver biopsy can be avoided in one-third (58 of 177) of patients by Lok's model. CONCLUSIONS: Lok's model ≥0.87 can be an early marker of liver fibrosis in HBeAg-negative CHB patients. Lok's model has clinical applications not only for CHC, but also for HBeAg-negative CHB.
Assuntos
Biomarcadores/análise , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/complicações , Cirrose Hepática/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/virologia , Humanos , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: Portal hypertension induced the formation of portal-systemic collaterals. Revealing the developmental change of portal-systemic collaterals is important for future therapy. METHODS: We observed the evolution of an accessible shunting vessel, the spleno-renal shunt (SRS), in rats after induction of portal hypertension by partial portal vein ligation (PVL). The hemodynamic and histological assessments of SRS were performed by transit time ultrasound and immunohistochemical studies. RESULTS: The portal pressure of PVL rats surged to 16.5 ± 1.1 mmHg on day 1 after ligation surgery and was maintained at a significantly higher level (13.0 ± 0.4 mmHg) to day 14 when compared to sham rats (p < 0.05). The size or flow of SRS in PVL rats did not change immediately after portal pressure surge. Instead, they increased rapidly on day 4, peaked on day 7, and stabilized thereafter. The size and flow were greater and the resistance of SRS was lower in PVL rats after day 7 (p < 0.05). The anti-Ki67 immunohistochemical study demonstrated positive staining of endothelium in SRS and negative in portal vein or aorta of PVL rats. In addition, the endothelial cells of SRS were stained positive for CD31 and KLF5. CONCLUSIONS: We concluded that the pressure-induced opening of pre-existing vessels was not the primary underlying mechanism in the formation of SRS. Endothelial proliferating and vascular remodeling process participated actively during the development of SRS. These observations can be used for studying the pathogenesis and developing more effective anti-portal hypertensive therapy in the future.
Assuntos
Circulação Colateral/fisiologia , Hipertensão Portal/fisiopatologia , Fígado/irrigação sanguínea , Animais , Pressão Sanguínea , Masculino , Sistema Porta/fisiopatologia , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND & AIMS: Activation of the (pro)renin receptor (PRR) up-regulates the expression of profibrotic genes in the kidney and heart. We aimed to investigate the role of PRR in hepatic fibrogenesis. METHODS: Human hepatic PRR levels were measured in patients with or without liver fibrosis. PRR expression was analyzed in primary mouse hepatic stellate cells (HSCs). Experimental fibrosis was studied in thioacetamide (TAA)-treated or methionine choline-deficient (MCD) diet-fed C57BL/6 mice. Lentivirus-mediated PRR short hairpin RNA was used to knockdown hepatic PRR expression. Lentiviral vectors expressing PRR short hairpin RNA or complementary DNA from the α-smooth muscle actin promoter were used for myofibroblast-specific gene knockdown or overexpression. RESULTS: PRR is up-regulated in human and mouse fibrotic livers, and in activated HSCs. Hepatic PRR knockdown reduced liver fibrosis by suppressing the activation of HSCs and expression of profibrotic genes in TAA or MCD diet-injured mice without significant changes in hepatic inflammation. Renin and prorenin increased the expression of PRR and production of TGF-ß1 in human activated HSC Lieming Xu-2 cells, and knockdown of PRR inactivated Lieming Xu-2 cells with decreased production of transforming growth factor (TGF)-ß1 and Mothers against decapentaplegic homolog 3 (Smad3) phosphorylation. Myofibroblast-specific PRR knockdown also attenuated liver fibrosis in TAA or MCD diet-injured mice. Mice with both myofibroblast-specific and whole-liver PRR knockdown showed down-regulation of the hepatic extracellular signal-regulated kinase (ERK)/TGF-ß1/Smad3 pathway. Myofibroblast-specific PRR overexpression worsened TAA-induced liver fibrosis by up-regulating the ERK/TGF-ß1/Smad3 pathway. CONCLUSIONS: PRR contributes to liver fibrosis and HSC activation, and its down-regulation attenuates liver fibrosis through inactivation of the ERK/TGF-ß1/Smad3 pathway. Therefore, PRR is a promising therapeutic target for liver fibrosis.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Receptores de Superfície Celular/deficiência , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores , Dieta , Suscetibilidade a Doenças , Fibroblastos/metabolismo , Expressão Gênica , Técnicas de Silenciamento de Genes , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Cirrose Hepática/patologia , Camundongos , Modelos Biológicos , Fosforilação , Receptor de Pró-ReninaRESUMO
BACKGROUND & AIMS: Liver injury serves as an excellent model of wound healing, characterized by increased synthesis of various cytokines and peptides, including the vasoactive peptide endothelin-1. In the liver, wound healing is mediated by effector cells such as hepatic stellate cells, which cause tissue contraction. Endothelin-1 has autocrine effects on stellate cells and induces their contractile activities. We explored the role of various extracellular matrix components, particularly of fibronectin, in regulating endothelin-1 production during liver injury. METHODS: Hepatic stellate cells were isolated from normal and injured rats. Real-time polymerase chain reaction immunoblot and enzyme-linked immunosorbent assay analyses were used to measure specific variables, including endothelin-1 production. Preproendothelin-1 promoter activity was determined by a luciferase assay. Stellate cell contraction was measured by a gel contraction assay. RESULTS: Fibronectin stimulated transcription of preproendothelin-1 messenger RNA and expression of endothelin through an integrin-dependent pathway in activated hepatic stellate cells. In these cells, fibronectin induced phosphorylation/activation of extracellular signal-regulated kinase (ERK) through a Shc- and Src-dependent mechanism; ERK activation was required for fibronectin-induced endothelin-1 expression. Fibronectin stimulation by stellate cells induced expression of smooth muscle alpha-actin and endothelin-1-mediated autocrine stellate cell contraction. Stellate cells isolated from injured livers of rats exhibited increased basal phosphorylation levels of Src, Shc, and ERK, as well as increased endothelin-1 synthesis. CONCLUSIONS: Fibronectin stimulates activated stellate cells to produce endothelin-1 and contract, via an ERK-dependent signaling pathway. The resulting autocrine functional effects of endothelin-1 are likely to be important in the wound-healing process in injured liver.
Assuntos
Endotelina-1/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibronectinas/farmacologia , Fígado/lesões , Transdução de Sinais/efeitos dos fármacos , Quinases da Família src/metabolismo , Análise de Variância , Animais , Células Cultivadas , Modelos Animais de Doenças , Endotelina-1/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Immunoblotting , Masculino , Fosforilação , Probabilidade , RNA Mensageiro/análise , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Quinases da Família src/efeitos dos fármacosRESUMO
BACKGROUND: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in HBeAg-negative chronic hepatitis B (CHB). This study aimed to clarify this relationship and identify factors associated with liver histology. PATIENTS AND METHODS: We investigated 152 consecutive, treatment-naïve, HBeAg-negative CHB patients who had undergone liver biopsies at a tertiary medical centre in Taiwan. Clinical indications for treatment included a serum alanine aminotransferase level more than twice the upper limit of normal and an hepatitis B virus DNA level > 2000 IU/ml. Factors associated with the histological indication (Ishak's grade > or = 7 and/or stage > or = 2) were analysed. RESULTS: The association between the clinical and the histological indications was significant (P=0.011). However, the agreement was poor (kappa value=0.197). In patients satisfying the clinical indication, age > 52 years [odds ratio (OR)=2.669, P=0.042], serum alpha-fetoprotein (AFP) level > 7 ng/ml (OR=7.070, P<0.001) and platelet count < 130 x 10(9)/L (OR=11.720, P=0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only an AFP level > 7 ng/ml (OR=10.345, P=0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level > 7 ng/ml to predict liver histology, the sensitivity and the negative predictive value could improve from 86 to 94.4% and 66.7 to 81% respectively. CONCLUSION: AFP level is associated with liver histology in HBeAg-negative CHB. Serum AFP level can serve as a surrogate indicator to identify patients who need antiviral treatment.
Assuntos
Biomarcadores/sangue , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/patologia , alfa-Fetoproteínas/análise , Adulto , Idoso , Alanina Transaminase/sangue , Biópsia , DNA Viral/sangue , Feminino , Antígenos E da Hepatite B/sangue , Técnicas Histológicas , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , TaiwanRESUMO
BACKGROUND: The aspartate aminotransferase to alanine aminotransferase ratio (AAR) was seldom applied for fibrosis assessment in primary biliary cirrhosis (PBC) patients. GOALS: To validate the AAR for evaluating hepatic fibrosis, disease severity, and prognosis in patients with PBC. STUDY: Ninety-two consecutive PBC patients were retrospectively evaluated to validate the AAR for assessing the severity of liver function, the degrees of hepatic fibrosis, and predicting outcomes. RESULTS: AAR showed modest correlations to Mayo score, model for end-stage liver disease score, and Child-Pugh score (r2=0.156,P<0.001; r2=0.084, P=0.005; r2=0.142, P<0.001, respectively)in evaluating the severity of liver function. For 46 patients who underwent liver biopsy, 35 were in early stage fibrosis and the other 11 were in advanced fibrosis. AAR was significantly higher in patients with advanced fibrosis than those with early fibrosis (mean+/-standard deviation; 1.40+/-0.44 vs. 0.98+/-0.65,P=0.001). The AAR yielded the highest area under the receiver operating curve of 0.847 than Mayo score, model for end-stage liver disease score, and Child-Pugh score in predicting advanced fibrosis. During a median follow-up of 44.5 months, 24 patients expired and 68 patients were alive. Patients with an AAR of 1 or less had significantly better prognosis than their counterparts(P=0.043). CONCLUSIONS: AAR is a simple and reliable marker to assess liver function and hepatic fibrosis as well as to predict outcomes in PBC patients.
Assuntos
Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Cirrose Hepática Biliar/enzimologia , Cirrose Hepática/enzimologia , Fígado/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Feminino , Humanos , Fígado/fisiopatologia , Cirrose Hepática/fisiopatologia , Cirrose Hepática Biliar/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Índice de Gravidade de DoençaRESUMO
BACKGROUND/AIMS: The portal hypotensive effect of vasopressin during hemorrhage is less effective than that during stable condition in cirrhotic patients or experimental portal hypertension (the so-called hyposensitivity phenomenon). Recent studies have demonstrated that constitutive nitric oxide activities and bradykinin in hemorrhage-transfused partially portal vein-ligated rats are responsible, at least partly, for the splanchnic hyposensitivity to glypressin (a long acting vasopressin analogue). This study investigated the relative contribution of nitric oxide synthase isoforms and the role of bradykinin in the pathogenesis of splanchnic hyposensitivity in rats with cirrhosis induced by common bile duct-ligation (BDL). METHODOLOGY: Five weeks after BDL, systemic and portal hemodynamics were measured in stable or bleeding BDL rats receiving intravenous infusion of glypressin (0.2 mg/kg). In the treatment groups, N(G)-nitro-L-arginine methyl ester (L-NAME, a non-selective nitric oxide synthase inhibitor), L-canavanine (a specific inducible nitric oxide synthase inhibitor) or HOE 140 (a bradykinin B2 receptor antagonist) was administered 45 minutes before the infusion of glypressin. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or various inhibitors. RESULTS: Splanchnic hyposensitivity to glypressin was demonstrated in the hemorrhage-transfused BDL rats. The infusion of L-NAME elevated the mean arterial pressure in the bleeding BDL rats without the modulation of portal pressure. The addition of L-NAME or HOE 140, but not L-canavanine, significantly and similarly potentiated the portal-hypotensive effects of glypressin. CONCLUSIONS: Constitutive nitric oxide synthase and bradykinin play major roles in the development of splanchnic hyposensitivity to glypressin observed in hemorrhage-transfused rats with biliary cirrhosis.
Assuntos
Bradicinina/fisiologia , Hipertensão Portal/fisiopatologia , Lipressina/análogos & derivados , Óxido Nítrico/fisiologia , Pressão na Veia Porta/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Canavanina/farmacologia , Ducto Colédoco , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Ligadura , Lipressina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Sprague-Dawley , TerlipressinaRESUMO
Aliskiren has been found to reduce chronic injury and steatosis in the liver of methionine-choline-deficient (MCD) diet-fed mice. This study investigated whether aliskiren has an anti-steatotic effect in HFD-fed mice, which are more relevant to human patients with non-alcoholic fatty liver disease than MCD mice. Mice fed with 4-week normal chow or HFD randomly received aliskiren (50 mg/kg/day) or vehicle via osmotic minipumps for further 4 weeks. Aliskiren reduced systemic insulin resistance, hepatic steatosis, epididymal fat mass and increased gastrocnemius muscle glucose transporter type 4 levels with lower tissue angiotensin II levels in the HFD-fed mice. In addition, aliskiren lowered nuclear peroxisome proliferator-activated receptor gamma and its down-signaling molecules and increased cytochrome P450 4A14 and carnitine palmitoyltransferase 1A (CPT1a) in liver. In epididymal fat, aliskiren inhibited expressions of lipogenic genes, leading to decrease in fat mass, body weight, and serum levels of leptin and free fatty acid. Notably, in the gastrocnemius muscle, aliskiren increased phosphorylation of insulin receptor substrate 1 and Akt. Based on these beneficial effects on liver, peripheral fat and skeletal muscle, aliskiren is a promising therapeutic agent for patients with NAFLD.
Assuntos
Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Amidas/farmacologia , Fumaratos/farmacologia , Insulina/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Família 4 do Citocromo P450/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Epididimo , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , PPAR gama/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The optimal timing of percutaneous cholecystostomy for severe acute cholecystitis is unclear. The aim of this study was to investigate the timing of percutaneous cholecystostomy and its relationship to clinical outcomes in patients with inoperable acute severe cholecystitis.From 2008 to 2010, 209 consecutive patients who were admitted to our hospital due to acute cholecystitis and were treated by percutaneous cholecystostomy were retrospectively reviewed. The time periods from symptom onset to when percutaneous cholecystostomy was performed and when patients were discharged were recorded.In the 209 patients, the median time period between symptom onset and percutaneous cholecystostomy was 23âhours (range, 3-95âhours). The early intervention group (≤24âhours, nâ=â109) had a significantly lower procedure-related bleeding rate (0.0% vs 5.0%, Pâ=â0.018) and shorter hospital stay (15.8â±â12.9 vs 21.0â±â17.5 days) as compared with the late intervention group (>24âhours, nâ=â100). Delayed percutaneous cholecystostomy was a significant independent factor for a longer hospital stay (odds ratio 3.03, Pâ=â0.001).In inoperable patients with acute severe cholecystitis, early percutaneous cholecystostomy reduced hospital stay and procedure-related bleeding without increasing the mortality rate.
Assuntos
Colecistite Aguda/cirurgia , Colecistostomia/efeitos adversos , Colecistostomia/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Complicações Pós-Operatórias/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Colecistostomia/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/mortalidade , Estudos Retrospectivos , Fatores Sexuais , Fatores de TempoRESUMO
Ninety-nine individuals with stools positive for Blastocystis hominis but negative for other parasites were identified from medical records of healthy adults who had received a physical examination at Taipei Veterans General Hospital from November 2000 to October 2002. The medical records of these 99 positive cases and 193 randomly selected controls, matched for age, sex, and date of examination, were retrospectively reviewed. The pathogenicity of B. hominis could not be demonstrated due to a lack of association with the development of gastrointestinal symptoms or pathologic findings on endoscopic examination. Multivariate analyses revealed that chronic hepatitis B infection was a predisposing condition to the acquisition of B. hominis (odd ratio = 2.848, 95% confidence interval = 1.299-6.242, P = 0.009), and concentration of urate was significantly lower in B. hominis-positive individuals (mean +/- SD = 361.64 +/- 87.44 versus 392.57 +/- 93.38 micromol/L; P = 0.009). Among the 64 individuals who underwent gastric biopsy, Helicobacter pylori was found more frequently in the individuals harboring B. hominis (19 of 26 versus 15 of 38; P = 0.017).
Assuntos
Infecções por Blastocystis/epidemiologia , Infecções por Blastocystis/etiologia , Blastocystis hominis , Animais , Infecções por Blastocystis/patologia , Estudos de Casos e Controles , Endoscopia Gastrointestinal , Fezes/parasitologia , Feminino , Infecções por Helicobacter , Hepatite B , Humanos , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND/AIMS: Hyperdynamic circulation observed in portal hypertension is characterized by generalized vasodilatation, increased cardiac index, and increased systemic and regional blood flows, and mediated at least partly by increased nitric oxide activities. Recent studies have demonstrated that Helicobacter pylori (H. pylori) infection can stimulate nitric oxide synthase expression and activities. This study investigated if chronic H. pylori infection might be involved in the development of hyperdynamic circulation in cirrhotic patients. METHODOLOGY: Fifty-eight patients with cirrhosis and thirty-six healthy subjects entered this study. The serologic evidence of H. pylori infection was determined with ELISA in both groups. In addition, in cirrhotic patients hemodynamic studies were performed by Swan-Ganz catheterization and thermodilution technique. RESULTS: No significant differences in age (65.5 +/- 0.8 vs. 63.7 +/- 1.1 years), sex (male/female: 43/15 vs. 29/7) and seroprevalence of H. pylori (74.1% vs. 80.6%) were observed between cirrhotic patients and healthy subjects (P > 0.05). The seropositive rate of H. pylori in patients with cirrhosis was not associated with severity of cirrhosis and size of esophageal varices (P > 0.05). There were no significant differences in systemic vascular resistance and hepatic venous pressure gradient between cirrhotic patients with and those without chronic H. pylori infection (P > 0.05). CONCLUSIONS: The seroprevalence of H. pylori in cirrhotic patients is similar to that of healthy controls, and not related to the severity of cirrhosis and degree of portal hypertension. Chronic H. pylori infection does not play a major role in the hyperdynamic circulation observed in cirrhotic patients.