| First Author | Oberholzer A | Year | 2001 |
| Journal | J Endotoxin Res | Volume | 7 |
| Issue | 5 | Pages | 375-80 |
| PubMed ID | 11753206 | Mgi Jnum | J:117350 |
| Mgi Id | MGI:3696290 | Citation | Oberholzer A, et al. (2001) Genetic determinants of lipopolysaccharide and D-galactosamine-mediated hepatocellular apoptosis and lethality. J Endotoxin Res 7(5):375-80 |
| abstractText | Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent upon endogenously produced TNF-alpha. Unlike the response to high dose lipopolysaccharide alone, death in this model is a direct result of hepatocyte apoptosis. In a series of recent studies, we have demonstrated that mortality and hepatic injury following lipopolysaccharide administration in D-galactosamine-sensitized mice is dependent upon secreted 17 kDa TNF-alpha acting primarily through the p55 TNF receptor. Transgenic mice expressing null forms of TNF-alpha, the p55 receptor, or expressing only a cell-associated form of TNF-alpha exhibited no mortality and only modest liver injury when challenged with 8 mg of D-galactosamine and 100 ng of lipopolysaccharide. Although Fas ligand expression is increased in the liver, it appeared to play no significant role in outcome, since mice expressing a mutant form of Fas ligand are still sensitive to LPS- and D-galactosamine-induced lethality. Finally, we have seen significant variation in LPS- and D-galactosamine-mediated lethality among different strains of mice. The non-obese diabetic or NOD mouse is highly resistant to LPS-and D-galactosamine-induced lethality, and this appears to be secondary to a post-receptor defect in p55 TNF receptor signaling. The studies confirm an essential role for TNF-alpha and p55 TNF receptor signaling in the hepatocyte apoptosis and lethality associated with lipopolysaccharide and D-galactosamine administration. |
