par Minsart, Charlotte 
;Gustot, Thierry
Référence Revue médicale de Bruxelles, 43, 3, page (203-208)
Publication Publié, 2022-05-01
;Gustot, Thierry Référence Revue médicale de Bruxelles, 43, 3, page (203-208)
Publication Publié, 2022-05-01
Article révisé par les pairs
| Résumé : | Acetaminophen overdose is one of the most frequent drug intoxication in the world, characterized by hepatic damage whose outcome can be fatal. Indeed, in case of severe overdose, hepatocytes eventually die leading to irreversible liver damage. The studies carried out in this field, for the most part, point to the intervention of innate immune cells to justify the hepatic damage. However, some grey areas still remain in the understanding of these mechanisms of hepatic toxicity. In this thesis work, we identify a cellular mechanism dependent on the High-Mobility Group Box 1 (HMGB1) protein, which amplifies and propagates the hepatic lesions initially induced by acetaminophen, and which does not require the intervention of innate immune cells. On the one hand, we demonstrate in vitro, that the HMGB1 protein is at the origin of a toxic positive feedback loop. Once released by necrotic hepatocytes, it is able to bind to neighboring hepatocytes and induce their death by necroptosis by activating a TLR4/TRIF/RIPK3 axis dependent signaling pathway. On the other hand, we demonstrate in vivo in mice, that the association of glycyrrhizin (HMGB1 inhibitor) with N-acetylcysteine (Lysomucil®), recognized treatment for acetaminophen overdose, have a therapeutic benefit. In conclusion, this thesis work confirmed the harmful role of HMGB1 in paracetamol overdose, highlighted a new mechanism of liver toxicity and finally opened new potential therapeutic avenues. |
