title: Primary cirrhotic hepatocytes resist TGFbeta-induced apoptosis through a ROS-dependent mechanism.
abstract: OBJECTIVE
  The cirrhotic liver manifests dysregulated hepatocyte growth by poor regenerative capacity, formation of regenerative nodules, and malignant transformation to hepatocellular carcinoma. The purpose of this study was to determine if dysregulated hepatocyte growth occurs through deficient apoptosis.
  
  
  METHODS
  Hepatocytes were isolated from normal and CCl(4)-treated mice and treated with TGFbeta, TNFalpha, and UV-C, known apoptotic agents.
  
  
  RESULTS
  Cirrhotic hepatocytes were less sensitive to TGFbeta- (45+/-5 vs. 15+/-3%; P<0.003), TNFalpha- (59+/-21 vs. 21+/-8%; P=0.02), and UV-C-induced (31+/-4 vs. 17+/-4%; P<0.03) apoptosis compared to normal hepatocytes. In normal hepatocytes, TGFbeta-induced apoptosis occurred through a ROS-, MPT-, and caspase-dependent pathway. Cirrhotic hepatocytes lacked caspase activation, had decreased procaspase-8 expression, failed to undergo the MPT, and had increased basal ROS activity compared to normal hepatocytes. After treatment with trolox, an antioxidant that reduced basal ROS activity, cirrhotic hepatocytes underwent apoptosis in response to TGFbeta treatment.
  
  
  CONCLUSIONS
  These findings suggest that increased ROS activity in cirrhotic hepatocytes plays a critical role in mediating cirrhotic hepatocyte resistance to apoptosis. Cirrhotic hepatocyte resistance to TGFbeta-induced apoptosis is ROS-dependent and is a mechanism of dysregulated growth in the chronically inflamed liver.
authors.affiliation: Division of Gastrointestinal Surgery, Department of Surgery, University of North Carolina, 320 Medical Wing E, Chapel Hill, NC 27599-7081, USA.
authors.forename: Dalliah
authors.initials: D
authors.lastname: Black
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bird
authors.forename: Charles M
authors.initials: CM
authors.lastname: Samson
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lyman
authors.forename: Patty A
authors.initials: PA
authors.lastname: Lange
authors.forename: Laura W
authors.initials: LW
authors.lastname: Schrum
authors.forename: Ting
authors.initials: T
authors.lastname: Qian
authors.forename: J J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Richard A
authors.initials: RA
authors.lastname: Rippe
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Behrns
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008930:Mitochondria, Liver / Q000187:drug effects / Q000502:physiology; D010539:Permeability; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D020169:Caspases