Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models.
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Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. / Leist, M; Gantner, F; Bohlinger, I; Tiegs, Gisa; Germann, P G; Wendel, A.
in: AM J PATHOL, Jahrgang 146, Nr. 5, 5, 1995, S. 1220-1234.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models.
AU - Leist, M
AU - Gantner, F
AU - Bohlinger, I
AU - Tiegs, Gisa
AU - Germann, P G
AU - Wendel, A
PY - 1995
Y1 - 1995
N2 - We investigated the role of hepatocyte apoptosis in four different murine models of acute inflammatory liver failure. Liver damage induced in D-galactosamine-sensitized mice by endotoxin infection was initiated by processes typical of apoptosis, ie, chromatin condensation, DNA fragmentation, and formation of intracellular apoptotic bodies. DNA was cleaved into oligonucleosomal fragments in the liver before a significant rise of alanine aminotransferase in plasma occurred. Passive immunization against tumor necrosis factor (TNF) completely inhibited the injury caused by endotoxin. Direct injection of recombinant TNF-alpha also caused DNA fragmentation followed by alanine aminotransferase release into the plasma. Pretreatment of mice with interleukin-1 beta, which is known to suppress TNF-induced lethality, completely prevented apoptosis and liver failure in this model. These results demonstrate the causal role of TNF in endotoxin-induced hepatic apoptosis. TNF-inducible hepatocyte apoptosis in vivo was not only observed in D-galactosamine-sensitized mice, but also when the alternative transcriptional inhibitor actinomycin D was used. In mice injected with the TNF-inducing T cell mitogen concanavalin A, hepatic apoptosis was even noticed without requirement of additional sensitizers. We conclude that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.
AB - We investigated the role of hepatocyte apoptosis in four different murine models of acute inflammatory liver failure. Liver damage induced in D-galactosamine-sensitized mice by endotoxin infection was initiated by processes typical of apoptosis, ie, chromatin condensation, DNA fragmentation, and formation of intracellular apoptotic bodies. DNA was cleaved into oligonucleosomal fragments in the liver before a significant rise of alanine aminotransferase in plasma occurred. Passive immunization against tumor necrosis factor (TNF) completely inhibited the injury caused by endotoxin. Direct injection of recombinant TNF-alpha also caused DNA fragmentation followed by alanine aminotransferase release into the plasma. Pretreatment of mice with interleukin-1 beta, which is known to suppress TNF-induced lethality, completely prevented apoptosis and liver failure in this model. These results demonstrate the causal role of TNF in endotoxin-induced hepatic apoptosis. TNF-inducible hepatocyte apoptosis in vivo was not only observed in D-galactosamine-sensitized mice, but also when the alternative transcriptional inhibitor actinomycin D was used. In mice injected with the TNF-inducing T cell mitogen concanavalin A, hepatic apoptosis was even noticed without requirement of additional sensitizers. We conclude that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Galactosamine/pharmacology
KW - Lipopolysaccharides/pharmacology
KW - Tumor Necrosis Factor-alpha/pharmacology
KW - Dactinomycin/pharmacology
KW - Apoptosis/drug effects/physiology
KW - DNA/analysis
KW - Liver/cytology/drug effects
KW - Liver Failure/etiology
KW - Multiple Organ Failure/etiology
KW - Proteins/analysis
KW - RNA/analysis
KW - Shock, Septic/complications
KW - Animals
KW - Male
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Galactosamine/pharmacology
KW - Lipopolysaccharides/pharmacology
KW - Tumor Necrosis Factor-alpha/pharmacology
KW - Dactinomycin/pharmacology
KW - Apoptosis/drug effects/physiology
KW - DNA/analysis
KW - Liver/cytology/drug effects
KW - Liver Failure/etiology
KW - Multiple Organ Failure/etiology
KW - Proteins/analysis
KW - RNA/analysis
KW - Shock, Septic/complications
M3 - SCORING: Journal article
VL - 146
SP - 1220
EP - 1234
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 5
M1 - 5
ER -
