The role of connexins, pannexins and their channels in liver fibrosis.

While connexin-based gap junctions have been historically considered as goal keepers of tissue physiology, connexin hemichannels and pannexin channels have lately gained considerable attention as drivers of pathological processes, including cell death and inflammation. The objective of this doctoral thesis project was to investigate the role of the latter 2 channel types, in particular hemichannels consisting of connexin32 (Cx32) and connexin43 (Cx43) as well as pannexin channels built up by pannexin1 (Panx1), in chronic liver disease. Focus was hereby put on liver fibrosis, which is characterized by scar formation in response to liver damage, oxidative stress and inflammation associated with several types of chronic liver disease. In a first study, it was found that administration of a specific Cx43 hemichannel inhibitor or a general connexin-based channel inhibitor to mice with liver fibrosis reduced hepatic oxidative stress and inflammation, respectively. Furthermore, both treatments alleviated liver fibrosis, thus underscoring the involvement of Cx43 hemichannels in chronic liver disease. In a second study, genetic ablation of Cx32 in mice revealed enhanced scar formation, liver damage and oxidative stress in a mouse model of liver fibrosis, pointing to a protective role for Cx32 signaling in liver fibrosis. In a third study, genetic ablation of Panx1 in 2 mouse models of liver fibrosis showed a different outcome with respect to scar formation, liver damage and inflammation, suggesting that the involvement of Panx1 in liver fibrogenesis is etiology-dependent. Collectively, the outcome of these 3 studies confirms the pathological role of connexin hemichannel and pannexin channel signaling and opens new perspectives for the clinical treatment of liver fibrosis.