The Influence of Mechanical Strain on Hepatic Stellate Cell Function in Relation to the Development of Hepatic Fibrosis

Liver scarring (fibrosis) and cirrhosis (end-stage scarring) are the consequence of virtually all long-term liver diseases that cause inflammation. These include inborn metabolic disorders, toxic damage, immune conditions and viral infections. Each year in the United Kingdom, approximately 4000 people die due to the consequences of cirrhosis, two-thirds of whom are aged under-65. At present, liver transplantation is the only definitive treatment but unfortunately its availability is severely limited. We must therefore develop new treatments to prevent and reverse liver fibrosis. Tissue swelling is an early part of injury and leads to the stretching of cells, which we believe contributes to the development of liver fibrosis. We know that the livers of children with congenital heart disease become congested, or stretched, leading to liver fibrosis and cirrhosis. We intend to use models of liver stretch in order to understand why this should happen and how it might be prevented. It is likely that these results could be used to understand how many different disorders cause liver and tissue scarring, leading to the development of new treatments. The research will be conducted in the MRC Centre for Inflammation Research under the supervision of Professor Iredale, a leading expert in liver fibrosis.

Background: Liver fibrosis and cirrhosis are a consequence of many chronic liver diseases. Each year in the United Kingdom, approximately 4000 people die due the consequences of cirrhosis, two-thirds of whom are aged under 65. Liver fibrosis also develops when the organ is congested by absolute or relative venous outflow obstruction. Recent work undertaken by Professor Iredale has characterised the development of hepatic fibrosis in a group of human subjects with passive hepatic congestion following Fontan surgery for inborn cardiac anomalies. Tissue swelling, resulting in cell stretch, is recognised as an early component of the inflammatory response to a diverse range of insults and may be fundamental to the development of liver fibrosis. Hepatic stellate cells (HSCs) appear to respond to stretch by initiating changes that lead to the development of tissue scarring. Additionally, when stretched, other surrounding cells, including endothelial cells and macrophages, may release mediators that contribute to this fibrotic response. Indeed compelling evidence that this occurs in vivo comes from pilot studies of a mutant mouse (Pharlap mouse), that develops right heart failure and passive liver congestion. Livers harvested from this mouse demonstrate evidence of HSC activation and infiltration by macrophages and lymphocytes early in hepatic congestion.

Aims: To investigate the hypothesis that tissue oedema and/or stretch may represent an early and common pathway through which various cellular insults lead to the important sequel of tissue repair and fibrosis. I aim to define the phenotypic response of HSCs and hepatic endothelial cells to mechanical strain. Furthermore, I will characterise the role of inflammatory cytokine production and the c-Jun N-terminal kinase (JNK) signalling pathway in this process.

Methods: Experiments will be conducted in a novel murine model (Pharlap mouse) in which chronic liver stretch occurs by virtue of a congenital malformation in heart function and a murine model in which the JNK pathway has been deleted. I will also employ a cell culture system in which individual cell types can be stretched and their responses characterised. Where relevant, observations from the murine model will be confirmed by immunostaining tissues from archived liver biopsies of patients with cardiac cirrhosis (Fontan liver). This will enable us to better understand why chronic hepatic congestion progresses to the important sequelae of liver fibrosis and cardiac cirrhosis. It will also provide insight into role of mechanical strain in chronic inflammation.