The role of connexins, pannexins and their channels in acute liver failure

In the past few years, connexin hemichannels and pannexin channels have emerged as so-called pathological pores, since they drive a number of deleterious events, including cell death and inflammation. The objective of this doctoral thesis project was to investigate the role of both channel types, in particular hemichannels consisting of connexin32 (Cx32) and connexin43 (Cx43) as well as pannexin channels built up by pannexin1 (Panx1), in liver disease. Specific focus was hereby put on hepatotoxicity induced by paracetamol, also called acetaminophen (APAP), which is characterized by a substantial degree of cell death and inflammation, and that presently is a major cause of acute liver failure worldwide. Throughout this project, considerable attention has been paid to the testing of the utility of currently available experimental tools to investigate Cx32 and Cx43 hemichannels as well as Panx1 channels. In this respect, the first study showed that whole-body Cx32 knock-out mice qualify less as models to study Cx32 signaling in APAP-induced hepatotoxicity. In the second study, it was found that hepatic Cx43 production increases in mice overdosed with APAP and that Cx43 signaling protects against this type of chemical insult. In the third study, the claimed specificity and efficacy of peptide-based inhibitors of Cx32 and Cx43 hemichannels was confirmed in vitro and their subsequent administration to APAP-intoxicated mice resulted in reduced adverse outcome. The latter was equally observed in the fourth study following treatment of APAP-overdosed mice with a peptide-based inhibitor of Panx1 channels. Overall, this doctoral thesis project showed the promising potential of connexin hemichannels and pannexin channels as clinical drug targets, in casu in the specific context of APAP-induced acute liver failure.