RESUMEN
BACKGROUND: The pathophysiology of intra-abdominal adhesions has not been studied extensively. The aim of this study was to elucidate the molecular mechanisms underlying adhesion formation in a murine model and in patients undergoing hepatectomy. METHODS: Partial hepatectomy was performed using bipolar forceps in mice. Wild-type mice, antibodies to CD4 and interferon (IFN) γ, IFN-γ, natural killer T (NKT) cells and plasminogen activator inhibitor (PAI) 1 knockout (KO) mice were used. Recombinant hepatocyte growth factor (HGF) was tested for its ability to prevent adhesions. Liver specimens were obtained during surgery from patients undergoing hepatectomy. Adhesion formation was evaluated using a scoring system that ranged from 0 (no adhesions) to 5 (severe adhesions). Levels of IFN-γ and PAI-1 mRNA, and protein concentration of PAI-I were measured, and fluorescence immunostaining was performed. RESULTS: Adhesion formation depended on IFN-γ produced by NKT cells, and NKT KO mice developed few adhesions (mean(s.d.) 1·7(0·3) versus 4·6(0·4) in wild-type mice; P = 0·037). In wild-type mice, the level of PAI-1 mRNA increased after hepatectomy, followed by a decrease in the tissue plasminogen activator (tPA) mRNA level. Adhesion formation was inhibited completely in PAI-1 KO mice (0(0) versus 4·1(0·8) in wild-type mice; P = 0·002). HGF inhibited formation of abdominal adhesions after hepatectomy by reducing IFN-γ and PAI-1 levels, and increasing tPA levels compared with those in mice treated with phosphate-buffered saline (P < 0·001, P = 0·002 and P = 0·035 respectively). In human liver specimens, NKT cells accumulated in the liver after hepatectomy, and PAI-1 expression was increased 5·25-fold (P = 0·030). CONCLUSION: IFN-γ is a key molecule for abdominal adhesion formation after hepatectomy, acting via the reciprocal balance of PAI-1 and tPA. This molecular mechanism may also regulate adhesion formation in patients following hepatectomy. HGF inhibited formation of adhesions by regulating IFN-γ and PAI-1, suggesting that it may be an important target for prevention of adhesions after hepatectomy. SURGICAL RELEVANCE: Postoperative intra-abdominal adhesions can be asymptomatic or cause significant morbidity and mortality. Adhesion formation after hepatectomy has not been studied extensively. In the present study, the molecular mechanisms underlying intra-abdominal adhesions after hepatectomy were investigated in a murine model and in patients. Interferon (IFN) γ produced by natural killer T cells is a key molecule for adhesion formation after hepatectomy in mice, acting via the reciprocal balance between plasminogen activator inhibitor (PAI) 1 and tissue plasminogen activator, the pivotal factors in fibrinolytic activity. This mechanism was also involved in the regulation of adhesions in human tissue samples. Hepatocyte growth factor (HGF) strongly inhibited adhesion formation by regulating IFN-γ and PAI-1. These results indicate that IFN-γ and PAI-1 are possible therapeutic targets, and HGF could prevent postoperative adhesion formation after hepatectomy.
Asunto(s)
Interferón gamma/fisiología , Inhibidor 1 de Activador Plasminogénico/fisiología , Adherencias Tisulares/fisiopatología , Animales , Antígenos CD4/farmacología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hepatectomía/efectos adversos , Factor de Crecimiento de Hepatocito/farmacología , Humanos , Células Asesinas Naturales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas RecombinantesRESUMEN
BACKGROUND: In hepatic ischaemia/reperfusion injury, activated liver macrophages (Kupffer cells) are dominantly regulated by a transcription factor, nuclear factor kappaB (NFkappaB), with respect to expression of inflammatory cytokines, acute phase response proteins, and cell adhesion molecules. AIMS: We assessed whether inactivation of NFkappaB in the liver could attenuate total hepatic warm ischaemia/reperfusion injury. METHODS: We studied rats with hepatic overexpression of inhibitor kappaBalpha super-repressor (IkappaBalpha SR) caused by a transgene introduced using an adenoviral vector. Hepatic ischaemia/reperfusion injury was induced under warm conditions by total occlusion of hepatoduodenal ligament structures for 20 minutes, followed by reperfusion. Controls included uninfected and control virus (AdLacZ) infected rats. RESULTS: IkappaBalpha SR was overexpressed in Kupffer cells as well as in hepatocytes, blocking nuclear translocation of NFkappaB (p65) into the nucleus after reperfusion. Gene transfection with IkappaBalpha SR, but not with LacZ, markedly attenuated ischaemia/reperfusion injury, suppressing inducible nitric oxide synthase and nitrotyrosine expression in the liver. Moreover, no remarkable hepatocyte apoptosis was detected under IkappaBalpha SR overexpression. CONCLUSIONS: Adenoviral transfer of the IkappaBalpha SR gene in the liver ameliorates short term warm ischaemia/reperfusion injury, possibly through attenuation of hepatic macrophage activation.
Asunto(s)
Proteínas I-kappa B/farmacología , Hígado/irrigación sanguínea , FN-kappa B/antagonistas & inhibidores , Daño por Reperfusión/prevención & control , Tirosina/análogos & derivados , Adenoviridae , Aldehídos/metabolismo , Animales , Western Blotting , Técnicas de Transferencia de Gen , Hepatocitos/metabolismo , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Inhibidor NF-kappaB alfa , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Transfección , Factor de Necrosis Tumoral alfa , Tirosina/metabolismoRESUMEN
The aim of this study was to target Kupffer cells (KCs) selectively and efficiently by the intraportal injection of fusigenic cationic liposomes with hemagglutinating virus of Japan components (HVJ cationic liposomes). Phosphorothioate FITC-oligodeoxynucleotides (FITC-ODNs) encapsulated in either HVJ cationic liposomes, HVJ anionic liposomes or conventional cationic liposomes without HVJ were transferred to the rat. FITC-ODNs in HVJ cationic liposomes administered via portal vein were selectively transfected to KCs for up to 24 h with no apparent cytotoxicity at higher transfection efficiency than FITC-ODNs in conventional cationic liposomes without HVJ administered via portal vein or tail vein. On the other hand, FITC-ODNs in HVJ anionic liposomes were observed mainly in hepatocytes, not KCs. This new method will be useful for the modulation of KCs activity in both basic research and clinical applications.
Asunto(s)
Técnicas de Transferencia de Gen , Macrófagos del Hígado/efectos de los fármacos , Oligodesoxirribonucleótidos/administración & dosificación , Virus Sendai/genética , Animales , Línea Celular , Fluoresceína-5-Isotiocianato , Inyecciones Intravenosas , Macrófagos del Hígado/enzimología , Operón Lac , Liposomas , Masculino , Microscopía Fluorescente , Oligodesoxirribonucleótidos/genética , Vena Porta , Ratas , Ratas Wistar , Transfección , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismoRESUMEN
Considerable evidence for a role of Kupffer cells in alcoholic liver disease has accumulated and they have recently been shown to be a predominant source of free radicals. Several approaches including pharmacological agents, knockout mice, and viral gene transfer have been used to fill critical gaps in understanding key mechanisms by which Kupffer cell activation, oxidant formation, and cytokine production lead to liver damage and subsequent pathogenesis. This review highlights new data in support of the hypothesis that Kupffer cells play a pivotal role in hepatotoxicity due to ethanol by producing oxidants via NADPH oxidase.
Asunto(s)
Etanol/toxicidad , Macrófagos del Hígado/metabolismo , Hepatopatías Alcohólicas/metabolismo , Oxidantes/biosíntesis , Adenoviridae/genética , Animales , Antígenos CD/genética , Antioxidantes/metabolismo , Depuradores de Radicales Libres/uso terapéutico , Humanos , Macrófagos del Hígado/fisiología , Hepatopatías Alcohólicas/tratamiento farmacológico , Ratones , Ratones Noqueados/genética , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral , Transgenes/fisiologíaRESUMEN
BACKGROUND/AIMS: Although beneficial roles of hepatocyte growth factor (HGF) and its variants on several hepatic disorders have been reported, their effects on hepatic ischemia-reperfusion (IR) injury remain undetermined. We investigated the action of a deleted form of HGF (dHGF) on hepatic IR injury in rats. METHODS: dHGF or phosphate-buffered saline was continuously infused intravenously for 20 h prior to a 20-min occlusion of hepatic vessels. Samples were taken before and after IR, for measurement of serum dHGF and released enzymes, liver gamma-glutamylcysteinyl glycine (GSH) level, as well as histological and immunohistochemical examinations. RESULTS: After reperfusion, histological injury, as well as increase in the serum activities of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and creatine kinase-BB were significantly attenuated in the dHGF-treated rats. dHGF maintained a high GSH level and suppressed oxidative stress and intercellular adhesion molecule-1 (ICAM-1) expression on sinusoidal endothelial cells (SECs), on which c-Met was not detected. IR caused activation of c-Met expression, which was milder in the dHGF-treated group, in hepatocytes at the pericentral region. CONCLUSIONS: dHGF attenuated liver injury after IR. It also maintained a higher GSH level, depressed oxidative stress and inhibited ICAM-1 expression on c-Met negative SECs, suggesting a paracrine effect of dHGF.
Asunto(s)
Desoxiguanosina/análogos & derivados , Factor de Crecimiento de Hepatocito/administración & dosificación , Hígado/efectos de los fármacos , Hígado/lesiones , Daño por Reperfusión/prevención & control , 8-Hidroxi-2'-Desoxicoguanosina , Empalme Alternativo , Animales , Desoxiguanosina/metabolismo , Glutatión/metabolismo , Factor de Crecimiento de Hepatocito/sangre , Factor de Crecimiento de Hepatocito/química , Factor de Crecimiento de Hepatocito/genética , Humanos , Inmunohistoquímica , Infusiones Intravenosas , Molécula 1 de Adhesión Intercelular/metabolismo , Hígado/irrigación sanguínea , Masculino , Proteínas Proto-Oncogénicas c-met/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangre , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Eliminación de SecuenciaRESUMEN
BACKGROUND: The aim of this study was to evaluate the clinicopathologic characteristics of patients with hepatocellular carcinoma (HCC) and bile duct thrombi (BDT). PATIENTS: Seventeen patients with HCC and BDT among 671 patients with HCC who underwent hepatic resection were enrolled in this study. RESULTS: There were no significant differences in the survival rates between patients with and those without BDT, although the rate of stage IV or portal vein invasion was significantly higher in patients with HCC and BDT than in those with HCC but without BDT. In 9 of 17 patients with BDT, preoperative jaundice was observed. Five of the 17 patients underwent a bile duct resection combined with hepatic resection, and 12 patients underwent hepatic resection with removal of the BDT without bile duct resection. None of the patients had histopathologic evidence of direct tumor invasion into the bile duct wall or of any tumor recurrence related to the BDT. There were no significant differences in the survival rates between patients who underwent bile duct resection and those who did not. CONCLUSION: Hepatic resection and the removal of BDT without bile duct resection were sufficient surgical interventions to treat patients with HCC and BDT.
Asunto(s)
Enfermedades de los Conductos Biliares/diagnóstico , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Trombosis/diagnóstico , Adulto , Anciano , Enfermedades de los Conductos Biliares/etiología , Enfermedades de los Conductos Biliares/patología , Enfermedades de los Conductos Biliares/cirugía , Conductos Biliares/patología , Carcinoma Hepatocelular/complicaciones , Femenino , Humanos , Neoplasias Hepáticas/complicaciones , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Trombosis/etiología , Trombosis/patología , Trombosis/cirugía , Resultado del TratamientoAsunto(s)
Neoplasias de los Conductos Biliares/diagnóstico por imagen , Carcinoma Hepatocelular/diagnóstico por imagen , Colangiopancreatografia Retrógrada Endoscópica , Cálculos Biliares/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana EdadRESUMEN
Tumor necrosis factor-alpha receptor 1 and Fas recruit overlapping signaling pathways. To clarify the differences between tumor necrosis factor alpha (TNFalpha) and Fas pathways in hepatocyte apoptosis, primary mouse hepatocytes were treated with TNFalpha or an agonist anti-Fas antibody after infection with an adenovirus expressing an IkappaB superrepressor (Ad5IkappaB). Treatment with TNFalpha induced apoptosis in Ad5IkappaB-infected mouse hepatocytes, as we previously reported for rat hepatocytes. Ad5IkappaB plus anti-Fas antibody or actinomycin D plus anti-Fas antibody rapidly induced apoptosis, whereas anti-Fas antibody alone produced little cytotoxicity. The proteasome inhibitor (MG-132) and a dominant-negative mutant of nuclear factor-kappaB-inducing kinase also promoted TNFalpha- and Fas-mediated apoptosis. Expression of either crmA or a dominant-negative mutant of the Fas-associated death domain protein prevented TNFalpha- and Fas-mediated apoptosis. In addition, the caspase inhibitors, DEVD-cho and IETD-fmk, inhibited TNFalpha- and Fas-mediated apoptosis. In Ad5IkappaB-infected hepatocytes, caspases-3 and -8 were activated within 2 h after treatment with anti-Fas antibody or within 6 h after TNFalpha treatment. Confocal microscopy demonstrated onset of the mitochondrial permeability transition (MPT) and mitochondrial depolarization by 2-3 h after anti-Fas antibody treatment and 8-10 h after TNFalpha treatment, followed by cytochrome c release. The combination of the MPT inhibitors, cyclosporin A, and trifluoperazine, protected Ad5IkappaB-infected hepatocytes from TNFalpha-mediated apoptosis. After anti-Fas antibody, cyclosporin A and trifluoperazine decreased cytochrome c release but did not prevent caspase-3 activation and cell-death. In conclusion, nuclear factor-kappaB activation protects mouse hepatocytes against both TNFalpha- and Fas-mediated apoptosis. TNFalpha and Fas recruit similar but nonidentical, pathways signaling apoptosis. The MPT is obligatory for TNFalpha-induced apoptosis. In Fas-mediated apoptosis, the MPT accelerates the apoptogenic events but is not obligatory for them.
Asunto(s)
Apoptosis , Hígado/fisiología , Receptor fas/fisiología , Animales , Caspasa 3 , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , Células Cultivadas , Inhibidores de Cisteína Proteinasa/farmacología , Activación Enzimática , Proteínas I-kappa B/metabolismo , Leupeptinas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , FN-kappa B/metabolismo , Oligopéptidos/farmacología , Permeabilidad , Ratas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. Here, its effect on alcohol-induced liver injury in an enteral alcohol feeding model was investigated. Male Wistar rats were given control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the cyclic pattern of ethanol in the urine were not different between the OTC-ethanol and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis and inflammation were elevated significantly by ethanol compared with appropriate high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) and the nuclear transcription factor nuclear factor kappaB (NFkappaB) 2-3 fold. NFkappaB in isolated Kupffer cells was also increased by ethanol. These effects were all blocked by OTC treatment. Additionally, superoxide production was higher in Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC also increased circulating glutathione (GSH) levels about 2-fold; however, GSH levels were not affected by ethanol or OTC in livers from the groups studied. Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer cells about 2-fold. Moreover, GSH (Ki-10 micromol/L) and cysteinyl-glycine, but not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in calcium in isolated Kupffer cells, possibly by activating a glycine-gated chloride channel due to their structural similarity with glycine. Collectively, it is concluded that GSH is protective, in part, by increasing circulating GSH, which blunts activation of Kupffer cells via the glycine-gated chloride channel.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Etanol/administración & dosificación , Glutatión/metabolismo , Hepatopatías/prevención & control , Tiazoles/farmacología , Animales , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Etanol/farmacología , Intubación Gastrointestinal , Macrófagos del Hígado/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/fisiopatología , Masculino , FN-kappa B/metabolismo , Necrosis , Profármacos/farmacología , Ácido Pirrolidona Carboxílico , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Tiazolidinas , Factores de Tiempo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Inhibition of the transcription factor nuclear factor kappa B (NFkappaB) induces marked hepatocyte apoptosis and liver dysfunction after partial hepatectomy (PH) in rats. Hepatocyte apoptosis may be due to direct inhibition of NFkappaB-induced hepatocyte survival genes or due to indirect increased signaling through the stress-activated protein kinase pathway (SAPK), resulting in increased c-Jun. c-Jun, an AP-1 transcription factor, induces apoptosis in fibroblasts. Our aim was to determine if hepatocyte apoptosis following inhibition of NFkappaB and partial hepatectomy in rats is due to increased c-Jun. Adult male Sprague-Dawley rats (200 g) were injected intraportally with 6 x 10(9) PFU adenoviral vector containing luciferase (Ad5Luc) or superrepressor IkappaB (Ad5IkappaB) transgene that inhibits NFkappaB translocation into the nucleus. Two-thirds PH was performed 24 h after vector administration, and the remnant liver was harvested 30 min or 24 h after PH. Northern and Western blots were performed to examine the presence of IkappaB and c-Jun. A GST c-Jun kinase assay was used to examine Jun-N-terminal kinase (JNK) activity. AP-1 DNA binding activity was assessed by electrophoretic mobility shift assay. TUNEL assay was performed to assess apoptosis. All rats receiving adenoviral vectors expressed the luciferase or superrepressor IkappaB transgenes. c-Jun mRNA, protein levels, and DNA binding activity were not increased in rats treated with Ad5IkappaB at 30 min after PH compared to rats injected with Ad5Luc. Jun kinase activity increased following partial hepatectomy, but activity was similar in Ad5Luc- and Ad5IkappaB-treated animals. AP-1 DNA binding activity was not altered substantially in rats treated with Ad5IkappaB. The percentage of apoptotic hepatocytes was similar between Ad5Luc- and Ad5IkappaB-injected animals at 0 h, but livers from Ad5IkappaB-treated rats had increased apoptosis at 24 h compared to Ad5Luc rats (24% vs. 4%) after PH. Hepatocyte apoptosis after NFkappaB inhibition and PH is not mediated by increased JNK activity or c-Jun.
Asunto(s)
Apoptosis , Hepatectomía , Proteínas Quinasas JNK Activadas por Mitógenos , FN-kappa B/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-jun/fisiología , Adenoviridae/genética , Animales , MAP Quinasa Quinasa 4 , Masculino , Proteína Quinasa 13 Activada por Mitógenos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Ratas , Ratas Sprague-Dawley , Factor de Transcripción AP-1/metabolismo , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
The case of a 74-year-old female patient who underwent a right hepatic lobectomy for hepatocellular carcinoma (HCC) which developed in primary biliary cirrhosis (PBC) is reported herein. During a follow-up examination for Parkinson's disease, an elevation of hepatobiliary tract-related enzymes and alpha-fetoprotein was uncovered. Diagnostic imagings showed a hypervascular, solitary, and encapsulated tumor measuring about 7 cm in diameter located mainly in the posterior segment. Positive antimitochondrial and antinuclear antibodies and a preoperative liver biopsy strongly suggested well differentiated HCC developed in PBC (Scheuer's classification stage II). Since the natural prognosis of PBC estimated by the Mayo risk score was fairly good and the liver function indicated sufficient tolerance for major hepatic resection, and preoperative computed tomography (CT) volumetry showed the atrophy of the right hepatic lobe, a right hepatic lobectomy was performed. A pathological examination revealed well encapsulated, moderately differentiated HCC with, in part, well-differentiated HCC in the tumor and stage II PBC in the noncancerous region. CT volumetry performed at postoperative day 14 showed a 146% enlargement of the remnant liver. An early detection of HCC and PBC by strict screening would prevent a limitation of surgical therapy due to a deteriorated liver function.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Hepatectomía , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/cirugía , Anciano , Carcinoma Hepatocelular/etiología , Femenino , Humanos , Hígado/diagnóstico por imagen , Neoplasias Hepáticas/etiología , Tomografía Computarizada por Rayos XRESUMEN
Alcohol treatment results in increases in the release of endotoxin from gut bacteria and membrane permeability of the gut to endotoxin, or both. Females are more sensitive to these changes. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanoids, TNF-alpha and free radicals. Prostaglandins increase oxygen uptake and most likely are responsible for the hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed which lead to tissue damage in oxygen-poor pericentral regions of the liver lobule.
Asunto(s)
Etanol/toxicidad , Hígado/efectos de los fármacos , Hígado/patología , Animales , Hipoxia de la Célula , Endotoxinas/sangre , Etanol/metabolismo , Femenino , Radicales Libres/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos del Hígado/efectos de los fármacos , Macrófagos del Hígado/metabolismo , Macrófagos del Hígado/patología , Hígado/metabolismo , Masculino , Ratas , Ratas Wistar , Factores SexualesRESUMEN
Total hepatic vascular exclusion (THVE) is an useful method enabling safe and sure hepatic resection in patients with liver tumors adjacent to the large hepatic veins or inferior vena cava (IVC), tumor thrombi, invasion of the IVC, etc. To avoid serious hypotension during THVE, test clamping of the IVC prior to the procedure is indispensable. Hemodynamics should be carefully maintained by blood transfusion and sufficient infusion of colloidal and electrolyte solutions during THVE. The veno-venous bypass method which shunts blood from the IVC and portal vein to the superior vena cava enables prolongation of the period of THVE and is useful to avoid postoperative renal dysfunction. In situ liver perfusion with cold solution during THVE is an additional modality by which the liver is protected from warm ischemic injury and the duration of THVE can be further prolonged. However, the maximum duration of THVE is still controversial, especially in patients with chronic liver damage. The most appropriate method for THVE should be carefully chosen in each case by considering the type of lesion, liver function, and the goal of the surgery.
Asunto(s)
Hepatectomía/métodos , Hígado/irrigación sanguínea , Constricción , HumanosRESUMEN
BACKGROUND/AIMS: The ability to transfer foreign genes into the biliary tract would be useful for the treatment of biliary tract diseases, including cancer, cystic fibrosis and other genetic diseases. To introduce a foreign gene precisely into the rat biliary epithelial cells, we developed a new technique, inserting a polyethylene catheter into the common bile duct through the papilla of Vater by use of a fusigenic cationic liposome with hemagglutinating virus of Japan (HVJ-cationic liposome). METHODS: Transfection efficiency was estimated with the use of FITC-oligonucleotides (FITC-ODNs) and cDNA of beta-galactosidase (pCAG-lacZ). RESULTS: FITC-ODNs encapsulated in HVJ-cationic liposome were effectively transfected into cell nuclei of human cholangiocellular carcinoma in vitro after a 30-min incubation as compared with the simple application of naked FITC-ODNs. After in vivo injection of FITC-ODNs using the HVJ-cationic liposome method through the papilla of Vater, fluorescence accumulation was observed only in the epithelial cells of the biliary tract, but not in the parenchymal cells of the liver. Beta-galactosidase expression was observed in the biliary epithelial cells 3 days after the transfection of pCAG-lacZ and was also detected at 14 days, but not at 28 days, without obvious cytotoxicity. CONCLUSIONS: HVJ-cationic liposome-mediated gene transfer to the biliary tract via the papilla of Vater is a minimally-invasive and an effective gene-delivery method for site-specific targeting to the epithelial cells of the biliary tract, which could be applied to the treatment of human biliary tract diseases.
Asunto(s)
Técnicas de Transferencia de Gen , Transfección/métodos , beta-Galactosidasa/genética , Animales , Neoplasias de los Conductos Biliares , Cateterismo , Núcleo Celular , Colangiocarcinoma , Conducto Colédoco , ADN Complementario , Fluoresceína-5-Isotiocianato , Genes Reporteros , Vectores Genéticos , Humanos , Liposomas , Masculino , Oligodesoxirribonucleótidos , Ratas , Ratas Wistar , Respirovirus/genética , Células Tumorales CultivadasRESUMEN
Recurrence of hepatocellular carcinoma after liver resection is usually observed in the remnant liver, and includes metachronous multicentric occurrence and intrahepatic metastasis. In stage I and II, disease-free survival rates of clinical stage I patients are significantly better than those of clinical stage II patients, although there are no differences in the disease-free survival rates of patients with advanced disease. Disease-free survival rates in long-term survivors decreased at a constant rate due to metachronous multicentric recurrence. Therefore it is important to follow postoperative patients as long as possible. In the treatment of recurrent tumors, every effort should be made to resect the tumor in the liver. Then, other regional therapies, such as percutaneous ethanol injection therapy, microwave coagulation therapy, and transcatheter arterial chemoembolization, are indicated for patients for whom re-resection is not indicated. To prevent recurrence of hepatocellular carcinoma, it is also important to suppress the hepatic necroinflammatory process due to viral hepatitis.
Asunto(s)
Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Humanos , Recurrencia Local de NeoplasiaRESUMEN
We report on a 65-year-old man who received asynchronous bilateral adrenalectomy for adrenal metastasis of hepatocellular carcinoma. Fifteen months after curative resection of right hepatic lobe for hepatocellular carcinoma, a metastatic lesion of the left adrenal gland was detected and left adrenalectomy was performed. Ten months after the second operation, a metastatic lesion in the right adrenal gland, associated with tumor thrombus in the inferior vena cava, was revealed. Transcatheter arterial embolization of the arteries feeding the metastatic tumor was performed, but its effects were incomplete. As there was the tumor thrombus in the inferior vena cava and no other intrahepatic recurrence or extrahepatic metastasis was found, resection of the right adrenal gland with tumor thrombus, without the employment of veno-venous bypass, was performed, followed by postoperative hormonal supplementation. Changes in the patient's alpha-fetoprotein level were clinically useful for the detection of the metastatic lesions and the evaluation of therapeutic effects. Metastasis to adrenal gland from hepatocellular carcinoma should be actively managed, and the appropriate surgical treatment selected, if intrahepatic recurrence and/or other extrahepatic metastasis are controlled. To achieve higher curability and better outcome in patients with bilateral adrenal metastasis of hepatocellular carcinoma, bilateral total adrenalectomy is indicated, accompanied by effective postoperative hormonal supplementation.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/terapia , Adrenalectomía , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Neoplasias de las Glándulas Suprarrenales/secundario , Anciano , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/secundario , Embolización Terapéutica , Estudios de Seguimiento , Hepatectomía , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Masculino , Recurrencia Local de Neoplasia/prevención & control , Flebografía , Tomografía Computarizada por Rayos X , Vena Cava InferiorRESUMEN
Intracaval tumor thrombus is one of the characteristic features of advanced hepatocellular carcinoma. To formulate an appropriate operative strategy for removing intracaval tumor thrombi, it is of great importance to accurately diagnose the location, any invasion into the wall of the vena cava, and the extent of intracaval tumor spread. Intravascular ultrasonographic imaging is a novel technology that enables the precise catheter-based assessment of the dimensions and morphology of the vascular structure and any lesions. We have applied this technology to the diagnosis of intracaval tumor thrombi originating from adrenal metastasis secondary to hepatocellular carcinomas. This modality was thus found to be useful in determining the best operative procedure for removing tumor thrombi in the inferior vena cava.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/secundario , Carcinoma Hepatocelular/secundario , Ultrasonografía Intervencional , Vena Cava Inferior/diagnóstico por imagen , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/etiología , Neoplasias de las Glándulas Suprarrenales/cirugía , Anciano , Carcinoma Hepatocelular/cirugía , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Invasividad Neoplásica , Sensibilidad y Especificidad , Trombectomía/métodos , Resultado del Tratamiento , Vena Cava Inferior/patología , Vena Cava Inferior/cirugía , Trombosis de la Vena/cirugíaRESUMEN
We report a patient with cholangiocellular carcinoma with tumor thrombi in the main portal trunk who has survived for 9.5 years after hepatic resection. A 57-year-old woman underwent an extended left lobectomy, and resection of the caudate lobe plus the main portal trunk for a liver tumor that had a portal tumor thrombus in the main portal trunk. The portal vein was reconstructed with an autologous vein graft obtained from the external iliac vein. Histological examination of the resected specimen revealed moderately differentiated tubular adenocarcinoma compatible with cholangiocellular carcinoma. Factors contributing to the patient's long-term survival are discussed. Aggressive surgical resection can be effective even for such an advanced case of cholangiocellular carcinoma.
Asunto(s)
Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirugía , Células Neoplásicas Circulantes , Vena Porta , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Toxins convert the hepatocellular response to tumor necrosis factor-alpha (TNF-alpha) stimulation from proliferation to cell death, suggesting that hepatotoxins somehow sensitize hepatocytes to TNF-alpha toxicity. Because nuclear factor-kappaB (NF-kappaB) activation confers resistance to TNF-alpha cytotoxicity in nonhepatic cells, the possibility that toxin-induced sensitization to TNF-alpha killing results from inhibition of NF-kappaB-dependent gene expression was examined in the RALA rat hepatocyte cell line sensitized to TNF-alpha cytotoxicity by actinomycin D (ActD). ActD did not affect TNF-alpha-induced hepatocyte NF-kappaB activation but decreased NF-kappaB-dependent gene expression. Expression of an IkappaB superrepressor rendered RALA hepatocytes sensitive to TNF-alpha-induced apoptosis in the absence of ActD. Apoptosis was blocked by caspase inhibitors, and TNF-alpha treatment led to activation of caspase-2, caspase-3, and caspase-8 only when NF-kappaB activation was blocked. Although apoptosis was blocked by the NF-kappaB-dependent factor nitric oxide (NO), inhibition of endogenous NO production did not sensitize cells to TNF-alpha-induced cytotoxicity. Thus NF-kappaB activation is the critical intracellular signal that determines whether TNF-alpha stimulates hepatocyte proliferation or apoptosis. Although exogenous NO blocks RALA hepatocyte TNF-alpha cytotoxicity, endogenous production of NO is not the mechanism by which NF-kappaB activation inhibits this death pathway.
Asunto(s)
Apoptosis/fisiología , División Celular/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas , División Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de Cisteína Proteinasa/farmacología , ADN/biosíntesis , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/fisiología , Proteínas I-kappa B , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/fisiología , Donantes de Óxido Nítrico/farmacología , Penicilamina/análogos & derivados , Penicilamina/farmacología , Ratas , Proteínas Recombinantes/metabolismo , S-Nitroso-N-Acetilpenicilamina , Timidina/metabolismo , TransfecciónRESUMEN
Previous research from this laboratory using a continuous enteral ethanol (EtOH) administration model demonstrated that Kupffer cells are pivotal in the development of EtOH-induced liver injury. When Kupffer cells were destroyed using gadolinium chloride (GdCl3) or the gut was sterilized with polymyxin B and neomycin, early inflammation due to EtOH was blocked. Anti-tumour necrosis factor (TNF)-alpha antibody markedly decreased EtOH-induced liver injury and increased TNF-mRNA. These findings led to the hypothesis that EtOH-induced liver injury involves increases in circulating endotoxin leading to activation of Kupffer cells. Pimonidazole, a nitro-imidazole marker, was used to detect hypoxia in downstream pericentral regions of the lobule. Following one large dose of EtOH or chronic enteral EtOH for 1 month, pimonidazole binding was increased significantly in pericentral regions of the liver lobule, which was diminished with GdCl3. Enteral EtOH increased free radical generation detected with electron spin resonance (ESR). These radical species had coupling constants matching alpha-hydroxyethyl radical and were shown conclusively to arise from EtOH based on a doubling of the ESR lines when 13C-EtOH was given. Alpha-hydroxyethyl radical production was also blocked by the destruction of Kupffer cells with GdCl3. It is known that females develop more severe EtOH-induced liver injury more rapidly and with less EtOH than males. Female rats on the enteral protocol exhibited more rapid injury and more widespread fatty changes over a larger portion of the liver lobule than males. Plasma endotoxin, ICAM-1, free radical adducts, infiltrating neutrophils and transcription factor NFkappaB were approximately two-fold greater in livers from females than males after 4 weeks of enteral EtOH treatment. Furthermore, oestrogen treatment increased the sensitivity of Kupffer cells to endotoxin. These data are consistent with the hypothesis that Kupffer cells participate in important gender differences in liver injury caused by ethanol.