INTRODUCTION
Chronic tissue injury leads to fibrosis in various organs (1). In liver, development of fibrosis, resulting from a wound-healing response that has gone out of control after tissue injury, is the first step toward the progression of cirrhosis and the associated complications (2,3). During this pathological fibrotic response, newly activated/differentiated myofibroblasts, which are not present in normal liver, are responsible of the excessive extracellular matrix (ECM) deposition, formation of fibrous scar and tissue remodeling (1). Evidence indicates that the perisinusoidal hepatic stellate cells (HSCs) are the main sources of myofibroblasts in fibrotic liver (4-6). Upon fibrogenic activation (i.e., TGFβ1), HSCs secrete fibrillary ECM components (type I and III collagens, fibronectin), express α-smooth muscle actin (αSMA) forming part of organized intracellular stress fibers and acquire contractile functions. Because formation of fibrous scar and activation/differentiation of ECM-producing myofibroblasts play central roles in the pathogenesis and progression of liver fibrosis, the identification of factors that limit or reverse these processes is critical for understanding the pathophysiology and identifying new therapeutic targets of several chronic hepatic disorders.
Cortistatin is a cyclic neuropeptide, initially discovered in brain cortex and hippocampus (7), which shows high-homology with somatostatin and recently emerged as a potent immunomodulatory agent (8). By regulating the production of inflammatory factors, cortistatin was able to indirectly impair fibrotic responses in various experimental models of inflammatory disorders, including sepsis, acute lung injury, myocarditis or inflammatory bowel disease (9-12), and its direct effect on pulmonary fibrogenic responses was recently described (M.D., manuscript under consideration). Some data point-out to a potential anti-fibrotic action of cortistatin in liver. Thus, cortistatin-receptors (somatostatin-receptors sstr1-5 and ghrelin-receptor GHSR) are expressed in fibroblasts and HSCs, and various sstr/GHSR-agonists were described that exert anti-fibrotic responses in liver (13-20). Moreover, in several non-fibroblastic cells, cortistatin inhibited signaling pathways that are involved in fibrogenic responses (20-23). Finally, in a preliminary analysis of public data bases (24-26), we found that cortistatin expression is significantly reduced in human fibrotic or cirrhotic livers compared to normal liver tissue of healthy individuals. The inverse correlation that exists between human liver injury/fibrosis and cortistatin expression together with the capacity of cortistatin to potentially signal through various antifibrotic-linked receptors and intracellular pathways support the hypothesis that it could act as an endogenous regulator of hepatic fibrosis.
In this study, we investigated the potential protective role of cortistatin in the development of pathological liver fibrosis by using well-recognized experimental mouse models that mimic the two general types of chronic liver diseases, hepatocellular injury (such as chronic viral hepatitis, hepatotoxicity and nonalcoholic steatohepatitis) caused by repeated injections of the toxic agent carbon tetrachloride (CCl4), and cholestatic injury (such as primary biliary cirrhosis and sclerosing cholangitis) caused by common bile duct ligation (BDL). We induced both experimental models of chronic hepatic injury in wild-type and cortistatin-deficient mice and evaluated the progression of fibrosis as well as the therapeutic effect of exogenously administered cortistatin. We also investigated the phenotype and genetic signature showed by HSCs lacking cortistatin gene.