The c-Jun-N-terminal kinase (JNK) pathway is strongly activated after partial hepatectomy (PH), but its role in hepatocyte proliferation is not known. In this study, JNK activity was blocked with the small molecule inhibitor JNK SP600125 in vivo and in vitro as shown by a reduction of c-Jun phosphorylation, AP-1 DNA binding activity, and c-jun messenger RNA (mRNA) expression. SP600125 inhibited proliferating cell nuclear antigen (PCNA) expression, cyclin D1 mRNA and protein expression and reduced mitotic figures after PH. Survival was reduced significantly 3 days after PH in SP600125-treated versus vehicletreated rats (3 of 11 vs. 8 of 9, P < .01). In epidermal growth factor (EGF)-treated primary cultures of rat hepatocytes, SP600125 decreased 3 H-thymidine uptake, cyclin D1 mRNA and protein expression, and inhibited the EGF-induced transcription of a cyclin D1 promoter-driven reporter gene. The defective regeneration and the decreased survival in SP600125-treated rats did not result from a major increase in apoptosis as shown by normal levels of caspase 3 activity and only slight increases in apoptotic figures. In conclusion, our data show that JNK drives G0 to G1 transition in hepatocytes and that cyclin D1 is a downstream target of the JNK pathway during liver regeneration. (HEPATOLOGY 2003;37: 824-832.)
JNK inhibition decreases hepatic necrosis and apoptosis after OLT, suggesting that JNK activation promotes cell death by both pathways. Inhibition of JNK may be a new therapeutic strategy to prevent liver injury after transplantation.
Proliferative cholangitis (PC) associated with hepatolithiasis develops the stricture of main bile ducts, and is the main cause of residual and/or recurrent stones after repeated treatments for hepatolithiasis. The aim of this study was to inhibit PC using the cytostatic gene therapy with direct adenovirus-mediated retinoblastoma (Rb) gene transfer to the biliary tract. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. The adenovirus vector encoding a nonphosphorylatable, constitutively active form of retinoblastoma gene product (AdRb) was administered directly into the biliary tract. The adenovirus vector encoding -galactosidase (AdlacZ) was also given as a control. The bile duct wall thickness and 5Ј-bromodeoxyuridine (BrdU) labeling index were compared among uninfected, AdlacZ-infected, and AdRb-infected PC rats. The Rb expression in the bile duct was detected using reversetranscription polymerase chain reaction (RT-PCR) and immunohistochemical study. AdRb-infected bile ducts showed inhibition of the epithelial and fibrous tissue proliferation and the peribiliary gland hyperplasia, resulting in a significant reduction of wall thickness compared with uninfected and AdlacZ-infected ones. The BrdU labeling index was 4.87% ؎ 3.06% in the AdRb-infected bile ducts, while those of uninfected and AdlacZ-infected ones were 15.48% ؎ 4.61% and 11.72% ؎ 1.23%, respectively (P F .05). In conclusion, our cytostatic gene therapy approach using direct Rb gene transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrences following treatments against hepatolithiasis. (HEPATOLOGY 1998;28:605-612.)
Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation. Am J Physiol Gastrointest Liver Physiol 291: G456 -G463, 2006. First published May 18, 2006 doi:10.1152/ajpgi.00480.2005.-Hemorrhagic shock and resuscitation cause endotoxemia and hepatocellular damage. Because lipopolysaccharide-binding protein (LBP) enhances cellular responses to endotoxin, our aim was to determine whether LBP contributes to hemorrhage/resuscitation-induced injury by comparing LBP knockout and wild-type mice. Under pentobarbital anaesthesia, wild-type and LBP-deficient mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer solution. Serum alanine aminotransferase (ALT) necrosis, neutrophil infiltration, and 4-hydroxynonenal by histology/ cytochemistry and stress kinase activation by immunoblot analysis were then determined. ALT in wild-type mice was 2,461 Ϯ 383 and 1,418 Ϯ 194 IU/l (means Ϯ SE), respectively, at 2 and 6 h after resuscitation versus sham ALT of 102 Ϯ 6 IU/l. In LBP-deficient mice, ALT was blunted at both time points to 1,108 Ϯ 340 and 619 Ϯ 171 IU/l (P Ͻ 0.05). Liver necrosis after 6 h was also attenuated from 3.5 Ϯ 0.8% in wild-type mice to 1.3 Ϯ 0.5% in LBP-deficient mice (P Ͻ 0.05). After hemorrhage/resuscitation, neutrophil infiltration increased 71% more in wild-type than LBP knockout mice. Similarly, hepatic 4-hydroxynonenal staining, indicative of lipid peroxidation, decreased from 33.8 Ϯ 4.5% in wild-type mice to 11.6 Ϯ 1.9% in knockout mice (P Ͻ 0.05).
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