Inflammation and Liver Fibrosis in Disease Progression

The transition from inflammation to scarring (fibrosis) in chronic hepatitis is driven by hepatocyte death and the subsequent accumulation and activation of hepatic stellate cells (HSC) which differentiate into myofibroblasts (MF), the major producers of type 1 collagen. HSC activation occurs in response to inflammatory cytokines, cellular interactions with immune cells and morphogenic signals. Acute hepatocyte death in a previously healthy liver triggers replication of surviving mature hepatocytes to replace the lost cells, and fibrosis does not occur. In chronic liver diseases, surviving mature hepatocytes have experienced various second “hits” and are unable to replicate. Replacement of dead hepatocytes thus requires expansion and differentiation of progenitor cells. If sustained, this results in MF accumulation and scar formation as part of tissue repair.

Data obtained to date suggests that adult tissue repair is regulated in part, by morphogens. Apoptotic hepatocytes produce Hedgehog (Hh) which promotes viability and proliferation of liver progenitor cells (LPC) and accumulation of MF. Importantly, Hh can induce LPC to undergo re-programming, thereby, increasing matrix-deposition. Hh is also capable of stimulating epithelial cells to produce chemokines that promote the recruitment of HSC, monocytes and lymphocytes including NKT cells. NKT cells produce and respond to Hh, which selectively activate and expand Th2 cytokine secreting NKT cells, thereby maintaining the local profibrogenic environment.

Linked with this pathway are recent studies showing osteopontin, a novel molecule involved in foetal development.  OPN is Hh-regulated and promotes HSC activation, while OPN deficiency leads to the repression of collagen genes in cell cultures and an attenuated fibrogenic response in steatohepatitis. OPN is secreted by epithelial cells, T cells and macrophages, in response to pro-inflammatory mediators including IL1 and TNF-a. OPN, in turn, enhances T and B-cell function.


The role of Osteopontin (OPN) in chronic hepatitis and fibrogenesis

Based on previously published work, it is hypothesised that OPN is the critical factor that links chronic hepatitis and scar formation in response to liver injury as part of a “Repair-Immune” cross-talk. The severity and type of inflammation predicts progression of chronic hepatitis to fibrosis and cirrhosis, and evidence suggests that lymphocyte recruitment from the circulation is the critical step in the development and progression of chronic hepatitis. Preliminary data have shown that OPN increases adhesion molecule (ICAM1, VCAM1) expression on human liver sinusoidal endothelial cells and promotes lymphocyte recruitment across endothelium under physiological flow by nearly 2 fold, thereby providing a mechanism by which it could regulate lymphocyte recruitment. 

Current studies are directed to dissecting the mechanisms by which OPN modulates lymphocyte migration across liver sinusoidal endothelium, and how OPN activates lymphocytes during migration, to prime their effector function or survival in tissues. Established cell isolation protocols are in place to determine the effects of OPN on individual liver cell function (macrophages, hepatic stellate cells, cholangiocytes / progenitor cells), and to understand how OPN drives scar formation.


Osteopontin isoforms: novel markers of hepatocellular carcinoma (HCC) development and recurrence

HCC development is associated with over-activation of the Hh pathway and it has been shown that inhibition of Hh signaling leads to a reduction in tumour load, improves overall survival, and is associated with a corresponding reduction in tissue levels of OPN. Studies have also shown that OPN levels are also increased in breast, stomach, and lung cancer tissues. OPN, however, exists as several protein variants (isoforms), which exhibit divergent biological functions, and may account for differences in patient outcomes. 

The hypothesis is that OPN is a critical factor in driving HCC development. The initial results obtained indicate that liver and blood OPN levels are increased in patients with liver fibrosis, a harbinger of cancer development. Whether OPN isoforms are increased in patients with HCC, and whether they constitute useful biomarkers of HCC development or recurrence following treatment, is also being examined. 


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