Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model

作者：Sara Crespo Yanguas, Tereza C. da Silva, Isabel Veloso Alves Pereira, Michaël Maes, Joost Willebrords, Valery I. Shestopalov, Bruna Goes, Marina Sayuri Nogueira, Inar Alves de Castro, Guilherme Ribeiro Romualdo, Luı́s Fernando Barbisan, Eva Gijbels, Mathieu Vinken, Bruno Cogliati · 发表于：Archives of Toxicology · 年份：2018 · DOI：10.1007/s00204-018-2255-3 · 被引用次数：23 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Advanced Glycation End Products research、Connexins and lens biology

Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. This chronic disease is characterized by excessive deposition of extracellular matrix components mainly due to transdifferentiation of quiescent hepatic stellate cell into myofibroblasts-like cells, which in turn is driven by cell death and inflammation. In the last few years, paracrine signaling through pannexin1 channels has emerged as a key player in the latter processes. The current study was set up to investigate the role of pannexin1 signaling in liver fibrosis. Wild-type and whole body pannexin1 knock-out mice were treated with carbon tetrachloride or subjected to bile duct ligation. Evaluation of the effects of pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, oxidative stress, inflammation and regenerative capacity. In parallel, to elucidate the molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. While pannexin1 knock-out mice treated with carbon tetrachloride displayed reduced collagen content, hepatic stellate cell activation, inflammation and hepatic regeneration, bile duct ligated counterparts showed increased hepatocellular injury and antioxidant enzyme activity with a predominant immune response. Gene expression profiling revealed a downregulation of fibrotic and imm...