Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure

Rodrigo García-Lastra , Beatriz San-Miguel , Irene Crespo , Francisco Jorquera , Marcelino Alvarez , Javier González-Gallego , María J. Tuñón

Management of fulminant hepatic failure (FHF) continues to be one challenging problem, and experimental animal models resembling its clinical conditions are still needed. Rabbit hemorrhagic disease (RHD) fullfils many requirements of an animal model of FHF. This work investigated changes in MAPK, NF-κB, AP-1 and STAT pathways during RHD-induced liver injury. Rabbits were infected with 2 × 104 hemagglutination units of an RHD virus isolate. Apoptosis was documented by the presence of caspase-3 activity and substantial PARP proteolysis at 36 and 48 h postinfection (pi). Infection induced a marked and maintained expression of TNF-α from 12 h pi, while there was only a transitory increase in IL-6 expression. Expression of phosphorylated (p)-JNK, p-p38 and p-ERK1/2 was significantly elevated at 12 h pi. At 48 h pi p-JNK expression was maintained at a maximum level, while that of p-p38 returned to normality and there was no p-ERK1/2 expression. Activation of NF-κB and AP-1 and increased expression of VCAM-1 and COX-2 were observed. No significant changes were detected in activation of STAT1 and STAT3, while SOCS3 expression increased significantly. The current findings suggest that activation of JNK is an essential component in liver injury mediated by the RHD virus and that lack of activation of STAT3, probably mediated by SOCS3 over-expression, would contribute to the inhibition of the regenerative response. Data show the presence of molecular mechanisms contributing to liver damage and the lack of regeneration and they support the usefulness of this model to investigate novel therapeutical modalities in FHF.

Mots clés: rabbit hemorrhagic disease; fulminant hepatic failure; mitogen-activated protein kinase; nuclear factor kappa B; signal transducer and activator of transcription

Domaines: Biologie moléculaire; Génétique animale; Biologie cellulaire; Interactions cellulaires [q-bio.CB]; Microbiologie et Parasitologie; Immunologie; Neurosciences [q-bio.NC]; Santé publique et épidémiologie; Biologie animale

Rodrigo García-Lastra, Beatriz San-Miguel, Irene Crespo, Francisco Jorquera, Marcelino Alvarez, et al.. Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure. Veterinary Research, 2010, 41 (1), ⟨10.1051/vetres/2009050⟩. ⟨hal-00903140⟩