Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury.
OBJECTIVE
Fulminant hepatic failure is a dangerous condition, which occurs when large parts of the liver become damaged beyond repair, and the liver is no longer able to function. This syndrome is induced by inflammatory processes, resulting in acute liver failure. Recently, the organotellurium compound, trichloro(dioxoethylene-O,O(')) tellurate (AS101), has been found by our group to be able to directly inhibit caspases, due to its Te(IV)-thiol chemistry. The aim of this study was to examine the potential of AS101 as an anti-inflammatory and anti-apoptotic compound in vitro and in vivo following liver injury.


METHODS
Propionibacterium acnes-primed LPS-induced liver injury was performed in Balb/c mice. ALT/AST, cytokines, caspase-1,-3 and-8 activities, and liver histology were assessed.


RESULTS
AS101 inhibited TNFalpha or anti-FAS-induced apoptotic processes in hepatocytes in vitro. A P. acnes+LPS in vivo liver injury model revealed lower serum ALT and AST and reduced necrosis and apoptosis in AS101-treated mice. IL-18 and IL-1beta reduced levels in AS101-treated mice were associated with caspase-1 activity inhibition. Our findings suggest IL-6, IL-17 and pSTAT3 as additional novel players in the pathogenicity of FHF. Inhibition of caspase-3, and-8 activities by AS101 treatment contributed to decreased hepatocyte death, resulting in increased survival.


CONCLUSIONS
We suggest that due to its interaction with key-target cysteine residues, AS101 mediates anti-inflammatory and anti-apoptotic effects in this FHF model, which may serve as a potent treatment for mitigation of hepatic damage.
Brodsky
Miri
M
C.A.I.R. Institute, The Safdiè AIDS and Immunology Research Center, The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, 52900 Ramat-Gan, Israel.
Hirsh
Shira
S
Albeck
Michael
M
Sredni
Benjamin
B
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005030:Ethylenes / Q000494:pharmacology / Q000627:therapeutic use*; D006505:Hepatitis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005030:Ethylenes; D008070:Lipopolysaccharides; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020169:Caspases