PMID- 11733355
OWN - NLM
STAT- MEDLINE
DCOM- 20011218
LR  - 20190607
IS  - 0002-9440 (Print)
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 159
IP  - 6
DP  - 2001 Dec
TI  - Cathepsin B knockout mice are resistant to tumor necrosis factor-alpha-mediated 
      hepatocyte apoptosis and liver injury: implications for therapeutic applications.
PG  - 2045-54
AB  - Tumor necrosis factor-alpha (TNF-alpha) contributes to liver injury by inducing 
      hepatocyte apoptosis. Recent evidence suggests that cathepsin B (cat B) 
      contributes to TNF-alpha-induced apoptosis in vitro. The aim of the present study 
      was to determine whether cat B contributes to TNF-alpha-induced hepatocyte 
      apoptosis and liver injury in vivo. Cat B knockout (catB(-/-)) and wild-type 
      (catB(+/+)) mice were first infected with the adenovirus Ad5I kappa B expressing 
      the I kappa B superrepressor to inhibit nuclear factor-kappa B-induced survival 
      signals and then treated with murine recombinant TNF-alpha. Massive hepatocyte 
      apoptosis with mitochondrial release of cytochrome c and activation of caspases 9 
      and 3 was detected in catB(+/+) mice 2 hours after the injection of TNF-alpha. In 
      contrast, significantly less hepatocyte apoptosis and no detectable release of 
      cytochrome c or caspase activation occurred in the livers of catB(-/-) mice. By 4 
      hours after TNF-alpha injection, only 20% of the catB(+/+) mice were alive as 
      compared to 85% of catB(-/-) mice. Pharmacological inhibition of cat B in 
      catB(+/+) mice with 
      L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-L-isoleucyl-L-proline (CA-074 Me) 
      also reduced TNF-alpha-induced liver damage. The present data demonstrate that a 
      cat B-mitochondrial apoptotic pathway plays a pivotal role in TNF-alpha-induced 
      hepatocyte apoptosis and liver injury.
FAU - Guicciardi, M E
AU  - Guicciardi ME
AD  - Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and 
      Foundation, Rochester, Minnesota 55905, USA.
FAU - Miyoshi, H
AU  - Miyoshi H
FAU - Bronk, S F
AU  - Bronk SF
FAU - Gores, G J
AU  - Gores GJ
LA  - eng
GR  - R01 DK041876/DK/NIDDK NIH HHS/United States
GR  - R37 DK041876/DK/NIDDK NIH HHS/United States
GR  - DK 41876/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Dipeptides)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 134448-10-5 (N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline)
RN  - EC 3.4.22.1 (Cathepsin B)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Cathepsin B/antagonists & inhibitors/genetics/*physiology
MH  - Chemical and Drug Induced Liver Injury
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Dipeptides/pharmacology
MH  - Drug Resistance
MH  - Female
MH  - Genetic Vectors/genetics
MH  - Genotype
MH  - Hepatocytes/*drug effects
MH  - I-kappa B Proteins/genetics
MH  - Liver/*drug effects/pathology
MH  - Liver Diseases/genetics/prevention & control
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/physiology
MH  - Signal Transduction/drug effects
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*pharmacology
PMC - PMC1850591
EDAT- 2001/12/06 10:00
MHDA- 2002/01/05 10:01
PMCR- 2002/06/01
CRDT- 2001/12/06 10:00
PHST- 2001/12/06 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/12/06 10:00 [entrez]
PHST- 2002/06/01 00:00 [pmc-release]
AID - S0002-9440(10)63056-8 [pii]
AID - 2940 [pii]
AID - 10.1016/s0002-9440(10)63056-8 [doi]
PST - ppublish
SO  - Am J Pathol. 2001 Dec;159(6):2045-54. doi: 10.1016/s0002-9440(10)63056-8.