Extracellular adenosine: a critical signal in liver fibrosis

Extracellular adenosine nucleoside is a potent, endogenous mediator that signals through specific G protein-coupled receptors, and exerts pleiotropic effects on liver physiology, in health and disease. Particularly, adenosinergic or adenosine-mediated signaling pathways impact the progression of hepatic fibrosis, a common feature of chronic liver diseases, through regulation of matrix deposition by liver myofibroblasts. This review examines the current lines of evidence on adenosinergic regulation of liver fibrosis and myofibroblasts, identifies unanswered research questions, and proposes important future areas of investigation.

The Role of Cytokines TGF-β1 and FGF-1 in the Expression of Characteristic Markers of Rat Liver Myofibroblasts Cultured in Three-Dimensional Collagen Gel

Rat liver myofibroblasts (MFB) are the key cells involved in the deposition of extracellular matrix in fibrotic liver. They were isolated by repeated passaging of non-parenchymal cell fraction and cultured in 3-dimensional (3D) collagen gel mimicking tissue. The transfer of MFB from plastic dishes to collagen resulted in the change in their shape from large and spread to slender with long extensions. The expression of transforming growth factor-β1 (TGF-β1) and of MFB markers, α-smooth muscle actin (α-SMA) and cellular fibronectin (EDA-FN), on protein level was significantly decreased in collagen gel. The gel did not change the expression of metalloproteinase MMP-2 but activated the proenzyme. The experiments with inhibitors of metabolic pathways showed that EDA-FN and α-SMA were differently regulated. The expression of EDA-FN required functional TGF-β1 receptors and was also dependent on the activity of protein kinases MEK1 and MEK2. α-SMA expression was primarily determined by the 3D environment. Fibroblast growth factor-1 (FGF-1) in combination with heparin decreased the expression of α-SMA and increased the expression of EDA-FN in the cells on plastic. The cellular environment may influence the cells per se and may modify the action of other agents.

New Developments on the Treatment of Liver Fibrosis

Liver fibrosis results from many chronic injuries and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation, which leads to the activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins, which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis.