PMID- 11410731
OWN - NLM
STAT- MEDLINE
DCOM- 20010802
LR  - 20200914
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 25
IP  - 6
DP  - 2001 Jun
TI  - Inhibition of caspases in vivo protects the rat liver against alcohol-induced 
      sensitization to bacterial lipopolysaccharide.
PG  - 935-43
AB  - BACKGROUND: The mechanisms of liver sensitization by alcohol to Gram-negative 
      bacterial lipopolysaccharide (LPS) remain elusive. The purpose of this study was 
      two-fold: (1) to test the hypothesis that alcohol-enhanced liver apoptosis may be 
      a sensitizing mechanism for LPS and (2) to further characterize the liver 
      apoptotic response to alcohol. METHODS: Rats were fed a high-fat, 
      alcohol-containing liquid diet for 14 weeks, treated with LPS (1.0 mg/kg of body 
      weight, intravenously) or saline, followed by injection of a pan-caspase 
      inhibitor IDN1965; 
      N-[(1,3-dimethylindole-2-carbonyl)-valinyl]-3-amino-4-oxo-5-fluoropentanoic acid; 
      10 mg/kg of body weight, intraperitoneally or vehicle, and killed. The following 
      parameters were assessed: plasma aspartate: 2-oxoglutarate aminotransferase 
      activity (AST); liver histology and terminal deoxyribonucleotidyl 
      transferase-mediated dUTP nick end labeling (TUNEL) response; caspase-3, -8, and 
      -9 activity; and mRNA and protein expression for two apoptosis-signaling 
      molecules: Fas receptor and Fas ligand; and three apoptosis adaptors: Bax, 
      Bcl-XL, and Bcl-2. RESULTS: Alcohol-feeding-induced liver steatosis, slightly 
      increased caspases' activity, the number of TUNEL-positive nuclei, and 
      facilitated the LPS necrotic effect without affecting mRNA expression of 
      apoptosis signals and adaptors. LPS induced a significant increase in AST and the 
      number of TUNEL-positive nuclei, both effects being more pronounced in 
      alcohol-treated rats. LPS produced hepatic necrosis only in alcohol-treated rats. 
      LPS effects were associated with up-regulation of mRNA expression for both 
      apoptosis adaptors and signaling molecules. IDN1965 administration 3 hr after LPS 
      injection strongly inhibited caspases' activity, particularly that of caspase-3. 
      IDN1965 also abolished the increase in TUNEL-positive nuclei, reversed the effect 
      of LPS on plasma AST in alcohol-treated rats, and prevented LPS-induced necrosis. 
      CONCLUSIONS: (1) Alcohol-enhanced liver apoptosis may not involve regulatory 
      steps at the transcriptional level. LPS-induced liver apoptosis seems to involve 
      transcriptional regulation of several apoptosis adaptors. Therefore, alcohol and 
      LPS may enhance liver apoptosis through different mechanisms. (2) 
      Alcohol-enhanced liver apoptosis precedes and may facilitate the hepatic effects 
      of LPS. LPS superimposed on alcohol further elevates the rate of apoptosis in the 
      liver. This may exceed the phagocytosing capacity of the liver so that all the 
      apoptotic cells are not phagocytosed, but rather die of necrosis.
FAU - Deaciuc, I V
AU  - Deaciuc IV
AD  - Division of Digestive Diseases, A. B. Chandler Medical Center, University of 
      Kentucky, Lexington, Kentucky 40536, USA. ivdeac0@pop.uky.edu
FAU - D'Souza, N B
AU  - D'Souza NB
FAU - de Villiers, W J
AU  - de Villiers WJ
FAU - Burikhanov, R
AU  - Burikhanov R
FAU - Sarphie, T G
AU  - Sarphie TG
FAU - Hill, D B
AU  - Hill DB
FAU - McClain, C J
AU  - McClain CJ
LA  - eng
GR  - AA 12314/AA/NIAAA NIH HHS/United States
GR  - AA00297K24/AA/NIAAA NIH HHS/United States
GR  - AA10762/AA/NIAAA NIH HHS/United States
GR  - AA12774/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Fas Ligand Protein)
RN  - 0 (Faslg protein, rat)
RN  - 0 (Indoles)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (N-((1,3-dimethylindole-2-carbonyl)-valinyl)-3-amino-4-oxo-5-fluoropentanoic 
      acid)
RN  - 0 (Oligopeptides)
RN  - 0 (RNA, Messenger)
RN  - 0 (fas Receptor)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.6.1.1 (Aspartate Aminotransferases)
RN  - EC 3.4.22.- (Casp3 protein, rat)
RN  - EC 3.4.22.- (Casp8 protein, rat)
RN  - EC 3.4.22.- (Casp9 protein, rat)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Aspartate Aminotransferases/blood
MH  - Caspase 3
MH  - Caspase 8
MH  - Caspase 9
MH  - *Caspase Inhibitors
MH  - Caspases/metabolism
MH  - Enzyme Inhibitors/*pharmacology
MH  - Ethanol/administration & dosage/*adverse effects
MH  - Fas Ligand Protein
MH  - Fatty Liver/chemically induced
MH  - In Situ Nick-End Labeling
MH  - Indoles/pharmacology
MH  - Lipopolysaccharides/*pharmacology
MH  - Liver/*drug effects/pathology
MH  - Liver Diseases, Alcoholic/pathology
MH  - Male
MH  - Membrane Glycoproteins/analysis/genetics
MH  - Necrosis
MH  - Oligopeptides/pharmacology
MH  - RNA, Messenger/analysis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - fas Receptor/analysis/genetics
EDAT- 2001/06/19 10:00
MHDA- 2001/08/03 10:01
CRDT- 2001/06/19 10:00
PHST- 2001/06/19 10:00 [pubmed]
PHST- 2001/08/03 10:01 [medline]
PHST- 2001/06/19 10:00 [entrez]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2001 Jun;25(6):935-43.