Involvement of tumor necrosis factor-α in development of hepatic injury in galactosamine-sensitized mice

Abstract

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 micrograms/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor-like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor-sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor-alpha with polyvalent rabbit anti-mouse tumor necrosis factor-alpha antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor-alpha on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor-alpha, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.

Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure

“…TNF-␣ is a key mediator in LPS/GalN-induced murine ALF 11,19 ; therefore, we assessed whether production of TNF-␣ is similar in Ron TK Ϫ/Ϫ mice compared with Ron TK ϩ/ϩ mice. Serum TNF-␣ levels were assessed at hourly time intervals after injection of LPS/GalN (Fig.…”

“…[9][10][11] LPS-induced effects on Kupffer cells, the resident macrophage population of the liver, play a prominent role in many human liver disease processes, including ALF. [12][13][14] LPS stimulates Kupffer cells to release tumor necrosis factor ␣ (TNF-␣) 15,16 as well as a cohort of additional inflammatory cytokines such as interleukin 6 (IL-6), IL-10, and interferon gamma (IFN-␥).…”

Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice

“…TNF-␣-induced hepatocyte apoptosis is the main event in this model. 6,9 TNF receptor I in hepatocytes transduces apoptotic signals through a cytoplasmic death effector domain. 10,11 In one apoptotic pathway, activation of caspase-8 through interaction of TRADD with FADD/MORT1 leads to sequential activation of ICE (caspase-1) and CPP32 (caspase-3).…”

“…7 Because rodents are more than 1,000-fold less sensitive toward LPS than humans, sensitization by D-galactosamine (GalN) together with LPS injection has been often used as an animal model of fulminant hepatic failure. 6,8,9 Mice treated with a combination of LPS ϩ GalN selectively develop hepatic failure, which is much more severe and more rapid than fulminant hepatic failure in humans, as well as liver injury in the mice, as induced by a high dose of LPS alone, without sensitization. 6,7 Studies showed that tumor necrosis factor ␣ (TNF-␣)-induced massive hepatocyte apoptosis is a predominant mechanism functioning in this model, while complex factors are involved like fulminant hepatic failure in humans.…”

“…6,7 Studies showed that tumor necrosis factor ␣ (TNF-␣)-induced massive hepatocyte apoptosis is a predominant mechanism functioning in this model, while complex factors are involved like fulminant hepatic failure in humans. 6,9 Kupffer cells activated by LPS secrete TNF-␣, 5 which binds to TNF receptor I on hepatocytes, and signal transduction pathways toward apoptosis and antiapoptosis with dual natures are activated. 10,11 While TNF-␣ induces a positive apoptotic signal leading to activation of the caspase (ICE family proteases) cascade via TRADD 12 and an additional apoptotic signal via RIP, 11,13 the TNF receptor I activates transcription factor nuclear factor-B, 10 which induces the expression of specific molecules that inhibit TNF-␣-induced cytotoxicity.…”