Final Report Summary - CONNECT (Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease)
Evidence has been accumulating over the past decade indicating that connexin (Cx) hemichannels and pannexin (Panx) channels can act as pathological pores that connect the cytoplasm of cells with the extracellular environment, and that facilitate cell death and inflammation. This is considered of high clinical relevance, as it offers the possibility to therapeutically limit the propagation of both processes and thus the manifestation of a plethora of diseases. The CONNECT project specifically addressed liver disease in this respect and had 2 main objectives, namely (i) to test connexin hemichannels and pannexin channels as drug targets for the clinical therapy of acute and chronic liver disease, and (ii) to test connexin and pannexin proteins as biomarkers for the clinical diagnosis of acute and chronic liver disease. Focus was put on 2 connexin species and 1 pannexin family member highly expressed in liver, namely Cx32, Cx43 and Panx1, as well as on 3 liver diseases, including acute liver failure induced by paracetamol, non-alcoholic steatohepatitis and liver fibrosis. A total of 10 studies has been performed in this research context in the period 1 March 2014 to 28 February 2019. Study 1 showed that Cx43 might be an interesting biomarker of acute liver disease that as such may alleviate hepatic injury. Study 2 revealed that reduction of Cx32 and Cx43 hemichannel activity by newly developed peptide-based inhibitors may be a promising way to clinically treat acute liver failure. In study 3, it was found that inhibition of Panx1 channel opening could represent a novel approach for the treatment of paracetamol-induced acute hepatotoxicity. This was reinforced by the outcome of study 4, showing that genetic ablation of Panx1 leads to protection against acute liver toxicity. Study 5 showed that Cx32-based signaling is not directly involved in fat accumulation as such, but rather in the sequelae of this process, which underlie the progression of non-alcoholic steatohepatitis. Study 6 identified the involvement of Cx32 and Cx43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggested a role as potential drug targets in this highly prevalent type of chronic liver disease. Study 7, based on genetic ablation of Panx1, demonstrated that Panx1 signaling drives the pathogenesis of non-alcoholic steatohepatitis. Study 8 showed that Cx32 signaling mediates tissue resistance against liver damage and that Cx32 signaling may serve a therapeutic purpose in the treatment of liver fibrosis. In study 9, it was found that Cx43 signaling through both gap junctions and hemichannels plays a facilitating role in the pathogenesis of liver fibrosis. Study 10 was the first to demonstrate an etiology-dependent role for Panx1 signaling in liver fibrosis and concomitantly characterized the therapeutic potential of Panx1-based communication in this type of chronic liver disease. The major conclusion of these 10 studies performed as part of the CONNECT project is that pharmacological inhibition of Cx32 and Cx43 hemichannels as well as of Panx1 channels reduces the clinical manifestation of acute liver failure, non-alcoholic steatohepatitis and liver fibrosis. This suggests a generic role for these channels as therapeutic drug targets in the hepatology field. In follow-up initiatives of the CONNECT project, focus will be put on the generation of novel compounds to inhibit Cx32 and Cx43 hemichannels as well as Panx1 channels that are better suited for clinical application and pharmaceutical development. It can be anticipated that upon further exploration, a solid basis will be laid in the upcoming years for a new generation of target-directed drugs for the effective treatment of acute and chronic liver disease. This is urgently needed given the worldwide epidemiological and economic relevance of hepatic pathologies.