Involvement of a serine protease, but not of neutrophil elastase, in tumornecrosis factor-induced lethal hepatitis and induction of platelet-activating factor

Background/Aims: Tumor necrosis factor (TNF) plays an essential role in sev eral types of acute and chronic hepatitis. Our aims in the present study we re to elucidate the mechanism by which TNF leads to acute lethal hepatitis, thereby focusing on the role of serine proteases and platelet-activating f actor (PAF). Methods: All experiments were performed in a model of acute hepatitis, indu ced by TNF in combination With D-(+)-galactosamine (GalN). Neutrophil elast ase (NE)-deficient mice, generated by gene targeting were used in the studi es. Results: We found that a serine protease plays an essential mediating role in the in vivo TNF effect as alpha (1)-antitrypsin (alpha (1)-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection. alpha (1)-AT and TTI, but not STI, reduce PAF blood levels, in duced by TNF/GalN, which is compatible with an elastase-like serine proteas e involvement in PAF synthesis. In our search for relevant serine proteases we believed that NE was an excellent candidate protease. However, we found that TNF/GalN-induced lethality is not attenuated in mice deficient in NE. Conclusions: The data suggest that TNF-induced lethal hepatitis is accompan ied by increases in circulating PAF and plasma clotting time, and mediated by a serine protease, but not by NE. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.