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.